The primary goal of this study was to determine whether administration of intrathecal morphine reduces postoperative pain. The secondary goal was to determine the effect of intrathecal morphine upon circulating levels of the weakly analgesic endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and the related lipids palmitoylethanolamide (PEA) and oleoylethanolamide (OEA).Forty two total knee arthroplasty (TKA) patients were enrolled in a prospective, double-blinded, randomized study. The intervention consisted of intrathecal morphine (200 μg) or placebo administered at the time of the spinal anesthesia. Postoperative pain was measured during the first 4 h after surgery while serum levels of AEA, 2-AG, PEA, OEA, and cortisol were measured at baseline and 4 h after surgery.p = 0.005) and reduced postoperative systemic opioid consumption (p = 0.001). At baseline, intrathecal morphine led to a significant reduction in AEA, 2-AG, and OEA levels but did not affect PEA or cortisol levels. In patients administered intrathecal placebo, 2-AG levels were elevated 4 h after surgery; whereas patients receiving intrathecal morphine showed reductions in AEA, PEA, and OEA when compared to placebo. At 4 h after TKA surgery cortisol levels were significantly elevated in the placebo group and reduced in those receiving morphine.Administration of intrathecal morphine reduced postoperative pain 4 h after TKA surgery compared to placebo (These results indicate that intrathecal morphine reduces postoperative pain in TKA patients. Furthermore, activation of central opioid receptors negatively modulates the endocannabinoid tone, suggesting that potent analgesics may reduce the stimulus for production of peripheral endocannabinoids. This study is the first to document the existence of rapid communication between the central opioid and peripheral endocannabinoid systems in humans.NCT02620631. Study to Examine Pain Relief With Supplemental Intrathecal Morphine in TKA Patients, NCT02620631, 12/03/2015.This trial was registered retrospectively. Trial registry:  The endocannabinoid system regulates nociception in rodents and humans both through central and peripheral mechanisms –3. EndocInteractions between the endocannabinoid and opioid systems are well documented –18. PrevTotal knee arthroplasty (TKA) is a procedure associated with significant acute and chronic postoperative pain –32. Althwww.clinicaltrials.gov NCT02620631). In addition, we performed ancillary analyses of assays for serum AEA, 2-AG, PEA, OEA, and cortisol at baseline and 4 h after surgery. No changes were made to the original clinical study design.This study was conducted as a single-center, prospective, double-blind, placebo controlled randomized study with a two arm parallel group design to validate the previously described analgesic effects of intrathecal morphine  in our TAll the experiments conducted were approved by the Stony Brook University institutional review board (#200362) and were performed in accordance with the Declaration of Helsinki (1964) . WrittenForty two patients scheduled for an elective unilateral TKA under spinal anesthesia and a femoral nerve block were enrolled for this study from March 24, 2011 to February 6, 2014. The participants were prospectively selected from the orthopedic clinic of Dr. Nicholson at the Joint Replacement Center, Department of Orthopaedics, Stony Brook University Hospital who also performed all of the surgical procedures. Patients were included if they fulfilled the following criteria: Adults between 18 and 80 years of age; ASA class 1–3; able to give informed consent and able to understand English. Patients with documented rheumatoid arthritis, patients scheduled for bilateral TKA, and patients scheduled for a TKA revision were excluded from the current study. In addition, we excluded patients allergic to morphine, morbidly obese patients (BMI > 45), patients with chronic respiratory disease, obstructive sleep apnea, patients with chronic pain with opioid usage of > 100 mg morphine-equivalents daily, and patients with a history of drug abuse. Demographic data, medical history, medications and other therapies used for treatment of pain were collected after consent was obtained from each patient’s electronic medical record at Stony Brook University Hospital. Patients were asked to abstain from all medication use for seven days prior to TKA surgery.A computer-generated blocked randomization method was used to allocate subjects to the placebo or intrathecal morphine intervention. The allocation sequence was generated by random number tables by the study coordinators, and the allocation concealed in sealed envelopes. Patients were randomized to receive either placebo or 0.2 mg of intrathecal morphine with their standard spinal anesthesia. A pharmacist who was not otherwise involved in the study prepared the study drug after being given the randomization envelope by the study coordinator. The physician received the study drug for the spinal procedure and was unaware of the treatment administered; as were the enrolled patients.Immediately prior to the surgery, at the time of the spinal anesthesia, blood was collected from the fasting patients. Intravenous sedation with midazolam (up to 2 mg) was administered approximately 5–10 min prior to the initiation of regional anesthesia after routine vital signs monitors had been positioned. All intrathecal injections were performed by a single operator. Spinal block: In either sitting or lateral patient positon subarachnoid bupivacaine 0.5% (12-15 mg) containing preservative-free morphine (0.2 mg) or placebo  was administered using a 25 g spinal needle at the L3/L4 or L4/L5 interspace.All patients received a COX-2 selective inhibitor (Celecoxib) and 10 mg of oxycontin immediately prior to surgery. Surgical anesthesia was achieved by spinal anesthesia in addition to a femoral nerve block and intraoperatively all patients were sedated with intravenous propofol. Patient controlled analgesia was initiated in the post-anesthesia care unit and was available to the patients during the entire postoperative period. For more details see previous work , 41.The primary end point of the prospective placebo-controlled intrathecal morphine study was the patient’s subjective assessment of average postoperative pain at rest 4 h after TKA surgery evaluated using the numerical rating scale. Secondary endpoints included changes in circulating levels of AEA, 2-AG, PEA, OEA, and cortisol at 4 h after surgery from pre-surgical baseline; in addition to postoperative consumption of systemic opioids via patient controlled analgesia.Pain was measured using a numerical rating scale  which is widely used in the perioperative setting including at our hospital. The patient’s primary nurse, who was blinded to the treatment administered, obtained pain scores over the first 4 h after surgery using the NRS. The average of the pain scores obtained from 2 to 4 h after surgery is reported here as average pain at 4 h. Importantly, all of the pain scores were obtained when the patients were at rest.Serum endocannabinoid levels were quantified as previously described , 41.Serum cortisol levels were measured using a Human Cortisol ELISA kit  according to manufacturer’s instructions. Each sample was measured in duplicate. The optical density of each well was read on a Multiskan FC Microplate Photometer  at 450 nm. The intra-assay coefficient of variation was calculated to be 2.19%, the inter-assay coefficient of variation was calculated to be 5.78%.To determine the sample size required for our study based on our hypothesis that the addition of 0.2 mg intrathecal morphine would reduce postoperative acute pain in TKA patients compared to placebo we performed a two sample independent t-test assuming homogenous variances. According to our published data , the avep-value < 0.05 as statistically significant and all analyses were conducted with SAS 9.4 and XLSTAT .Due to slower than expected recruitment of patients the study was terminated by Helene Benveniste and Syed Azim, who were subsequently unblinded and an interim analysis of the data was performed midway through the study. For the primary outcome, the analyses were performed according to the group to which the patients were randomized to and all data were included in the analysis, which is the intention to treat population. For the secondary outcome analyses, serum samples were not available for all patients; however, no imputations were made to account for missing observations. The effects of intrathecal morphine upon postoperative pain and postoperative morphine use were analyzed using the Mann Whitney test. All collected samples were subjected to endocannabinoid and cortisol analyses. The data are presented as mean ± standard deviation. NRS pain scores between placebo and morphine groups were analyzed by t-test. Repeated measures ANOVA (Mixed Effects Model Repeated Measures) was used to compare whether the changes in endocannabinoid and cortisol levels over time were different between placebo and morphine groups by testing the Group by Time interaction term. Estimated mean difference in change over time between morphine and placebo groups  for each endocannabinoid and cortisol are presented. We considered a p = 0.0049). Intrathecal morphine also reduced postoperative systemic opioid consumption measured using patient controlled analgesia . Serum endocannabinoid and NAE levels were examined in patients receiving intrathecal morphine or placebo; and pre-surgical baseline (0 h) blood was drawn approximately 10–15 min after morphine administration. There were no differences in serum PEA levels between the placebo and morphine groups . In contrast, AEA (p < 0.0001), 2-AG (p = 0.0008), and OEA (p = 0.0025) levels were significantly lower in the morphine group at baseline compared to placebo  4 h after surgery while the change in levels of AEA (p = 0.424), PEA (p = 0.143), and OEA (p = 0.474) were not significant , PEA (p = 0.0001), and OEA (p = 0.0008) were significantly reduced in the morphine group while the change in 2-AG levels was not significant (p = 0.0698). Trajectories of changes in serum endocannabinoid levels between the 0 and 4 h time points are shown in Fig. p = 0.0072) for the placebo and morphine groups  between the placebo and morphine groups  while they were reduced in the morphine group . A significant group by time effect (p = 0.0103) was observed for cortisol for the placebo and morphine groups  of systemically circulating endocannabinoids is not well defined. Previous work has demonstrated that leukocytes produce and secrete endocannabinoids , 51. IntEndocannabinoids are also produced in primary sensory neurons in a calcium-dependent manner , 53, 54.General anesthesia reduces circulating AEA and augments 2-AG levels during the postoperative period –58. In oSurgical procedures induce a rapid increase in circulating cortisol levels and more effective analgesia blunts this postoperative cortisol response , 52, 59.One major limitation of the current study is the lack of baseline circulating endocannabinoid levels measured prior to intrathecal morphine or placebo administration. Another limitation stems from our inability to demonstrate that the suppression of the endocannabinoid tone after intrathecal morphine administration arises from its analgesic effects. Although we speculate that the reduction in endocannabinoids after morphine administration may reflect morphine analgesia and reduced necessity to recruit analgesic endocannabinoids, our study lacked patients without underlying chronic pain to validate this claim. We cannot rule out the possibility that the postsurgical increase in 2-AG in the placebo group might reflect pain-induced stress, which is known to increase 2-AG production  and whicIn conclusion, our study demonstrates that intrathecal morphine significantly reduces acute postoperative pain after TKA surgery. In addition, this study is the first to document a previously undescribed regulation of peripheral endocannabinoid levels by spinal opioid receptor activation and extends the previously documented cannabinoid-opioid interactions observed in rodents and non-human primates to humans , 20, 21.


The polymerization of HbS under low oxygenation conditions causes red blood cells (RBCs) to become rigid and sickle-shaped, increasing the risk of vascular occlusion, ischemia and vaso-occlusive pain crises (Sickle Cell Disease (SCD) affects between 90,000–100,000 Americans  and is an crises . Under an crises  infarctin crises .Brain imaging studies  have shoAnimal models of neuropathic pain have demonstrated that a region in the brainstem called the locus coeruleus (LC) and its central ascending noradrenergic (NA) projections can facilitate and exacerbate non-SCD neuropathic pain . LC axonThe aim of this study was to investigate RS-FC of the LC in patients with SCD compared to patients having anemia without chronic pain  using neuroimaging, seed-based and graph theory connectivity analyses. The seed-based resting-state connectivity analysis allowed us determine where connectivity differences were present in precise regions, while the graph-theory based connectivity analysis allowed us to determine what differences were present in network influence  in respect to the LC. We hypothesized that patients with SCD would show greater functional LC connectivity and centrality with other key brain regions that play roles in chronic pain compared to ACs.22.1N = 14), Hispanic (N = 3), and Middle Eastern (N = 1) patients with SCD along with Asian (N = 6), and White (N = 6) anemic controls were recruited from the Children's Hospital Los Angeles (CHLA) hemogloinopathy center. All procedures were approved by the institutional review board (IRB) and all participants provided written informed consent. A total of 12 anemic controls  and 18 patients with SCD  were included after quality control of the MRI data. Eight patients with SCD and ten ACs were undergoing transfusions. In the SCD population, 14 patients had hemoglobin SS and 4 hemoglobin SC disease. Three of the SCD patients exhibited chronic widespread pain. In the AC population, 2 patients had E-beta thalassemia, 4 patients had Beta Thalessemia Major, 2 patients had Hereditary Spherocytosis, 1 patient had Congenital Dyserythropoietic Anemia, 1 patient had Autoimmune Hemolytic Anemia, 1 patient had Thalessemia Intermedia, and 1 patient had Hemoglobin H Constant Spring. No patients with AC exhibited chronic pain. A subset of 8 sickle cell patients had been recieving regular 2-week transfusions for at least a year to reduce hemoglobin SS concentration and prevent progression of vascular disease. Regular transfusions were scheduled to keep the percent of hemoglobin SS <30% in hopes of reducing strokes. This stops intermittent vaso-occlusive pain crises, but does not affect chronic regional pain syndromes. Sub-analyses of this cohort compared to SCD patients without transfusions did not change the outcome findings. Young adults with previous overt strokes or known cerebrovascular disease were not included in the study. Other exclusion criteria included pregnancy, occurrence of acute chest pain or pain crisis hospitalization in the past month, and additional diagnosed conditions such as epilepsy or traumatic brain injury. SCD patients who had chronic pain (N = 3) were identified by the patient's hematologist and co-author (TC) based on clinical status and characteristics of their pain consistent with ongoing neuropathic pain  lasting >6 months. These data were used to perform an additional exploratory analysis. All patients were in their steady-state, and no focal neurologic deficits were documented in their medical records.African-American , a complete blood count (CBC) panel was recorded on all patients.2.3All imaging was conducted on a 3 T Phillips Achieva. After careful positioning of the subject, padding of the head to reduce movement, and application of noise-reducing headphones, a standard high-resolution T1-weighted 3D structural scan, covering the whole brain  was obtained; . Afterwards, an 8-min resting state functional scan  was obtained . Subjects were instructed to close their eyes, not think of anything, not fall asleep, and keep as still as possible.2.4Imaging data were processed using SPM12. Preprocessing for quality control included bias-field correction, co-registration, motion correction, spatial normalization, tissue segmentation, and Fourier transformation. Structural images were included in subsequent analyses based on compliance with acquisition protocol, full brain coverage, minimal motion, Gibbs ringing, absence of flow/zipper and minor atrophy/vascular degeneration. Functional imaging pre-processing included transformation from DICOM into NIFTI, slice-time correction, co-registration with high-resolution structural images, spatial normalization into MNI space, realignment to correct for subject movement and unwarping to correct for the movement-by-distortion interaction (using Unwarp in SPM12), and resampled to a voxel size of 2 × 2 × 2 mm. Functional images were included in subsequent analyses based on compliance with acquisition protocol, full brain coverage, motion estimate of <2 mm in the three directions of translation and three directions of rotation, minimal signal loss, and proper co-registration and normalization with the structural image.2.5Z values. The connectivity between the 167 brain regions was indexed by a matrix of Fisher Z transformed correlation coefficients reflecting the association between average temporal BOLD time series signals across all voxels in each brain region. Functional connections were retained at Z ≥ 0.3 and all values below that threshold were set to 0. The magnitude of the z-score represents the weights in the functional network. As a sensitivity analysis, absolute thresholding was also applied at 0.2, 0.4, 0.5, 0.6, 0.7, and 0.8  Strength: reflecting the weighted version of the number of connections to an ROI, (3) Betweenness Centrality: reflecting the ability of an ROI to control information flow and modulate information (act as a bridge) between two other modules, and (4) Eigenvector Centrality: reflecting the global prominence of the region due to connections with other highly connected nodes Thresholded single-subject functional networks were then used to calculate network metrics using in-house scripts and Graph Theory Toolbox (GTG) in MATLAB . Measure2.7p(FDR) < 0.05.To determine group differences in network metrics, GLM-based non-parametric permutation testing was performed, controlling for age and sex, at 5000 iterations in MATLAB. Permuted probability values were further corrected using the false discovery rate (FDR) to calculate significance at 2.8t-test was conducted using Statistical nonParametric Mapping (p < .001 and significance level was set at p(FWE) < 0.05. To determine the effect of chronic transfusion status on the results, we repeated the analyses including an indicator variable representing whether a subject was receiving blood transfusions as a covariate. Additionally, as an exploratory analysis within patients with SCD, we compared 3 patients who actively exhibited symptoms of chronic pain to patients who did not actively exhibit chronic pain. This was done by exporting the eigenvalues for the connectivity dyad within Statistical Parametric Mapping (SPM) for every subject and then conducting a Welch's t-test between the groups.The 2 mm spherical seeds in the bilateral LC  were use Mapping , specify2.9t-tests were conducted along with Cohen's d calculations to measure effect size. Cohen's d, independent of sample size, is used to indicate the magnitude of the difference between two means, and is calculated by subtracting one group mean from another and dividing it by the pooled standard deviation. A value of d < 0.5 is considered a small effect, 0.5 < d < 0.8 a medium effect, and d > 0.8 a large effect  = 1.99, p = .06, d = 0.66), although this result did not achieve statistical significance). See Results from the seed-to-voxel analysis revealed that patients with SCD had greater connectivity between the left LC and left dorsolateral prefrontal cortex (dlPFC). Specifically, connectivity results showed patients with SCD had increased connectivity between the left LC and left dlPFC . No othe3.2betweenness centrality in the left LC and greater strength in the right LC. These results were consistent across some  but not all threshold levels, showing significant results when observing denser networks. See Results from the network metrics analysis revealed that patients with SCD exhibited greater 4As hypothesized, group differences in functional connectivity of the LC were found in patients with SCD compared to anemic controls using seed-to-voxel and graph theoretical methods examining LC-based connectomes. Past brain imaging research has found that patients with S.CD with high pain intensity have greater RS-FC in pronociocptive areas such as the ACC, somatosensory cortex, and insula,  as well 4.1Patients with SCD compared to ACs had greater LC betweenness centrality – indicating that this region is critical for mediating communication between other brain regions  – and grProviding tentative support for the idea that hyperconnectivity of the LC-dlPFC circuit may be present in chronic pain, the three SCD patients suffering from chronic pain had greater functional connectivity between the LC and dlPFC compared to SCD without pain (Cohen's d = 0.66). Although compelling, this hypothesis requires further systematic study in a larger sample using systematic assessments of chronic pain as well with assessment of frequency of vaso-occlusive crises.Additionally, since SCD patients overall had greater LC-dlPFC connectivity compared to anemic controls, this hyperconnectivity could possibly be a precursor to the development of vaso-occlusive crises or of chronic pain via a hyperactive autonomic nervous system (discussed in the next section). We pose these hypotheses for testing.Moreover, the dlPFC is a core region in the executive control network that is involved in working memory, cognitive flexibility, selective attention and response inhibition . One mig4.2Our findings also suggest clinically relevant outcomes, such as the possibility that peripheral blood-flow may be altered due to hyperconnectivity of the LC and dlPFC. Since arterioles are innervated by sympathetic neurons, increased microvascaular transit time due to increased sympathetic activity – which the LC modulates  – can re4.3There appears to be neurological differences in patients with SCD that may play a role in pain mediation. Neurological hypersensitivity has been observed in SCD subjects in response to respiratory control  and painFuture studies investigating potential therapeutic pain prevention strategies or targeted analgesic treatments for chronic pain in SCD should monitor the level of the LC centrality in neural connectivity. The goal would be to reduce noradrenaline release and the strength of connectivity of the LC with the dlPFC. Such changes could enhance prefrontal cortical control by shifting prefrontal processes. For example, activity in the ventromedial prefrontal cortex (vmPFC) has been shown to be involved in the process of resilience and positive behavioral adaptation in the face of adversity or trauma  IncreaseAt the level of the dlPFC, various non-invasive treatments such as repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS) have been shown to be effective in patients with chronic pain  who also5The findings of the current study support greater connectivity of the LC-dlPFC circuit, along with a connectome showing a greater amount of information flow in the LC to other parts of the brain in patients with SCD. These are the first findings we know of that establish this LC-dlPFC hyperconnectvity link in humans with SCD and provide the basis for further investigation of cellular mechanisms such as noradrenaline activity underlying this link, the modulatory role that the LC may play in altering other brain networks, and associating it with chronic pain symptoms and physiological activity in the periphery. Additionally, it provides the basis for investigating methods of treatments to regulate dysfunctional noradrenaline activity originating at the LC along with non-pharmacological treatments such as TMS, tDCS, meditation, and hypnotherapy aimed at diminishing activity in the dlPFC and reducing painful symptoms.


To describe self‐management recommendations for sickle cell disease (SCD) care among health professionals who manage SCD in Ghana.Nine health care professionals  who work in SCD were interviewed. The semistructured interviews were recorded, transcribed, and analysed using the qualitative content analysis method. Self‐management recommendations were conceptualised as preventive health, self‐monitoring, self‐diagnosis, self‐treatment, and self‐evaluation.Preventive health recommendations were the commonest, where the professionals described similar topics including avoidance of cold temperature, frequent oral hydration, and healthy nutrition. Self‐monitoring recommendations included regular checks for pallor, urine colour, and splenic enlargement. Self‐diagnosis recommendations were captured as warning signs and included pain, fever, unusual feelings, and enlarged spleen. Pain and fever management were the focus of most self‐treatment advice, and there were some self‐treatment recommendations for dactylitis, anaemia, and priapism. There was considerable variation in the strategies recommended for the management of individual SCD‐related problems.Ghanaian health professionals involved in SCD care provide limited and inconsistent self‐management recommendations. There is a need for the development of SCD standards and guidelines that support effective self‐management. Health professionals working in SCD require continuing education in self‐management. It concerns the purposeful performance of specific learned tasks, skills, activities, and behaviours to manage the medical, psychosocial, and life impact of LTCs.Internationally, SCD self‐management research has generally been conducted among patients22.1This study forms the second stage of a 4‐stage sequential mixed method study that investigated self‐management strategies among people living with SCD in Ghana.2.2The participants included nurses (n = 6), doctors (n = 2) and a physician assistant. To be eligible for selection, participants had to have at least 3‐month experience in providing clinical care and patient focused education or psychosocial care to patients and families at SCD clinics or the SCD Association Table . The 9 p2.3As phone interviews from New Zealand were the means to conduct the interviews, a local coordinator assisted with recruitment. The coordinator first contacted the potential participants to inform them about the study and distributed consent forms and information sheets. The principal investigator (PI) then followed up with phone calls and e‐mails to solicit agreement to participate in the study.The interviews were all carried out by the PI and followed a semistructured interview guide. The interview began with an overarching question, “what do you tell your clients with SCD and their families to do for SCD care at home?” Specific questions were asked to capture responses that reflected the topics  in the conceptual framework of the main study. Questions included (1) what they ask patients to do to keep well, (2) how they ask patients to monitor their health, (3) how they advise patients to recognise a sickle cell‐related problem, (4) what actions they advise patients to take when there are problems, and (5) what self‐management practices they have observed in their clinical practice. Each interview continued until information redundancy was observed or when a participant had no more information to share. The interviews were audiotaped and transcribed verbatim.2.4The analysis process involved a 10‐stage iterative process of deductive and inductive approaches informed by 2 publications on qualitative content analysis.The deductive approach was warranted, as the study was guided by a conceptual framework and a codebook developed through a review of literature on SCD and other genetic diseases, as well as theories and models of self‐management for chronic diseases and SCD.33.1The participants were among the few professionals who have run dedicated SCD clinics in Ghana. Their experience with SCD care averaged 8.6 years range 4–19)  said they advised patients on the importance of the daily intake of supportive medications, including folic acid, B Complex, multivite, and penicillin prophylaxis. Folic acid supplementation was recommended the most, and many participants commented on its haematogenous abilities. In addition, some participants mentioned advising on the use of penicillin prophylaxis as a means of preventing infectious diseases among SCD children.Almost all participants considered visits and interactions with health professionals as important for routine health checks, when patients suspect or experience acute problems such as painful crisis or when their home strategies fail to alleviate their symptoms. They highlighted the role of the hospital in helping patients to learn about self‐care from health professionals and from patient role models. The latter were patients who have lived a long life with SCD. The participants noted that poor financial resources served as a barrier to access care. To address financial concerns, NUR2 and NUR4 said they advise patients to register with the National Health Insurance Scheme, and NUR5 reported providing direct financial support by herself.Preventive care advice focused on what must be avoided, or performed with caution, to prevent exacerbation of disease. Advice included avoiding extreme temperatures, preventing dehydration, reducing over‐activity, and avoiding food substances that can trigger crisis. Eight participants spoke of advising patients to avoid exposure to cold temperatures, including exposure to cold weather without adequate warm clothing, taking cold baths, or having cold drinks. Many participants spoke of supporting their advice with explanations about the physiological mechanism between cold and painful crisis and emphasised the need for patients to avoid all forms of cold and keep warm. Key among these recommendations was for patients to wear warm clothes most of the time.Seven participants (DR3 and NUR1–NUR 6) spoke of advising patients to avoid activities involving the use of physical strength or that were vigorous in nature. Strategies to mitigate the impact of over‐activity on the health of SCD patients were noted, including being aware of energy limits, rest breaks, hydration, and exemption from strenuous activities. Three participants reported advising school children to be exempted from strenuous activities at school by providing medical certificates for school authorities. Participants considered it important that patients understood the relationship between over activity, oxygen deprivation, and painful crisis.The participants also reported advising patients to avoid diseases including malaria and worm infestation, as these can cause crises and anaemia. Many of them spoke about malaria prevention strategies including the use of insecticide‐treated bed nets and chemoprophylaxis. Three participants  advised patients to endeavour to avoid injuries, as wounds on SCD patients are difficult to heal.3.2.2Six participants  outlined physical and physiological indicators that they advise patients to check periodically, including pallor, urine colour, fever, jaundice, splenic enlargement, pain, and general demeanour (for children). The commonest recommendations were checking pallor, urine colour, and fever  specified patients should check their urine daily to see if it is co‐cala colour or dark. Four participants  said they advised patients how to check for fever using either a thermometer or the back of the checker's hands. Participants reported advising patients not to consider all fever as malaria and to avoid taking antimalarial medications for all fevers.Two participants (NUR3 and DR2) reported advising on routine splenic palpation. Different strategies were recommended for patients with apparent splenic enlargement and those without. Three participants  also commented that mothers should be aware that prolonged crying by children could be an indication of painful episodes. NUR6 advised parents to palpate crying children for areas of tenderness. Other recommendations mentioned by different participants included observing for general demeanour, jaundice, and growth of children.3.2.3All the participants used terms such as “emergency signs,” “warning signs,” and “complications” to describe self‐diagnostic indicators. These indicators included fever, changes in urine colour, jaundice, unusual feelings, enlarged or tender spleens, and prolonged crying in children Table .There were objective and subjective recommendations to what constitutes the degree of fever that patients should recognise as problematic. Participants either specified a temperature level of 37°C or higher (DR3 and NUR4) or advised patients to note when the body is warm to touch. Change in the colour of urine was the second commonest indicator the participants recommended for self‐diagnosis. Three participants  specified dark or “coca cola” urine as an abnormal sign that required attention. The participants related these changes as indicative of physiological abnormalities such as dehydration, vaso‐occlusive crises, and kidney malfunctions and said they urged patients and parents to report immediately to hospital if these should occur.Four participants  referred to jaundice as a diagnostic sign and reported advising patients who developed emerging or worsening jaundice to seek immediate care.3.2.4Pain and fever management were the focus of most self‐treatment advice, and there were a few recommendations concerning dactylitis, anaemia, pneumonia, and priapism management Table .All participants, except NUR5, reported advising on pain management strategies including the use of analgesics, increased oral fluid intake, heat applications, massage, relaxation, and periodic movement. NUR5 advised that patients experiencing painful events should seek care at the health facility without engaging in any self‐treatment. Among children who cannot verbalise pain, NUR1 recommended applying hot compresses around the whole body of a child if they were crying profusely. Four participants  recommended patients to manage fever at home using antipyretic medication and tepid sponging with lukewarm water. Three participants  mentioned advising parents to treat dactylitis by increasing the child's hydration. They also advised the application of topical analgesic to the affected part, taking oral analgesics, and avoiding vigorous rubbing of the affected area, as this can result in bleeding. DR3 commented that patients experiencing priapism should increase their fluid intake.The participants also spoke about how they discourage harmful traditional self‐treatment practices that they had observed patients doing. These included advising against the use of raw herbs, binding painful limps, placing heavy objects on painful limbs, and making incisions on painful limbs or distended abdomens. They also caution against the frequent use of haematinics for anaemia and dressing leg ulcers with unsterile equipment.4The 9 health professionals surveyed considered they provide advice on many SCD self‐management topics. However, the content of the advice mainly concerned what people should do to prevent painful crisis rather than remaining well generally, and there was considerable variation in what they reported advising patients to do regarding self‐management. This variation probably occurs because of the lack of international standards and guidelines for the self‐management of SCD.The professionals' responses mainly focused on preventive health, where many of them described similar topics including temperature, hydration, nutrition, safety with physical activities, taking folic acid supplements, and analgesia. In terms of the specific SCD‐related problems, most of the professionals described similar strategies for pain management, namely, increasing oral fluid intake, applying heat, and topical medicines. As no study has reported self‐management recommendations from the perspectives from health professionals, there are no studies to provide comparison with the current findings. However, the findings for preventive health are similar to research findings on self‐management recommendations and practices from patients and relatives' perspectives in the United States, Brazil, and Jamaica, as well as recommended measures for healthy living and crisis prevention for SCD management.The findings indicate that recommendations for self‐monitoring and diagnosis, using objective methods and measurements such as thermometers, splenic palpation, and self‐assessment tools, are limited in the Ghanaian health professionals' recommendations. In contrast, researchers of SCD self‐management in the United States have focused on objective measurements for pain self‐monitoring to understand pain frequency, characteristics, related symptoms, and home management.Pain was the only problem addressed by all the participants and was the underlying reason for most recommendations. This finding is consistent with most of the SCD literature, as pain has been the focus of SCD research. Other problems were described mainly in relation to different categories. This variability may reflect the different roles the nurses and doctors have and when they see patients, but also highlights a lack of a systematic approach to self‐management in Ghana. Problems such as undernutrition, anaemia, malaria, and pneumonia were described in relation to preventive health, whereas abdominal pain, vomiting, splenic enlargement, impaired growth, changes in urine colour, and jaundice were described in relation to diagnosis. Complications described in terms of self‐treatment were pain, fever, dactylitis, and priapism. Apart from pain, where similar strategies were described by most participants, less than half of the participants described recommendations for all the other complications, with wide variations in the types of strategies recommended. Given that pain was the only complication described by all professionals, patients in Ghana could be missing out on important advice concerning other SCD‐related conditions.There are 4 main limitations to this study. Firstly, a semistructured interview approach was used, asking participants to share what they did. Using a survey approach with closed questions may have revealed different answers about practices. Secondly, some of the professionals' roles in SCD care have been reduced with the closure of the screening programme in 2010. Hence, their ability to recall what they recommend to patients and parents may be limited. Thirdly, limited distinction was made by the professionals regarding recommendations for adults and children in this study. We acknowledge that some recommendations may be more applicable to one group than the other. Future research is required to categorise recommendations for different age groups. Finally, saturation of findings was not achieved. However, the study did recruit all health professionals in the Ashanti region who met the inclusion criteria. Expanding the study to other regions might have produced additional information and generated less variability amongst the advice given.5The lack of international standards and guidelines for self‐management of SCD results in arbitrary self‐management advice being given by Ghanaian health professionals to patients with SCD. As self‐management actions by patients can improve general health and well‐being as well as minimise the likelihood of people with SCD developing crises, there needs to be a more consistent approach to advising on self‐management actions and strategies.6Given the vast experiences of the professionals in SCD care, the professionals' recommendations in this study provide insight into important topics and measures that can be helpful in improving patients' self‐management and health outcomes. The recommendations provided are likely to be useful for patients and health professionals who are not directly involved in SCD care to improve their knowledge and care for SCD. Guidelines for structured self‐management support are required to assist health professionals to effectively support patients' self‐management in Ghana and other countries with similar health systems. The topics identified in this study can be considered in developing guidelines. More research into health professionals' knowledge and patients' preferences for SCD self‐management is also required internationally to understand what is important to teach patients.This study was financed by the Victoria University of Wellington.None.Conceptualisation: Andrews Adjei Druye, Katherine NelsonFormal Analysis: Andrews Adjei Druye, Katherine Nelson, Brian RobinsonFunding acquisition: Andrews Adjei Druye, Katherine NelsonMethodology: Andrews Adjei Druye, Katherine NelsonInvestigation: Andrews Adjei DruyeProject Administration: Andrews Adjei Druye, Katherine NelsonSupervision: Andrews Adjei Druye, Katherine NelsonValidation: Andrews Adjei Druye, Katherine Nelson, Brian RobinsonVisualisation: Andrews Adjei Druye, Katherine Nelson, Brian RobinsonWriting – Original Draft Preparation: Andrews Adjei Druye, Katherine Nelson, Brian Robinson


Failed back surgery syndrome (FBSS) is a major, worldwide health problem that generates considerable expense for healthcare systems. A number of controversial issues concerning the management of FBSS are regularly debated, but no clear consensus has been reached. This pitfall is the result of lack of a standardized care pathway due to insufficient characterization of underlying pathophysiological mechanisms, which are essential to identify in order to offer appropriate treatment, and the paucity of evidence of treatment outcomes. In an attempt to address the challenges and barriers in the clinical management of FBSS, an international panel of physicians with a special interest in FBSS established the Chronic Back and Leg Pain (CBLP) Network with the primary intention to provide recommendations through consensus on how to optimize outcomes. In the first of a series of two papers, a definition of FBSS was delineated with specification of criteria for patient assessment and identification of appropriate evaluation tools in order to choose the right treatment options. In this second paper, we present a proposal of a standardized care pathway aiming to guide clinicians in their decision-making on how to optimize their management of FBSS patients. The utilization of a multidisciplinary approach is emphasized to ensure that care is provided in a uniform manner to reduce variation in practice and improve patient outcomes. A significant proportion of patients who have undergone lumbar spinal surgery continue to suffer from persistent pain and impaired function, referred to as failed back surgery syndrome (FBSS) –5. PatieFailed back surgery syndrome is a condition that is difficult to treat successfully because of (a) lack of a precise pathophysiology and complexity of presentation , 6–10,  approach is important for the optimization of outcomes –22. HoweTo address the challenges of defining a comprehensive FBSS care pathway, an international panel of physicians with a special interest in FBSS established the Chronic Back and Leg Pain (CBLP) Network with the goal to provide recommendations on the management of patients with FBSS based on a multidisciplinary input. The work is presented in a series of two papers. The first paper focused on the definition of FBSS and outlined the criteria for appropriate diagnosis, with recommendations of validated tools to improve patient assessment . The goaParticipants in the CBLP panel were selected based on their extensive clinical and scientific experience in managing FBSS patients with focus on representation of the three specialties that are most involved in the treatment of this patient population: orthopaedic surgery, neurosurgery, and pain medicine/anesthesiology. Invitations were sent to potential participants all over Europe and accepted prior to engagement in the panel. Formal face-to-face meetings were held on a regular basis from 2012 to 2016 with additional follow-up teleconferences. All meetings were chaired by a trained facilitator to help the consensus process. Additional input was provided on an ongoing basis by relevant clinical specialists involved in the multidisciplinary evaluation and treatment of patients with FBSS .MEDLINE: (“Failed back surgery syndrome” OR “Chronic Back pain” OR “Chronic leg pain”) AND LILACS: (“Failed back surgery syndrome”) AND (“Multidisciplinary” OR “Interdisciplinary” OR “Team” OR “Pathway” OR “Guideline” OR “Protocol” OR “Algorithm”)Systematic literature searches in PubMed, MEDLINE, LILACS, Embase, and the National Guideline Clearinghouse were conducted by two separate reviewers  on a regular basis up to September 2018, without any restrictions regarding the language or year of publication. The search strategy was developed in order to maximize sensitivity of article identification, using controlled vocabulary and title/abstract words combining variations of “Failed back surgery syndrome,” “Back pain,” “Chronic leg pain” with “Multidisciplinary” OR “Team,” “Clinical pathway” OR “Practice guideline” OR “Algorithm” OR “Guideline” OR “Protocol” (detailed description hereafter). The literature searches in this paper focus on therapeutic strategies and algorithms. For the independent reviewer (GB), the term “Failed back surgery syndrome” was cross-referenced with terms pertaining to clinical guidelines or algorithms . Hand-searching of reference lists of identified reports and relevant review articles was also carried out. For the group reviewer (NN), the search strategy varied according to the database as follows:All references retrieved from databases were exported to Zotero to identify and exclude duplicated studies.The two literature searches were pooled and crossed to converge into one final diagram. Our methodology is summarized in The final literature review ensured that the CBLP Network members had access to the same body of evidence during the panel discussions.Consensus was defined as full agreement on the set goals which was achieved during the facilitated round table discussions, based on the outcomes of the literature overview, each member's personal experience, and the additional input from relevant clinical specialists. The consensus process did not include any individual (independent and anonymous) rating rounds based on the Delphi method since the number of participants was considered to be too small and the purpose of the discussions was not to measure consensus based on specific statements, but to resolve disagreements (reach full consensus) on the set task . The limThe composition of the CBLP Network and the methodology used to develop the proposed standardized FBSS care pathway adhere to the outlines presented in our first paper on FBSS definition and guidelines for patient assessment :ParticipSix comprehensive FBSS care pathways or algorithms were identified by the literature searches  2, 12, , 24–26. In response to the identified limitations of current practice in the caretaking of FBSS patients, the CBLP Network developed a care pathway based on an MDT input to serve as a quick reference decision resource . The patIf a specific spinal aetiology for pain has been identified without demonstrating the need for further surgery and significant psychosocial comorbidities have been ruled out, Level One treatment can be initiated . The goaConsideration should at first hand be given to physiotherapy, rehabilitation, and management of psychological and social factors . It is iAt this stage in the care continuum, pharmacological therapy traditionally includes the World Health Organization (WHO) Step I and II analgesics only, preferentially utilizing nonnarcotic medication, such as nonsteroid anti-inflammatory drugs (NSAIDs) and paracetamol for treatment of pain of nociceptive origin . AdjuvanThe pharmacological treatment of FBSS with a predominant neuropathic radicular component is based on the use of gabapentinoids  and antidepressants (amitriptyline and duloxetine) . Two-druThe patient should be prescribed at least two different drugs consecutively for six weeks or more to determine treatment effects. If therapy is effective (at least a 30% improvement) , the firTranscutaneous electrical nerve stimulation may provide an alternative/complement to medication in patients with FBSS. Its effectiveness in chronic low back pain is, however, still controversial , 51. OthLevel Two treatment includes minimally invasive interventional therapies/diagnostic procedures. Several reviews and evidence-based clinical practice guidelines and recommendations for interventional techniques in the diagnosis and treatment of chronic spinal pain, including FBSS, have been published and may be consulted for guidance –56. BefoSecond-line procedures also include selective nerve root block injections for neuropathic pain. If successful, pulsed radiofrequency or spinal cord stimulation (SCS) (see Level Three Treatment) may be considered to achieve a more sustained effect , 65. PraSeveral systematic reviews have demonstrated sustained pain relief (up to 24 months) with percutaneous epidural adhesiolysis in the management of FBSS due to epidural/perineural fibrosis or scarring as the anticipated pain generator , 66–68. Level Three treatment includes interventional electrical neurostimulation therapies which mainly target the neuropathic pain component in FBSS. Before third-line treatment with neurostimulation is initiated, the patient should be assessed by an MDT to determine eligibility. Spinal cord stimulation (SCS) is the most commonly used interventional neurostimulation treatment for refractory chronic pain, the beneficial effects of which may persist for many years , 69, 70.For a patient whose pain is not sufficiently controlled by or who is ineligible for minimally invasive interventional pain management techniques, WHO Step III analgesic pain medication with strong oral opioids may be prescribed and monitored until the patient experiences intolerable drug-related adverse events or fails to achieve the primary aim of improvement in function because of development of tolerance or hyperalgesia. This approach is controversial and has been subject to intense debate during the last years since high-dose medication with potent opioids is often associated with severe side effects, such as hormonal dysfunction, weight gain, constipation, hyperalgesia, development of tolerance with time and the potential for dependence, abuse and addiction, and death by overdose –95. In aBefore initiating Level Four treatment, predictors of risk of long-term opioid use, such as duration of opioid intake in the year before lumbar surgery, refusion surgery, and any diagnosis of depression, have to be identified . PatientChemical neuromodulation by continuous intrathecal drug delivery (IDD) based on morphine or ziconotide administration may be considered for patients preferentially with neuropathic pain who have responded to strong oral opioids in the presence of severe adverse events –100. No If Level Four treatments are unsuccessful, a final MDT assessment is performed to inform the patient about the prognosis of the disease, to motivate the need of avoiding further invasive treatments, and to review and promote all available noninvasive options.The CBLP Network recommends that structured physical and rehabilitation therapy and psychological support are provided on an ongoing basis and that a patient's disability/function and HRQoL are reevaluated before each new line of therapy using the same instruments as those administered before treatment for FBSS was initiated . In caseClinical guidelines and treatment algorithms have increased in popularity in disease management in an era of rising healthcare costs. Because of higher demands for efficient care, the availability of costly technologies, variations in service delivery among and between providers, and the overuse of inappropriate services and therapies, clinicians, payers, and policy-makers view such decision tools as instruments that can make healthcare delivery more efficient and consistent , 103.Failed back surgery syndrome remains difficult to treat successfully not only because of the lack of a precise pathophysiology and complexity of its clinical presentation , 6–10 buThe development of the care pathway presented by the CBLP Network has been driven by an interest in and understanding the role and application of the available treatment options for FBSS in real-life practice, particularly in view of the recent reports of higher harm rates and inefficacy of opioids and gabapentinoids in treatment of chronic nonmalignant pain. Compared to previously published FBSS care pathways and algorithms, the CBLP Network's pathway puts an emphasis on amalgamation of three main criteria to further improve the quality and reliability of the pathway and to facilitate its adoption into clinical practice. The three cornerstones are (i) focus on all available aspects and means for patient evaluation and optimal utilization of therapeutic options, (ii) emphasis on the involvement of an MDT to improve decision-making, and (iii) involvement of a wide variety of experts who provide consensus in the development of the pathway. A quick reference care pathway for the assessment, treatment, and evaluation of outcomes with an integrated multidisciplinary approach is an important resource for specialist and nonspecialist clinicians who manage patients with FBSS –22.One major challenge in the development of the presented care pathway was that the evidence of the clinical outcomes in the FBSS population has not been clearly determined in the available literature, even though a multitude of clinical trials using different therapeutic approaches with the intention of relieving pain and improving function have been conducted. Only a few studies have systematically analyzed and evaluated the overall clinical trial data using an evidence-based approach. Because of the paucity of evidence-based guidelines in the management of FBSS, the CBLP Network chose to adhere to a consensus-based approach to achieve the set goals to define FBSS and design outlines for appropriate patient evaluation and to propose a concise treatment pathway. Limitations of the used approach are discussed in the first of the two papers in this series on how to optimize outcomes of FBSS .In a recent systematic review, the literature on various modalities for treating the back pain and/or radiating leg pain component in FBSS was critically analyzed by means of quality assessment and level of evidence for each modality . The revIn a second review which also specifically investigated treatment options for FBSS patients with refractory chronic pain, it was concluded that evidence is weak for medications and reoperation, but strong (Level I-II) for active exercise, and some interventional procedures, such as epidural adhesiolysis and SCS . In summAmong the interventional techniques, SCS has been proven to be a very safe and effective therapy in the long term for a variety of chronic pain conditions, and therefore, its use earlier in the treatment algorithm for several of these conditions, including FBSS, has been advocated , 105–107Failed back surgery syndrome results from a cascade of medical and surgical events that have led to and left the patient with chronic back and radicular pain. This pain often remains refractory to sporadic  management strategies for a considerable proportion of these patients, highlighting the need for a global, multidisciplinary-based approach. A clear and concise, standardized care pathway comprising recommendations for assessment, treatment, and outcome evaluation using an MDT approach would be an important resource for specialists and nonspecialists who manage patients with FBSS. A comprehensive reference FBSS care pathway has the potential to improve decision-making, reduce variation in practice, and optimize treatment outcomes for this often hard-to-treat condition.


Background: Video-assisted thoracoscopic surgery (VATS) causes less postoperative pain than thoracotomy; however, adequate analgesia remains vital. As part of a multi-modal postoperative analgesia, a continuous surgeon-placed extrapleural block catheter is an option. The aim of this retrospective study was to evaluate the analgesic efficacy of a continuous extrapleural block as part of a multimodal analgesic regimen after VATS in general, and VATS lobectomy and wedge resection in particular.Methods: Case records for patients having undergone VATS surgery and been provided a multi-level continuous extrapleural block with an elastomeric pump infusing levobupivacaine 2.7 mg/ml at a rate of 5 ml/h during 2015 and 2016 were reviewed. Pain  at rest and mobilisation as well as opioid requirement  were analysed.   Results: In all, 454 records were reviewed: 150 wedge resections, 264 lobectomies and 40 miscellaneous cases. At rest, pain was mild median NRS rated 3-3-1-1 for postoperative day (POD) 0 to 3, during movement, pain was rated moderate during POD 0 and 1 and mild the remaining days (median NRS 4-4-3-3 for POD 0-3). The proportion of patients exhibiting mild pain at rest increased from 55% on POD 0 to 81 % on POD 3. The percentage of patients experiencing severe pain at rest decreased from 15% to 6%. Median oxycodone consumption was 10 mg per day for POD 1-3. Pain after VATS wedge resection was significantly lower at POD 1 and 3 compared to pain after VATS lobectomy.Conclusion: We found a continuous surgeon-placed extrapleural catheter block to be a valuable and seemingly safe addition to our multimodal procedure specific analgesia after VATS. Whether the efficacy of the block can be improved by increasing local anaesthetic and/or adding adjuncts warrants further investigation. Even though it is not as painful, VATS still requires adequate postoperative analgesia. As part of a multimodal analgesic regimen, different techniques using local anaesthetics can be used to block pain impulses from the surgical area. Epidural, paravertebral and intercostal blocks are all possible modalities. Compared to epidural block, using continuous extrapleural, paravertebral or intercostal block is thought to offer a more limited thoracic block, with possibly fewer side-effects.Minimally invasive thoracic surgery by means of video-assisted thoracoscopic surgery (VATS) has been shown to cause less postoperative pain than thoracotomy8. The benefit vs. risk for the paravertebral technique has, however, been argued9.For thoracotomy, several prior studies, including a Cochrane systematic review from 2016, all conclude that epidural and paravertebral block offer similar pain relief, with a paravertebral block possibly having fewer complicationset al.10 could not provide any firm recommendation. No firm conclusion could be drawn assessing available evidence around thoracic epidural, multilevel and single paravertebral, paravertebral catheter, intercostal catheter, interpleural infusion and long thoracic nerve block. The most recent study comparing epidural and percutaneous paravertebral block by Kosińskiet al.11 showed that the paravertebral continuous block technique was a feasible and safe alternative to epidural analgesia. Hutchinset al.12 found ultrasound-guided continuous paravertebral catheter to provide prolonged pain control and superior patient satisfaction compared with single-shot intercostal block after VATS.The optimal pain management approach following elective VATS is still not known. A review by SteinthorsdottirIn 2014, continuous extrapleural block after VATS was implemented as a standard technique for pain management following VATS surgery at Karolinska University Hospital.The aim of the study was to assess the quality of pain treatment after VATS with the routine use of a multi-level continuous extrapleural block as part of a multimodal analgesic strategy.This is a retrospective patient chart study. The study protocol was approved by the regional Human Research Ethics Committee, Stockholm, Sweden (Dnr. 2017/500-31). The need for informed consent was waived by the Ethics Committee. All patients who underwent VATS and received a continuous extrapleural block were included. Records for patients who received an extrapleural block between January 2015 and December 2016 were reviewed. Patient demographics, type of surgery, occurrence of post-operative nausea and vomiting (PONV) or other adverse events, and the postoperative pain course were reviewed and compiled. Data on other analgesics including opioids were also collected. If needed, opioid dose was converted to oral oxycodone equivalents .During surgery, a multiply perforated 19-cm extrapleural catheter was inserted by the surgeon, under thoracoscopic control, in a posterolateral position parallel to the spine, thereby covering multiple intercostal spaces. An initial bolus of 75 mg levobupivacaine was followed by an additional bolus of mepivacaine 100 mg at the end of surgery. An elastomeric pump infusing levobupivacaine 2.7 mg/ml at a rate of 5 ml/h (13.5 mg/h) was connected to the catheter and subsequently continued for up to 3 days.Patients received oral slow-release paracetamol  and NSAID  if tolerated. Patients received oral slow-release oxycodone twice daily with rescue short-acting oxycodone if needed.14. From the charts, we extracted the NRS score describing the most intensive pain at rest and during ambulation for each day from the day of operation (POD 0) to postoperative day 3 POD3.Pain was assessed by Numeric Rating Scale (NRS)For analysis, surgeries were categorised into two groups. In this report, we considered single and multiple wedge resections procedures causing similar trauma and postoperative pain. Similarly, lobectomy, bi-lobectomy and segment resection were considered as comparable procedures. Consequently, surgical procedures are reported as either a) wedge resection or b) lobectomy.Demographics are presented as median and range. Pain is presented as median and range and further classified into categories; mild pain as NRS <4, moderate pain as NRS 4-7 and severe pain as NRS >7. For statistical analysis categorized pain was compared as mild versus non-mild (moderate and severe). After calculating the median opioid requirement, we categorized postoperative opioid need as either no opioid if none, low opioid dose if lower than the calculated median opioid requirement or high opioid dose if higher than the calculated median opioid requirement. Categorical data is presented as frequency and percent. Chi-square test was used for test of significant differences between pain categories, age groups, sex and procedure. Mann-Whitney U-test was used for test of significant differences in cumulative opioid dose for different age groups and procedure.A total of 510 patients received an extrapleural catheter during the period studied.A thoracotomy was performed as the primary procedure in 26 patients. The remaining 484 patients were scheduled for VATS procedures. In 30 cases VATS was converted to thoracotomy. Neither patients that underwent primary thoracotomy nor patients converted to thoracotomy are included in our analysis. Of 454 cases analysed, 150 procedures were classified as wedge resection, 264 cases as lobectomy and the remaining 40 cases as miscellaneous , cyst or hamartoma and decortication with or without wedge resection) .Baseline characteristics are presented inAt rest, pain was rated as mild, with median NRS rated 3-3-1-1 for POD 0 to 3. Assessed during movement, pain was rated moderate during POD 0 and 1 and mild the remaining days (median NRS 4-4-3-3 for POD 0 to 3). The proportion of patients exhibiting mild pain at rest increased from 55% on POD 0 to 81% on POD 3. The percentage of patients experiencing severe pain at rest decreased from 15% to 6% .Pain at rest after VATS wedge resection was reported as median NRS 2-2-1-1 compared to pain after lobectomy with median NRS 3-3-2-2 for POD 0 to 3. At rest, more patients were experiencing mild pain and fewer patients were experiencing severe pain after wedge resection than lobectomy all postoperative days except POD 2 where an equal percentage of patients were experiencing mild, moderate and severe pain . The paiFor POD 0 to 3 median NRS reported in movement was 3-4-3-2 after wedge resection and NRS 5-5-3-3 after lobectomy (p = 0.05 for POD 0).Median oxycodone consumption was 10 mg per day for POD 1 to 3 . Median cumulative oxycodone consumption for POD 1 to 3 was 35 mg (range: 0 to 600 mg).After VATS, opioid treatment was not required by 25% of patients at POD 1, 28% at POD 2 and 20% at POD 3. During the first three postoperative days in total, 15% of patients did not require oxycodone at all .The percentage of patients not requiring opioid POD 1 to 3 was minimally higher after VATS wedge resection. Conversely, the percentage of patients with a high opioid dose was larger for all postoperative days after lobectomy . PatientOlder patients (>65 years of age) reported significantly less pain (mild pain vs more than mild pain) at rest (p = 0.01) and in movement (p = 0.002) at the day of surgery. Patients older than 65 had a significantly lower cumulative opioid dose during POD 1 to 3 than younger patients .Pain at rest after VATS overall was similar for women and men. POD 1, women experienced more often more than mild pain in movement after VATS (p = 0.04) and at rest after wedge resection (p = 0.04). We found no difference between sexes in cumulative oxycodone dose for any procedure.Adverse effects were rarely documented in the patient records. For 16% of the patients, symptoms of PONV were reported. No major complications related to the procedure  were reported during the 2-year period this audit covers.Raw patient data assessed in the present studyData include pain scores at postoperative days (POD) 0-3 at rest and with movement, alongside basic demographic information.Click here for additional data file.Copyright: © 2018 Larsson M et al.2018Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).In this retrospective study we found that a surgeon placing an extrapleural catheter with continuous infusion of levobupivacaine 2.7 mg/ml at a rate of 5 ml/h was a valuable part of our multimodal pain treatment. Pain was well controlled, pain was at rest overall reported as mild and rated moderate initially and mild from POD 2 during movement. We found VATS lobectomy to be more painful than VATS wedge resection.To achieve this level of analgesia, a median dose of only 10 mg oxycodone per day was needed. However, only 15% of our patients did not need any oxycodone at all and 47% needed more than a low dose of oxycodone during the postoperative course. This indicates that there is a potential to further improve the non-opioid part of our multimodal analgesic strategy. We did, however, see a relatively low incidence of opioid-related adverse effects, PONV was experienced in only 16% of patients.15. Addition of adrenaline might allow for more local anaesthetics to be infused. Kosińskiet al.11 observed that better analgesia was achieved using a mixture of bupivacaine and adrenaline when infused through a continuous paravertebral block rather than continuous epidural, even implying an additive effect of adrenaline itself. Future trials should address systemic absorption and toxicity for continuous blocks, measuring plasma concentrations of the local anaesthetic used.It should be acknowledged that we used a fixed continuous infusion of 13.5 mg levobupivacaine per hour after an initial bolus of 75 mg regardless of age, body weight and surgery. To our knowledge, the optimal dose for a continuous extrapleural  block is not known. A higher dose of local anaesthetic, either through higher concentration or higher rate of infusion, might offer superior analgesia. Simultaneously, the risk for adverse events due to toxicity might increase. This dose was chosen taking recommended maximal daily doses into account. Single-shot paravertebral with ropivacaine and adrenaline has been shown to decrease the systemic uptake of ropivacaineet al.16 showed that adding dexmedetomidine to a single-shot paravertebral block with ropivacaine resulted in better analgesia from 8 to 48 hours after VATS. For patients with unilateral multiple rib fractures, Mohtaet al.17 showed equal pain relief with a lower dose of ropivacaine when a continuous paravertebral block contained a low dose of fentanyl in addition to ropivacaine and adrenaline. At the same time, Baueret al.18 did not show an additional analgesic effect of sufentanil added to ropivacaine in a continuous paravertebral block. Whether a surgical extrapleural continuous block in VATS combining local anaesthetics, adrenaline and a short-acting opioid is superior to a block with only local anaesthetics is, to our knowledge, unknown.Another possibility to increase the analgesic effect of our extrapleural catheter could be to add adjuncts other than adrenaline to the local anaesthetic infused. In a prospective study, Xu21.We used levobupivacaine for our block. It is possible that alternative local anaesthetics offer better analgesia. Lidocaine may be an alternative having both a local block effect as well as systemic anti-inflammatory and possibly analgesic propertiesThis study shows also that different procedures with a difference in trauma applied cause a varying intensity in pain. However, we did not find a significant difference in opioid requirement for different procedures, even though fewer patients needed a high oxycodone dose after VATS wedge resection. Still, tailored analgesia with different types of regional analgesia or different contents infused may be the way to offer patients the optimal balance between analgesia and side-effects, which may improve postoperative recovery.There are weaknesses in our study. This is a retrospective patient-record-based study, and all patients operated during the period were included. The wide range of oxycodone dose (0-210 mg/day) may be a result of our retrospective approach. Patients with a preoperative history of chronic pain and/or ongoing opioid treatment were not specifically identified. We used 5-mg increments in oral oxycodone dose. Using a patient-controlled analgesia regimen might have shown a more accurate opioid requirement. It should also be acknowledged that several patients were discharged before POD 3. It is not unlikely that patients discharged earlier and lost to follow-up could have experienced the least pain and least need for opioid treatment. This might skew our results towards higher median pain and higher opioid requirement.We found that a continuous surgeon-placed extrapleural catheter block to be a valuable and seemingly safe addition to our multimodal procedure specific analgesia after VATS. Whether the efficacy of the block can be improved by increasing local anaesthetic and/or adding adjuncts warrants further investigation.The data referenced by this article are under copyright with the following copyright statement: Copyright: © 2018 Larsson M et al.Data associated with the article are available under the terms of the Creative Commons Zero "No rights reserved" data waiver (CC0 1.0 Public domain dedication).Dataset 1. Raw patient data assessed in the present study. Data include pain scores at postoperative days (POD) 0–3 at rest and with movement, alongside basic demographic information. DOI:https://doi.org/10.5256/f1000research.16857.d22436422. In this retrospective patient-record-based study, Larsson and colleagues present the analysis of pain treatment quality in 454 patients who received a continuous surgical multi-level extrapleural block for video-assisted thoracoscopic surgery. All patients who underwent VATS and received a continuous extrapleural block were reviewed . The subject taken up by the authors is undoubtedly interesting. This is an important voice in terms of quality and ideal management of postoperative pain after thoracic surgery. The authors have shown the use of an analgesia method with a potentially lower risk of complications than EDA and that the paravertebral block is effective, and satisfactory results could be obtained in this group of patients regardless of the scope of VATS operation. The method of analgesia used by the authors is undoubtedly safe and satisfactory, which is confirmed by the results presented, but for obvious reasons, it is not perfect. The described method of anesthesia in VATS operations is, according to the authors' opinion, the standard conduct in their center since the 2014 year. In the authors’ study, an initial bolus of 75 mg levobupivacaine was followed by an additional bolus of mepivacaine 100 mg at the end of surgery. An elastomeric pump infusing levobupivacaine 2.7 mg/ml at a rate of 5 ml / h (13.5 mg / h) was connected to the catheter and continued for up to 3 days. This dose was chosen for the maximal daily checks. Reading the text raises some questions, for example, whether there have been attempts to modify this method of analgesia in their center. Also interesting was the comment on the quality of this method of anesthesia in comparison with the methods used earlier . Because patients underwent major thoracic surgery, chest tube removal timing seems very short. It would be interesting to know which criteria the authors followed to safely remove the chest tubes, as the authors did not specify them in their otherwise very good paper. The authors addressed the limitations of their study well, including a wide range of oxycodone dose, and no PCA method used, lost to follow-up in patients discharged earlier before the third post-operative day. As mentioned by the authors, it is difficult to compare their study to those available in literature because of differences in technique and study design.    In conclusion: the paper is well written, and the presented data are conclusive. This is an important and valuable work dealing with difficult issues of optimal postoperative analgesia in patients after major thoracic surgery.I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. The authors have conducted a retrospective review of a large sample of patients undergoing VATS with surgeon placed extrapleural catheters. The study is well done and well reported. They found that most patients had mild pain only, and only 15% had severe pain, which diminished to 6% by day 3 – suggesting good analgesic efficacy of the technique. I have no major problems with the methods of the paper, and it is well written. They did find a difference between VATS lobectomy compared to other VATS, but the authors have not offered any potential reason for this. It is possible that the surgeons place more intercostal catheters in lobectomy patients, which could increase stimulation beyond the analgesic boundary of the extrapleural catheter? Further in the VATS group, how many patients were included who had a pleurodesis? It is possible that the inflammation produced by pleurodesis could cause stimulation outside of the extrapleural block, and therefore requires additional pain relief.I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard.


To assess the cost-effectiveness of acupuncture for pelvic girdle and low back pain (PGLBP) during pregnancy.Pragmatic-open-label randomised controlled trial.Five maternity hospitalsPregnant women with PGLBP1:1 randomization to standard care or standard care plus acupuncture (5 sessions by an acupuncturist midwife).Efficacy: proportion of days with self-assessed pain by numerical rating scale (NRS) ≤ 4/10. Cost effectiveness : incremental cost per days with NRS ≤ 4/10. Indirect non-healthcare costs included daily compensations for sick leave and productivity loss caused by absenteeism or presenteeism.96 women were allocated to acupuncture and 103 to standard care . The proportion of days with NRS ≤ 4/10 was greater in the acupuncture group than in the standard care group . The mean Oswestry disability score was lower in the acupuncture group than with standard care alone . Average total costs were higher in the control group (€2947) than in the acupuncture group , resulting from the higher indirect costs of absenteeism and presenteeism. Acupuncture was a dominant strategy when both healthcare and non-healthcare costs were included. Costs for the health system (employer and out-of-pocket costs excluded) were slightly higher for acupuncture .Acupuncture was a dominant strategy when accounting for employer costs. A 100% probability of cost-effectiveness was obtained for a willingness to pay of €100 per days with pain NRS ≤ 4. Pelvic girdle and low back pain (PGLBP) is common during pregnancy affecting 5 to 76% of pregnant women, depending on clinical definition–4. PGLBPBecause it results in poor functional and quality of life scores ,10–12,PGAs for treatment, European guidelines recommend individualized exercises focusing on stabilizing exercises, information and reassurance, and a limited choice of pain medications, with acetaminophen as first choice. Over 50The Trial of Acupuncture for Pelvic and low back Pain in Pregnancy (TAPP) was a pragmatic randomized open-label trial, conducted with pregnant women from five maternity units from the Paris area (France) between 2012 and 2014. We advertised the trial by posters in waiting rooms. When doctors or midwifes found an eligible patient, they sent a datasheet to the Centre d’Investigation Clinique in which acupuncture was performed, and an appointment was given for inclusion visit.Women were randomized in parallel to receive standard care or standard care plus acupuncture with a 1:1 allocation ratio. Inclusion criteria were a singleton pregnancy, maternal age 18 or older, gestational age between 16 and 34 weeks, low back pain for at least two weeks, with pain greater than 4 on a 10-point numerical rating scale (NRS) and at least one positive provocation test. Pregnant women were not included if they had obstetrical complications such as preeclampsia or a small for gestational age foetus, if they had pelvic or low back pain before pregnancy, or if they did not have social insurance coverage. Patients were not involved in the study design or funding. However, a preliminary unpublished survey showed that a majority of pregnant women with low back pain would have liked to benefit from acupuncture and that half of them declared they would accept to participate in a trial.Weizhong and AShi points. We added points were as a function of pain location  on top of standard treatment. There were 2 sessions in the first week, followed by three weekly sessions. Additional sessions could be done at the patient’s request. Acupuncture points’ selection was based on pain location and traditional Chinese medicine (TCM) diagnosis of “Qi kidney deficiency” versus “blood stagnation” .Baselinelocation Deqi response. Needles were retained for 30 minutes per treatment.Points were needled bilaterally. The patient lied on her left side, using cushions to make her comfortable. We used Dong Bang needles  25 or 40 mm in length and 0.25 mm in diameter. While inserting the needle, the operator performed manual stimulation to elicit the Standard treatment in both groups consisted of pregnancy belt, lifestyle recommendations, and exercises, explained by the midwife in charge of the trial. Painkillers, rest and sick leaves were prescribed by the referring physician or midwife.The primary endpoint was the percentage of days, between inclusion and delivery, with daily greatest pain self-assessed by numerical rating scale (NRS) ≤ 4/10Secondary endpoints were:Last week worst pain self-assessed by numerical rating scale, at the week-5 visit, expressed as differences between groups and within each group by the difference between baseline and week-5,Last week worst pain measured at the week-5 visit by analogic rating scale expressed as differences between groups and within each group by the difference between baseline and week-5,Mean Oswestry disability index collected weekly between inclusion and delivery, measured by the Oswestry disability self-questionnaire,Percentage of days with a reduction of 2 points of the self-assessed NRS pain compared to baseline,Percentage of weeks with Oswestry disability index of 20/100 or lower,Percentage of weeks with a reduction of at least 15 points in the Oswestry index compared to baseline.Women were randomized between acupuncture or control group with a central web based randomization system, using block randomization with a block size of four, an allocation ratio of 1:1 and stratification for hospital. The web-based randomization system generated a unique number with allocation code.Trial endpoints and healthcare utilization details were collected prospectively from the case report form filled by the investigator and from the patient’s logbook (self-assessment). At inclusion and five weeks later (week-5 visit), the investigator recorded pain location, and pain intensity by visual analogic rating scale (VAS). Patients filled self-questionnaires to assess pain intensity by numerical analogic rating scale (NRS) and disability (Oswestry disability self-questionnaire—OSW). The invAt inclusion, the investigator gave patients a logbook on which they reported daily health outcomes and use of resources until delivery. They rated their greatest pain perceived using a ten point NRS. A day with a successful outcome was defined as a day with NRS of 4/10 or lower. Patients filled the Oswestry disability questionnaire weekly. Each week a research technician called patients in order to remind them to fill the logbook. After each session and at the week-5 visit the acupuncturist asked patients about bruising, fatigue, dizziness, headache using a standardized questionnaire. We assessed non-specific adverse events, retrospectively, by analysing the medical records after delivery. We based the estimation of costs on the logbook on which patients recorded the use of pain medications, hospitalisations, healthcare consultations and any analgesic practice. After delivery, we checked the duration of hospital stays in the medical records.The prospective economic evaluation was concurrent with the randomized trial, in accordance with the CHEERS statement for single trial based studies. All ecohttps://www.ameli.fr). Out-of-pocket healthcare expenses were pregnancy belt, osteopathy, relaxation, yoga, gym, massages.Hospitalizations were valued using the hospital perspective, based on mean hospital costs per day, estimated by the French Agence Technique de l'Information sur l'Hospitalisation. The cosIndirect non-healthcare costs included daily compensations for sick leave and additional maternity leave paid by the health insurance . We estiA cost-effectiveness analysis was conducted to estimate incremental costs per incremental day with pain NRS ≤ 4, per difference between baseline and week-5 (W5) NRS, or per incremental week with OSW ≤ 20. Incremental costs were the difference in mean per-patient costs between groups. We assessed the cost-effectiveness of acupuncture treatment versus standard treatment alone until delivery, using imputation for missing data. Costs were not discounted due to the short time horizon (between inclusion to delivery). Incremental cost-effectiveness ratios (ICER) were calculated, defined as the ratio between net total costs and net effects expressed in days with pain NRS ≤ 4: (Cost acupuncture− Cost control) / (Effectiveness acupuncture − Effectiveness control). We performed probabilistic sensitivity analyses and represented graphically the bootstrapped cost-effect pairs on a cost effectiveness plane. Acceptability curves were calculated, which showed the probability that a treatment is cost effective at a specific ceiling ratio –30.Rare missing observations for baseline variables were imputed using chained equations. We used a two-step chained equations method to impute rare missing data on healthcare resources use and work stoppage. The Sensitivity analysis was performed without imputation.For more frequent missing data (more than ten percent), i.e. for pain NRS and Oswestry score we suspected data to be not missing at random (NMAR), thus resulting in incidental sample selection. For these, we implemented a Heckman two-step procedure for the imputation of missing data, in order to correct for the suspected selection bias–34. This16, we assumed, that four weeks after enrolment, women in the control group would present an average maximum pain of 5/10, and women in the acupuncture group an average maximum pain of 3/10. Using the inter quartiles of reported by Elden et al, we estimated the standard deviation of the pain at baseline and at 4 weeks would be 0.21. We further assumed that women in the control group would exhibit a constant mean pain level of 0.5 standard deviation (SD 0.21) while women in the acupuncture group would show their mean pain level drop to 0.3 (SD 0.21) at 4 weeks after inclusion and raise to 0.4 at the end of follow-up. An additive random effect, based on a random walk with a 0.003 per day standard deviation was considered to account for intra individual variability. Based on these figures and on the ability to detect a clinically relevant difference of 25% in percentage of days with pain NRS ≤ 4 between groups, we estimated that 150 patients in each group would give a power of 80% and a two sided α-risk of 5%.The calculation of the number of patients to enrol in the study required a numerical estimation of the primary endpoint. Based on data from Elden Categorical data were reported as frequencies, and continuous data are reported as mean ± standard deviation (SD). Comparisons of clinical endpoints between groups were standardized on a theoretical follow-up duration of 80 days. Discrete variables were compared using the Fisher exact test. Normally distributed continuous variables were compared using Student t test, and non-normally distributed data were compared using the Wilcoxon rank-sum test. Cost data were reported as mean values and were compared using a t-test. Bootstrapping (2000 replicates) was used to estimate uncertainty in the joint distribution of costs, ENS and OSW for each treatment group; all the 95% confidence intervals (95% CI) were estimated with this bootstrap technique.(The R Core Team. R: 2016).All analyses were performed with R version 3.3.1 The study was approved by the ethic review board “Comité de Protection des Personnes Ile de France VI”. Decision number: IDRCB: 2012-A00240-43. Date of decision: July 2nd 2012.All patients provided written informed consent, after receiving verbal and written information specifying the design of the study, the duration of their participation, practical issues on the trial, and the fact they could withdraw their consent at any time.The protocol was registered on clinicaltrials.gov under reference NCT01848587. We registered on ClinicalTrials.gov on March 6th 2013, whereas the trial commenced in September 2012. This delay was due to an error in managing the trial. We made no change in the protocol between inclusion of the first participant and registration on ClinicalTrials.gov. We confirm that all ongoing and related trials for this intervention are registered.During the study period, there were approximately 14800 deliveries per year in the maternity hospitals that recruited patients for the trial. Two hundred patients were randomized between October 2012 and September 2014: 96 patients to acupuncture group and 104 to standard treatment (control group). One patient was excluded after randomization because not fulfilling the inclusion criteria. Overall, 174 patients (87%) were followed up until delivery . All datBaseline clinical data are displayed on Acupuncture plus standard care was more effective than standard care alone regarding pain and disability . Before Differences in pain intensity were clinically and statistically significant between the two groups. The pain numerical analogic rating scale at week 5 was lower in the acupuncture group than in the standard care group, resulting in an average reduction from baseline of 2.3 points in the acupuncture group versus 1.4 in the standard care group .As for disability, the differences in mean Oswestry disability scores between inclusion and delivery were also significantly in favour of acupuncture We found no significant difference between groups for obstetrical and neonatal morbidity. In the acupuncture group, caesarean rate was 23%, mean birth weight was 3406g; four babies were admitted to neonatal care unit, 2 were born before 37 weeks. In the standard care group, caesarean rate was 20%, mean birth weight was 3327g, 7 babies were admitted to neonatal care unit, and one was born before 37 weeks .Acupuncture-specific side effects occurred in 32 (33%) patients and included bruising , fatigue , dizziness  and headache n = 1 (1%).There was no difference between the acupuncture and the control group regarding non-specific adverse events . The number of patients with at least one nonspecific adverse event was 29 (30%) in the acupuncture group and 30 (29%) in controls. In the acupuncture group, 10 patients were hospitalised because of a nonspecific adverse event, versus 9 in the control group. The total number of adverse events was 40 in the acupuncture group and 36 in controls. These events included cholestasis, gestational diabetes, hypertension/ preeclampsia, unexplained transient fever, urinary infection, viral infection, other infection, threatened premature labour, premature delivery (34–36 weeks), intrauterine growth restriction, and thrombocytopenia.From the societal perspective, average total costs were higher in the control group (€2947) than in the acupuncture group (€2635), with a difference of 312 euros . The lower cost in the acupuncture group was essentially due to indirect costs of absenteeism and presentism . With beWe ran three deterministic sensitivity analyses in addition to the bootstrap probabilistic analyses. For the first one, we choose as primary outcomes the proportion of days with pain NRS ≤ 4 defined as a self-assessed worst daily pain of 2/10 or lower. For the second run, we excluded extreme values. Only two patients in the acupuncture groups presented substantially high length of stay for hospitalizations. These patients were excluded in a sensitivity analysis. For the third analysis, we restricted costs estimation only to direct costs, as required by the French health authority. We did not identify drivers of uncertainty.Pregnant women with pelvic girdle and low back pain treated with acupuncture in addition to routine care reported less pain and disability than those who received routine care alone. Acupuncture with routine care dominated (cheaper and more effective) routine care alone from the perspective of society and cost an additional €22 for each additional day with a pain score ≤ 4 from the perspective of the hospital. From the societal perspective, the higher direct healthcare costs of acupuncture were offset by lower indirect costs of absence from work.As for evaluating the effectiveness of acupuncture, the fact that the endpoint was measured up to delivery for both pain and disability adds to previous studies that focussed on short-term outcome–18. UsinThe external validity of our results may be limited by a potential selection bias in the recruitment process. Pregnant women with low back pain who elected to participate may have been more psychologically prone to benefit from acupuncture than those who did not show up. We are not able to ascertain this bias. Regarding internal validity, the absence of placebo acupuncture precluded evaluation of the placebo effect of acupuncture, which may be substantial during pregnancy. BecauseWe choose not to exclude a “do-nothing” strategy in the control group, but to provide patients with information on physical activity and pregnancy belt. Drugs, physiotherapy, or other actions were prescribed by the physician or midwife in charge, in order to reflect usual practice.The trial was stopped before we reached the planned number of cases, due to lack of funding. This is not likely to alter the interpretation of results, since we found a significant difference in outcome between the intervention group and controls.16. Whether the effect of acupuncture results from needling per se, or from the attention and care given by a dedicated professional remains unclear.So far no cost effectiveness study was undertaken to evaluate acupuncture as treatment of low back pain during pregnancy. Previous studies in non-pregnant persons concluded to a modest health benefit for minor extra cost compared with usual care, from the point of view of the health care system or of soIn addition to standard care, acupuncture was beneficial to pregnant women with PGLBP. Acupuncture represented an additional cost from the hospital point of view, but was a dominant strategy, i.e. cost saving and more effective, from the point of view of society at large, when both healthcare and non-healthcare costs were included These results could help public health decision-makers consider providing acupuncture for pelvic and low back pain in pregnancy. For example, hospitals could offer acupuncture for low back pain as routine practice, which would require specific funding. Alternatively, health insurance programs could reimburse acupuncture in specific indications.S1 File(DOCX)Click here for additional data file.S2 File(DOCX)Click here for additional data file.S3 File(PDF)Click here for additional data file.S1 FigWe performed 2,000 bootstrap replications of the cost effectiveness ratio. The outcome was the decrease in pain numerical rating scale between baseline and week 5 after inclusion, expressed as a difference between acupuncture and standard care. All costs were taken into account.(TIF)Click here for additional data file.S2 FigWe performed 2,000 bootstrap replications of the cost effectiveness ratio. The outcome was the number of days with pain NRS ≤ 4/10 between inclusion and delivery expressed as a difference between acupuncture and standard care. Only hospital costs were taken into account. From a hospital perspective, acupuncture was more effective and more costly than routine care.(TIF)Click here for additional data file.S3 FigWe performed 2,000 bootstrap replications of the cost effectiveness ratio. The outcome was the number of weeks with pain Oswestry score ≤ 20 between inclusion and delivery, expressed as a difference between acupuncture and standard care. All costs were taken into account. Acupuncture was more effective and less costly than standard care.(TIF)Click here for additional data file.S1 TableTraditional Chinese medicine diagnosis was based on clinical examination at inclusion. It was the first step of acupuncture treatment.(DOC)Click here for additional data file.S2 TableBaseline points were applied to all patients in the acupuncture group. Other points were used according to pain location and to traditional Chinese medicine (TCM) diagnosis.(DOC)Click here for additional data file.S3 TableWe calculated costs from the perspective of the health care system , the patient (costs at the patient’s charge), and the employer (sick leave and presenteeism).(DOC)Click here for additional data file.S4 TableSocial back ground was similar in the acupuncture group and in the control group.(DOC)Click here for additional data file.S5 TableThere was no significant difference between the acupuncture and the control group.(DOC)Click here for additional data file.S6 TableWe calculated costs from the perspective of the health care system , the patient (costs at the patient’s charge), and the employer (sick leave and presenteeism).(DOC)Click here for additional data file.