Although the recovery of patients suffering from low back pain is highly context dependent, patient preferences about treatment options are seldom incorporated into the therapeutic plan. Shared decision-making (SDM) offers a tool to overcome this deficiency. The reinforcement by the general practitioner (GP) of a ‘shared’ chosen therapy might increase patients’ expectations of favourable outcomes and thus contribute to recovery.In the Netherlands, a clustered randomised controlled trial was performed to assess the effectiveness of shared decision-making followed by positive reinforcement of the chosen therapy (SDM&PR) on patient-related clinical outcomes. Overall, 68 GPs included 226 patients visiting their GP for a new episode of non-chronic low back pain. GPs in the intervention group were trained in implementing SDM&PR using a structured training programme with a focus on patient preferences in reaching treatment decisions. GPs in the control group provided care as usual. The primary outcome was the change in physical disability measured with the Roland-Morris disability questionnaire (RMD) during the six-month follow-up after the first consultation. Physical disability (RMD), pain, adequate relief, absenteeism and healthcare consumption at 2, 6, 12 and 26 weeks were secondary outcomes. A multivariate analysis with a mixed model was used to estimate the differences in outcomes.Of the patients in the intervention and the control groups, 66 and 62%, respectively, completed the follow-up. Most patients (77%) recovered to no functional restrictions due to back pain within 26 weeks. No significant differences in the mean scores for any outcome were observed between intervention patients and controls during the follow-up, and in multivariate analysis, there was no significant difference in the main outcome during the six-month follow-up. Patients in the intervention group reported more involvement in decision-making.This study did not detect any improvement in clinical outcome or in health care consumption of patients with non-chronic low back pain after the training of GPs in SDM&PR. The implementation of SDM merely introduces task-oriented communication. The training of the GPs may have been more effective if it had focused more on patient-oriented communication techniques and on stressing the expectation of favourable outcomes.The Netherlands National Trial Register (NTR) number: NTR1960. The trial was registered in the NTR on August 20, 2009.The online version of this article (10.1186/s12875-018-0776-8) contains supplementary material, which is available to authorized users. Nonspecific low back pain is defined as back pain localised below the costal margin and the inferior gluteal folds, with or without referred leg pain, and without a specific somatic origin , 2.Low back pain can be divided into acute, with a duration of complaints < 6 weeks, subacute, with a duration of complaints between 6 and 12 weeks, and chronic, with complaints lasting longer than 3 months [Low back pain has a lifetime prevalence of 60–85% . Most epThe therapeutic guidelines on low back pain focus on the continuation of physical activity, as the effectiveness of most therapeutic interventions does not exceed the placebo effect . In addiThe illness perceptions of a patient, such as avoidance beliefs and fear of the duration of the illness, predict the patient’s recovery and their return to work –9. In meSDM is defined as follows: A situation in which the professional and patient share their perspective and jointly decide on a treatment plan. SDM provides the possibility of incorporating patient preferences into clinical decision-making . The phiSince the introduction of SDM in clinical care, research has focused on the process of SDM implementation and its effect on clinical outcomes . At presFor patients with low back pain, SDM could improve the prognosis if patients were more adherent to treatment, as the expectation of a favourable outcome is incorporated into the treatment decisions .It has been empirically proven that the positive outcome expectations of the patient benefit the health status of the patient, and the reinforcement of these treatment expectations could endorse these effects , 19.Although widely advocated in guidelines, the effectiveness of SDM in the management of low back pain has not been evaluated in general practice .Therefore, we conducted a large randomised controlled trial among primary care patients with non-chronic low back pain in the Netherlands and report the effectiveness of SDM followed by positive reinforcement of the therapeutic choice (SDM&PR) on recovery and healthcare consumption.The aim is to assess the effectiveness of shared decision-making followed by a positive reinforcement of the chosen therapy (SDM&PR) on patient-related clinical outcomes in patients with non-chronic low back pain in general practice.A cluster-randomised controlled trial was performed in the practices of 68 general practitioners (GPs) in the academic primary care network around Utrecht in the Netherlands.GPs were recruited between August 2009 and May 2011. Each participating GP was requested to include ten patients with non-chronic nonspecific low back pain.between 18 and 65 years of age, andin consultation for a new episode of non-chronic nonspecific low back pain  , 21.The inclusion criteria were as follows:duration of low back pain longer than three months,any previous episode of low back pain within the three months prior to the onset of the present episode,pregnancy, andinsufficient mastery of the Dutch language.The exclusion criteria were as follows:Because the causes and pathophysiology of low back pain might be different in patients younger than 18 or older than 65 years, those who are pregnant or in those with a longer disease duration, we excluded these patients .GPs were randomly assigned to the usual care (UC) group or the intervention (IV) group immediately after consenting to participate in the trial. Randomisation was done by research staff members who were not otherwise in the research project. Allocation was blinded using allocation cards in sealed envelopes in an initial block of 40 followed by blocks of ten envelopes. GPs in the control group were kept unaware of the communicative techniques that were trained. Auxiliary staff members recruited the patients. Patients and auxiliary practice staff members were not informed about the allocation of the GP or about the communicative techniques in the training programme. Auxiliary practice staff members collected questionnaires from the patients after inclusion. A follow-up questionnaire with a pre-paid envelope was given to each patient with instructions on when to complete it and send it to the research team. Patients were reminded to send the questionnaires two, six, twelve and twenty-six weeks after the consultation by email or phone just before the correct time and, if necessary, again two weeks later.GPs in the intervention group were trained to perform SDM&PR during their consultations with the included patients. SDM followed the following process steps: inform the patient about therapeutic options, discuss the patient’s preferences, concerns and expectations, confirm the patient’s understanding, assess the patient’s preferred level of involvement in decision-making and finally make a joint decision about the optimal therapeutic regimen. GPs were trained to positively reinforce treatment outcomes after SDM.GPs in the intervention group received two training sessions of two and a half hours. Training sessions were held in small groups of approximately three to five participants and were given by a peer GP with expertise in training SDM skills (AS).The training was based on the learning principles of Kolb and the behavioural process elements of Elwyn . To suppIn the control group, the GPs provided the usual standard of care. Although routine management was not predefined in the instructions for the study, GPs in the Netherlands are reported to follow the professional guidelines on low back pain in 70% of patients . DiscussThe primary outcome was the difference between the intervention and the control group in the course of functional disability during the six-month follow-up. Functional disability was measured daily during the first two weeks and at two, six, twelve and twenty-six weeks after the first consultation.As secondary outcomes, we assessed the difference in functional disability at the time of each of the separate measurements , the difference in severity of back pain and the percentage of patients with adequate relief on separate measurement dates and at the end of the study.As indicators of economic effect, we evaluated the differences in absenteeism and health care consumption between groups over the complete study period and on the separate measurement dates.To be able to test for potential confounding, we measured illness perceptions at the baseline. To check the fidelity of the intervention, we questioned patients after the consultation about the level of involvement in decision-making.Functional disability was assessed by the Dutch version of the Roland-Morris disability questionnaire (RMD). This validated questionnaire contains 24 closed questions about restrictions in daily activities during the previous day. The score is the total number of positive answers . Pain seAbsenteeism was measured by the response to a question referring to the time before the baseline or since the previous questionnaire: ‘Because of my back pain, I refrained from work (absenteeism),’ yes/no/not applicable (expressed as a percentage of patients), followed by an inquiry about the number of days of sick leave.Healthcare consumption data were derived from patient questionnaires by counting follow-up contacts, via telephone or at the practice, and expressed as the mean number of contacts per patient since the previous questionnaire.Illness perceptions were assessed by the Dutch version of the abbreviated illness perception questionnaire (IPQ) . This inThe actual level of shared decision-making, as experienced by the patient, was evaluated by their response to one simple question immediately after the consultation: ‘Were you involved in decision-making?’ Mean scores were calculated from a range of one to four points corresponding to the answers ‘no’, ‘mostly no’, mostly yes’ or ‘yes’.The observed effects of the training were reported in a separate article on the evaluation of the training .The primary outcome (RMD) and the VAS was assessed daily during the first 14 days by a diary and at two, six, twelve and twenty-six weeks after consultation by questionnaires. All other secondary outcomes were assessed at two, six, twelve and twenty-six weeks  or the control group (n = 34). GPs in the intervention group did not differ from control GPs with regard to sex, age, professional age, number of included patients or percentage of GP trainers per group.Sixty-eight GPs agreed to participate and were randomised to the intervention (n = 19), did not have back complaints (n = 1) or were younger than 18 years old (n = 1). Ultimately, 114 patients in the control group and 112 in the intervention group were included in the analysis . Twenty-one of these patients did not meet the inclusion criteria because they did not align with the definition of non-chronic low back pain (Patients in the intervention and control groups were comparable across most baseline measurements (Table p = 0.017) and were younger . They did not differ significantly in other baseline measurements.During the follow-up, 76 (67%) of the control patients and 80 (70%) of the intervention patients completed all questionnaires. Overall, 71 (62%) patients in the control group and 75 (66%) patients in the intervention group completed the diary and all questionnaires , 2.1 (SDM&PR) and 2.3 (controls) after 12 weeks  and 2.0 for both groups after 26 weeks  (Table The mean disability score among the patients in the intervention and the control groups declined to 4.1 (SDM&PR group) and 4.3 (control group) after 2 weeks , 14.2 (SDM&PR) and 12.4 (controls) after 12 weeks  and 13.6 (SDM&PR) and 16.3 (controls) after 26 weeks . The percentage of patients with adequate relief was 70% (SDM&PR) and 62% (controls) after 2 weeks , 49% in both groups after 6 weeks, 69% (SDM&PR) and 62% (controls) after 12 weeks, and 66% (SDM&PR) and 64% (controls) after 26 weeks. The mean number of days of absenteeism and mean health care consumption at 2, 6, 12 and 26 weeks did not differ between the two groups (Table The mean pain score in the two groups was 18.9 (SDM&PR) and 20.3 (controls) after 2 weeks   Table . The mea2) Table .Table 3DOf the 8 dimensions of illness perception, only consequences  0.14–2.35), timeline (β = 1.38 CI 0.27–2.48) and concern (β = 1.45 CI 0.34–2.56) were significantly associated with disability at 12 weeks. However, when the interaction term of each of these three items with the intervention was added to the multivariate model, no significant effect of illness perception on disability at 12 weeks was found.p-value 0.005).In both groups, patients reported a substantial degree of involvement in decision-making. However, the patients in the intervention group reported a significantly higher level of patient involvement (2.92 standard deviation (SD) 1.21; range 1–4) than the controls (2.44 SD 1.23)  of the pre-set sample size. Participating GPs experienced problems that hampered recruitment, possibly due to unforeseen changes in the healthcare system, such as the introduction of direct access physiotherapy. However, the fact that the results of the patients in the intervention and control groups did not differ in any of the outcome measures at any moment in time demonstrates in our view the consistency of the results, and even if differences were demonstrated at the pre-set sample size, these differences would have been small and of questionable clinical relevance.Dropout rates of GPs and patients are similar in the intervention and control groups and are in line with other studies on patients suffering from nonspecific low back pain in primary care in the Netherlands . We cannAlthough we have observed significant differences in the perception of SDM between the experimental groups, we believe that the difference should be evaluated in the context of treatment fidelity. In a recent publication evaluating the intervention from an observational perspective, we found significant differences in the use of physical examination and in the consultation duration between groups . MoreoveUnfortunately, as with many other studies on the effects of SDM on health outcomes, the effects are too small to allow conclusions about the impact of the separate communicative techniques, SDM and positive reinforcement of treatment expectations. Theoretically, we expected a positive interaction between the two techniques. The consistent pattern of very small potential positive treatment effects of the combined intervention above the usual standard of care could be explained by a stronger positive effect of one technique counteracted by the effect of the other Fig. . For insStudies on the effects of learned communicative strategies frequently face problems with blinding. We downsized the risk of non-blinding by sorting patients per GP, by recruiting patients via auxiliary staff members unaware of the allocation, and by not providing details of the trained communicative strategy to control GPs, auxiliary staff members and patients.We did not perform a full health economic assessment but restricted the economic impact analysis to measuring the absenteeism of workers. However, in a detailed cost-effectiveness analysis, the reported 20% difference in the duration of the consultation time should be considered .As in other studies on interventions for non-chronic low back pain, we did not find substantial or significant effects .This finding could be attributed to different factors. Such as an excessively diverse study population in the duration of the complaints or in patient characteristics –38.Although we think that the risk of contamination was limited, GPs in the control group may have incorporated SDM in their consultations as well. This might be reflected in the fact that the mean score for the question of whether patients felt involved in the decision-making was between ‘mostly yes’ and ‘mostly no’. The difference in the results of the intervention group, where the mean score was ‘mostly yes’, was significant but limited. However, the observational study demonstrates low levels of SDM in both groups despite the significant effect of training in SDM behaviour , 39, 40.Because most patients quickly recover from their back pain, the intervention simply might not have had sufficient discriminative content above the spontaneous course. In their review of psychosocial interventions for non-chronic low back pain in primary care, Ramond et al.  advise tContextual factors play an important role in the symptom perception, prognosis and recovery of low back pain , 4. We iAlthough the GPs were extensively trained before participating in the intervention group and the patients recognised SDM during the actual consultations, we question, based on the results of the evaluation of the training, whether the training did result in adequate SDM performance , 43.Trained GPs became more aware of the need to better inform patients about treatment options and to incorporate patients’ expectations during the intake phase of the consultation, but they persisted in providing a paternalistic, guideline-oriented choice.In a review on the effects of the implementation of SDM in clinical encounters measured by an external observer, Couët et al.  reportedSo far, task-oriented issues, such as performing process steps and information exchange, are emphasised in the implementation of SDM . HoweverFuture research on the involvement of patients in treatment decisions should therefore focus more on professional attitude and equality in the patient professional relationship as a condition for successful SDM.Training of GPs in the application of SDM&PR during consultations with patients with non-chronic low back pain did not significantly improve clinical recovery. Although it may have improved the ‘knowledge and rationalise expectations’ of the patients, this did not lead to less functional impairment, shorter pain duration or less absenteeism from work than routine practice. Most patients recovered from their low back-pain within 12 weeks, and this positive effect was persistent at the 26-week follow-up, which confirms the benign natural course of low back-pain as reported in the literature. A potential small positive effect of either SDM or positive reinforcement of treatment expectations cannot be excluded. As the prognosis of low back pain is predominantly determined by psychosocial factors, we suggest that further research on the positive health effects of communicative techniques should focus on a more patient-oriented approach, combined with the reinforcement of positive recovery expectations, than on task-oriented techniques such as SDM.Additional file 1:Appendix 1. Desktop tool translated Original Dutch version and translation of the desktop tool (DOCX 17 kb)Additional file 2:Appendix 2. BT imputed Baseline Table of imputed dataset Baseline demographic and clinical characteristics of patients in imputed dataset. (DOCX 16 kb)Additional file 3:Appendix 3. Complete case analysis. Difference in mean scores between the control and intervention group during the six-month follow-up in complete cases. (DOCX 18 kb)


Orofacial pain (OFP) is an undesirable sensation frequently associated with head and neck cancer (HNC) and its treatment. OFP negatively impacts the quality of life of oncological patients. The approach to OFP diagnosis and management can differ if the patient visits a dentist or physician. The aim of this study was to present a case series of HNC with OFP managed by a dentist team and to discuss its role in the management of OFP.We recruited twenty-two adult patients with OFP and previous diagnosis of HNC referred to an academic dental clinic from 2015 to 2017.Nociceptive was more frequent than mixed and neuropathic pain, however 54,4% of the cases showed a neurological component. All types of pain were managed by dentist through removal of pain’s cause and appropriated local and systemic treatment. The intensity of pain was reduced in 86,3% of patients, and 45,4% of them reported absence of pain at the end of treatment.Dentist’s assessment plays a distinct and crucial role in the diagnosis and management of OFP in HNC patients throughout the oncological treatment. Key words:Pain, orofacial, neoplasm, head and neck, dentist. Head and neck cancer (HNC) are a group of malignant neoplasms that arises in the oral cavity (40%), oropharynx and hypopharynx 15%), and larynx 25%)  “pain is an undesirable sensation of discomfort, an unpleasant human experience that decreases the quality of life in patients with cancer” . Therefo “pain isOFP may be caused by direct cancer involvement of anatomical structures, toxicity of oncological treatment or patient comorbidities ,3. In thPreventive measures and effective analgesia are the basis of multidisciplinary cancer pain management ,3. The aThis study aimed to report our experience in the diagnosis and management of OFP in HNC patients referred to an academic dental outpatient clinic and to discuss the importance of a dentist in the multidisciplinary approach to oncological patients with OFP.This study was approved by the Institutional Ethics and Research Committee (protocol number 904.529). We recruited adult patients with OFP and previous diagnosis of HNC referred to an academic dental clinic from March 2015 to November 2017. Eligible patients that accepted to participate and provided an informed consent entered the study.-Dentist’s structured interview Clinical examination started with a structured interview to assess demographic data; type, localization and stage of HNC; timing of oral assistance ; modality  and duration of oncological therapy; smoking and alcohol abuse; and co-morbidities.The OFP history included the following data: location and radiation ; timing ; quality  ; intensiPatients with HNC rated pain intensity, according to a validated VAS . The use-Oral and maxillofacial examinationA dentist with expertise in orofacial pain realized a complete face, head, neck, and oral cavity examination by inspection, palpation, percussion, and auscultation. Mandibular active range of motion, standardized temporomandibular joint, masticatory and cervical muscle palpation were also done, according to research diagnostic criteria for temporomandibular disorders (RDC/DTM) . For nocDental and periodontal examination was done by a combination of clinical and radiographic analysis. Cold stimuli to the clinical crown by Endo Ice spray was done when caries, restorations  or tooth pain history was present. Periodontal status was defined after probing and dental mobility analysis.-Dentist diagnosis and managementThe types of dental treatment protocols were categorized according to anti-cancer therapy timing -18. For The complete dental treatment protocol was also the option for patients after CRT. For patients with indication of tooth extraction in the field of radiation were prescribed the osteonecrosis prevention protocol which included amoxicillin (2 g) or clindamycin (600 mg) taken orally one hour before the surgery and half of dose every eight hours for seven days after extraction; and antibacterial mouthwashes with 10 ml of chlorhexidine gluconate 0.12% solution for one minute twice a day starting seven days before extraction and continued for seven days after extraction ,18.Severity of oral mucositis was defined by World Health Organization (WHO)  as GradeTMD was managed through thermotherapy  , oral muDiagnostic anesthetic blocks  were use-Case seriesTwenty-two patients  agreed to participate in the study  and tobacco  consumption. Ten patients  interrupted this consumption after malignancy diagnosis. Nine patients  presented co-morbidities: arterial hypertension , urinary tract infection , hypothyroidism , diabetes mellitus type II , depression , gallbladder stones  and gastritis .-Pain diagnosis and managementOFP was associated with more than one diagnosis in 50% of the patients. The etiologies included: neurological , musculoskeletal (50%), pulpitis , periodontitis , mucositis (9%) and bite in oral mucosa . The most frequent type of pain was nociceptive , followed by mixed type  and neuropathic pain . Eight patients  reported continuous pain. In all other patients, pain was intermittent  though lasting for more than two hours. Ten patients  reported severe pain according to VAS. Five patients  referred moderate pain and seven  reported mild pain. Twenty patients  reported a specific type of pain sensation: stinging , throbbing , pressure , burning , needle prick (9%), tingling  and painful cold sensation . Four patients  complained simultaneously by two or more pain sensations.Two patients (9%) reported spontaneous pain. The others  had at least one pain trigger or aggravating factors: chew (59%) of fibrous food ; ice (50%), hot , seasoned 22,7%) or sweet , and one patient also underwent PBM (5J/cm2) once a week in all teeth because of dental sensibility. One patient was managed with fluoride therapy for white spot lesion in all teeth with sensibility and direct restoration.Two patients presented tongue and labial mucositis and were treated with PBM (2J/cm2) once a week. In one patient, dental trauma in oral mucosa was diagnosed as the pain’s cause, and exodontia was undertaken. One patient presented BMS that was managed with topical capsaicin and benzocaine three times a day. Thermotherapy in pain site was recommended for five patients .Systemic pain medication was recommended to fourteen patients , such as anticonvulsant , muscle relaxant , nonsteroidal anti-inflammatory (9%), common analgesic , opioid  and antidepressant . For two patients (9%) a combination of two systemic pain drugs was recommended. One patient received intramuscular anesthetic (lidocaine 2% + epinephrine 1:100.000) to define the type of pain.The follow-up ranged from fourteen to 390 days . Ten patients  reported absence of pain and six  referred mild pain after oral care. Three patients  maintained severe pain, although slightly reduced. One patient reported no response and two patients abandoned treatment.The present case series reflects the typical scenario of HNC in Brazil, where oral cancer represents the fifth commonest malignant neoplasm in men. Tobacco smoking and alcohol consumption are the most prevalent risk factors, and its diagnostic still remains late in the majority of cases . In thisOFP diagnosis is a challenging condition for both dentist and physician. General practitioners commonly refer OFP patients to ear, nose and throat, neurology, or pain medicine , whereaset al., clinical presentation of OFP depends on cancer stages and its associated therapy. At the beginning, pain could be associated with neoplasm and its growth or paraneoplastic neuropathy. Perineural spread of HNC can give trigeminal neuropathic symptomatology in up to 80% of patients (According to Epstein patients . This ocpatients . All patPain during therapy may be associated with neural and mucosal damage due to cytotoxicity of CRT or post-surgery anatomical abnormalities ,27. In tThe majority of patients in the present study were in post-therapy period that is characterized by long-term consequences of cancer treatment ,16. In tDefinition of OFP’s type based on pathophysiological classification is essential to determine its appropriated pain management . IntermiIn our series, a mixed-type OFP was diagnosed in some cases, with both neuropathic and nociceptive components resulting in variable pain characteristics. This pain was efficiently treated with analgesic and adjuvants drugs, such as nonsteroidal anti-inflammatory, anticonvulsant, and antidepressives, associated with removal of local causes of pain when it was necessary. Pharmacological choice was based on the medical, social, and emotional individual history and followed the WHO’s analgesic step-up approach .One patient was diagnosed with BMS secondary to CRT. As with other chronic neuropathic pain conditions, BMS can be managed by pharmacological or by psychological means or by a combination of both ,29. In tWe decided to report four unconcluded cases to discuss the vulnerability of the patients and their families that depend on public health service. A Brazilian study  highlighet al., OFP in many cases never returns to its baseline status after beginning cancer therapy. These findings were not reproduced in this study where pain scores changed from severe or moderate to no pain in 45,4% of cases. We believe that our approach was successful due to an individual approach and to careful pain diagnosis and treatment.According to Epstein There are a limited number of studies assessing OFP in HNC patient. Studies addressing the dentist diagnosis and management of pain impact in the overall quality of life of patients with cancer are needed to improve oncological therapy.OFP could be associated to tooth, musculoskeletal, and some neurological disorders whose diagnosis and treatment depends on the dentist. In this cases report, oral care approach enabled pain reduction in 86,3% of patients, and pain relief was achieved in 45,4% of them. Oncological patients should be treated by a multidisciplinary team including dentists.


In the treatment of patients with rib fractures (RFs), pain reduction is the most important consideration. Various studies have examined the effectiveness of treatments administered to RF patients, such as lidocaine patches, IV drugs, nerve blockers, and surgery. In this study, we evaluated the difference in the effectiveness in pain reduction between 2 groups of RF patients: 1 group who received a rib splint constructed in the ER (ER splint) and another group who received a Chrisofix Chest Orthosis (CCO) manufactured rib splint.A pilot study for a prospective randomized clinical trial was conducted to compare subjects using the CCO (Group A) with those using the ER splint (Group B) before and after the intervention. The primary outcome was difference in the level of pain based on the visual analogue scale (VAS) and the pulmonary function (PF) variables between before and after intervention in each group during forceful and resting respiration.P < .001; Group A forceful: 9.83 ± 0.41 vs 7.17 ± 0.75, P < .001; Group B resting: 8.83 ± 1.60 vs 4.50 ± 1.38, P < .001; and Group B forceful: 9.67 ± 0.82 vs 7.33 ± 1.51, P = .003). The PF variables showed that the intervention was significantly effective in each group .A total of 24 subjects were enrolled in this study. The VAS results showed that the intervention was significantly effective in each group (before vs after: Group A resting: 8.50 ± 1.05 vs 4.17 ± 1.33, Applying either the CCO or the ER splint to RF patients effectively reduced pain, and no significant differences in pain level were observed between these 2 techniques. RFs disrupt the stability of the chest wall and decrease the respiratory volume, thus causing restrictive as well as obstructive breathing difficulty, along with unpredictable effects on bronchial secretion. Poor pain control can lead to pulmonary complications as a direct consequence of decreased ability to ventilate. For instance, pneumonia develops in one-third of patients with multiple RFs. Considering that injury to the ribs and the subsequent pain trigger this cascade of negative consequences, optimal pain control is expected to shorten the length of stay and reduce the number of pulmonary complications in RF patients. Thus, in the treatment of patients with RFs, pain reduction is the most important factor.In general, rib fractures (RFs) are considered a common injury that results from blunt thoracic trauma. However, none of these methods has been shown to be completely effective alone, especially in the long term. Additionally, intravascular or oral systemic opioids can cause sedation, decreased respiration, and decreased mental clarity. Each of the other methods is invasive, thus exposing patients to possible complications such as bleeding, pneumothorax, and infection. In addition, these invasive methods are difficult to perform and are impractical in an emergency room (ER) setting.Numerous methods of pain control have been described for RFs; these methods include systemic opioids or NSAIDs, epidural anesthesia, intercostal nerve blockers, intrathecal opioids, intrapleural analgesia, paravertebral blockers, and transcutaneous electrical nerve stimulation. Several other adhesive bandaging methods have been advocated. These methods are poorly accepted at present because they decrease the vital capacity of the lung. Recently, rib splints have been designed to simultaneously provide pain reduction and increase vital capacity.Malgaigne proposed a thorax-fixing bandage in his book in 1851. However, this product is very expensive, and its size is inadequate for application to patients with multiple RFs or a flail chest. Therefore, we have designed a rib splint that is easily constructed using common materials such as adhesive hydrocolloid dressing material, double-sided adhesive tape, and splint, all of which are typically present in the ER.Chrisofix Chest Orthosis (CCO) can be used to reduce pain, the length of stay, and the number of pulmonary complications.In this study, we hypothesized that the effects of a rib splint constructed in the ER (ER splint) are similar to those of the CCO rib splint.22.1This study was a prospective randomized single-blinded human clinical trial. The investigation was approved by the relevant institutional review board, and informed consent was obtained from all subjects. The local ethics committee approved this study (IRB No. 2015-09-013). We registered the study protocol in the Clinical Research Information Service clinical trials database before study initiation .2.2This study was conducted at an emergency department of an academic medical center. The primary investigators were emergency physicians and/or emergency residents working in the emergency department. The sample size was calculated based on a pilot study that examined the delta PEF before and after the intervention. The delta PEF (mean ± standard deviation (SD)) values were as follows: Group A delta PEF (81.49 ± 35.97) and Group B delta PEF (83.53 ± 31.59). The sample size was analyzed using G-power 3.1.2  with an α error of 0.05 and a power of 0.8. We estimated that 11 participants would be adequate for each group with a 10% dropout rate. Thirty-one patients were initially enrolled. We ultimately enrolled 24 RF patients who were over 18 years of age and who agreed to participate in this study. These patients completed a predesigned written consent form before participating in this study. We excluded 7 patients with cardiopulmonary dysfunction, polytrauma, flail chest, damage to an internal organ, or alcoholism and patients who did not consent to participate  Fig. .We used ML3500 MicroLab Spirometer  the visual analogue scale (VAS) to assess the level of pain and pulmonary function (PF) in patients with RFs.2.4First, we performed VAS and spirometer assessments to determine the level of pain in the patients with RFs during resting and forceful respiration. In addition, we applied either the CCO rib splint or the ER splint to the RF patients in a randomized order. At 30 minutes after splint application, we repeated the VAS during resting and forceful respiration and the spirometer assessment. Subsequently, additional pain control was provided via intravascular drug injection.2.5We recorded the PF values, including the forced vital capacity (FVC), forced expiratory volume in 1 second (FEV1), peak flow rate (PFR) and the VAS scores during resting and forceful respiration before and after application of the ER splint or the CCO rib splint. We compared the 2 values (before and after intervention) to determine the change in the VAS score and PF in each group during resting and forceful respiration.2.6The data were compiled using a standard spreadsheet application  and were analyzed using the Statistical Package for the Social Sciences (SPSS) 20.0 KO for Windows . We generated descriptive statistics and presented them as frequencies and percentages for categorical data or as the means with the standard deviation (SD) for continuous data.t test was used to compare the difference in the VAS score and PF after the intervention.To evaluate the effects of both the CCO rib splint and the ER splint, the paired Further, to compare the differences in the VAS score and PF between applying the CCO rib splint and applying the ER splint, an equivalence test was used for continuous variables. Furthermore, to find confounding factors, a multivariable linear regression analysis was performed using several variables .P < .05 was considered statistically significant.For all analyzed data, 33.1Twelve patients were enrolled in this study, and none were excluded. The baseline characteristics of the patients are shown in Table 3.2Overall, each treatment was significantly effective Table .P < .001) and during forceful respiration . In addition, the CCO rib splint significantly improved PF .In Group A, application of the CCO rib splint significantly reduced the VAS score during resting respiration  and during forceful respiration  .In Group B, application of the ER splint significantly reduced the VAS score during resting respiration  or during forceful respiration  . However, there was a statistically significant difference in the improvement in FEV1 between Groups A and B .There was no significant difference in pain relief between Groups A and B during resting respiration  Table . There w3.5P = .04) . The age of patients was shown to have a statistically significant influence on ΔPEF .There was a statistically significant impact of the number of fractures on ΔVAS during forceful respiration  may be increased when the number of fractures increases. In other words, this result suggests that the ER splint is more effective in patients with more RFs in reducing pain, even though the maximum number of fractures was 4 in this study. The ΔPEF was decreased by approximately 0.6 as the age was increased by one. The PEF is likely to decrease with age. Thus, the extent of improvement in PEF with the splint will decrease as the age increased. Pain reduction is the most important consideration for RF patients because pulmonary complications due to hypoventilation resulting from pleuritic pain exert an important influence on the prognosis of these patients. reported in 2006 that RF fixation may reduce ventilator requirements in patients with severe thoracic injuries but that the long-term functional outcomes of such a surgical procedure need to be assessed. In 2010, Nirula Mayberry reported that surgical fixation methods may be effective in decreasing RF pain but may also increase the risk of iatrogenic bleeding or pulmonary damage. Because surgical fixation methods are invasive, iatrogenic complications are possible. Therefore, the safety of these methods should be considered when treating RF patients.Concerning more invasive methods, Nirula et al investigated the effectiveness of transdermal opioids for patients with RFs and reported no significant difference in effectiveness between transdermal opioid combined with intercostal nerve blockade and IV patient-controlled analgesia combined with intercostal nerve blockade. They concluded that transdermal opioid treatment is safe, noninvasive and effective for patients with RFs. Similarly, Zink et al reported no significant difference in effectiveness between a lidocaine patch and narcotic administration. Thus, they concluded that the lidocaine patch is a safe, effective treatment method.Several studies have examined less invasive or noninvasive treatment methods. For instance, Solak and Öz  found no significant difference in effectiveness between a lidocaine patch and a placebo patch; thus, they concluded that the lidocaine patch does not significantly reduce pain in patients experiencing multiple traumas with RFs. In Japan, Nakae et al reported that the difference in the effects on RF-related pain between the traditional Japanese medicine Jidabokuippo and NSAIDs was not significant. Bayouth et al reported that early IV administration of ibuprofen reduced the requirement for narcotics and the length of stay among patients with RFs.However, Ingalls et alNo previous study had compared the effectiveness between the CCO rib splint and a simply constructed rib splint made in the ER. Based on the results of this study, this less expensive rib splint that was simply constructed in the ER expands the applicability of a rib splint for patients with RFs and significantly reduces RF-related pain.Nevertheless, there were several limitations in this study. First, there was selection bias because we enrolled only patients lacking damage to internal organs in the thoracic cage. The effectiveness of rib splints for patients with RFs could be exaggerated because this study did not enroll patients with traumatic pneumothorax, hemothorax, lung contusion, etc. Another limitation of this study is that we excluded multiple trauma patients, who experience injuries to sites in addition to the thorax. However, based on the results of this study, we suggest that the less expensive ER splint can be effective in patients with only RFs.Second, we used minimum sample size. However, we have calculated the sample size based on the results of pilot study. It is possible that the ER splint provides similar benefits to those of the CCO rib splint. Therefore, based on the findings of this study, we will perform further evaluations of length of stay, requirement for analgesics and narcotics, etc.Third, some results of this study were not quantitative, and the VAS score is insufficient to establish the effectiveness of the intervention. However, we have evaluated the PF of patients before and after interventions.Fourth, we did not follow up the enrolled patients. As a result, we did not analyze the patients after they left the ER. Accordingly, we did not compare the effectiveness between the CCO rib splint and the ER splint over time.Fifthly, we did not verify the durability of the ER splint because we did not follow up the enrolled patients. However, judging by the results of this study, if the durability of the ER splint is similar to that of the CCO, we hypothesize that the results of follow would be similar as well.5In conclusion, both the CCO rib splint and the less expensive ER splint effectively reduced pain and improved PF in patients with RFs.Conceptualization: YOONJE LEE, Sang-Hyun Lee, Changsun Kim, Hyuk Joong Choi.Data curation: Hyuk Joong Choi.Formal analysis: YOONJE LEE, Sang-Hyun Lee.Investigation: YOONJE LEE, Sang-Hyun Lee.Methodology: YOONJE LEE, Sang-Hyun Lee.Supervision: Changsun Kim.Validation: Changsun Kim.Writing – original draft: YOONJE LEE.Writing – review & editing: Sang-Hyun Lee.


To investigate the differences in clinical characteristics and long-term treatment outcomes according to antinuclear antibody(ANA) and rheumatoid factor(RF) positivity and the correlation between pain-related and hematological indices in temporomandibular disorders(TMD) patients.Clinical examinations were done following the Research Diagnostic Criteria for TMD in 257 patients. Comprehensive screening along with psychological and hematological evaluations  were conducted. Clinical characteristics and treatment outcomes were statistically compared between ANA/RF positive and negative groups.p = 0.033) and maximum mouth opening(MMO)(p = 0.016) ranges with more painful neck muscles on palpation when RF/ANA positive. Pain duration, intensity, disability days and psychological distress levels were also higher in RF/ANA positive male patients. Significant correlation was shown in ESR with pain duration(p < 0.05) and numeric rating scale(NRS) before treatment(p < 0.05), CRP with NRS before treatment(p < 0.01), and red blood cell (RBC) with pain intensity(p < 0.05), NRS before treatment(p < 0.01), CMO(p < 0.01), pain on palpation of cervical muscles(p < 0.01), CMO(p < 0.05), and MMO(p < 0.05) 6 months after treatment.Thirty-nine patients showed ANA/RF positivity. Male patients had smaller comfortable mouth opening(CMO)(These results may point towards a nonspecific autoimmune disposition in a subgroup of TMD patients. RF and ANA could be considered as a screening test for the detection of autoimmune phenomena in TMD. Temporomandibular disorders (TMD) is one of the most common musculoskeletal pain syndromes in the orofacial region mainly known as a clinical dysfunction of the temporomandibular joint (TMJ) and surrounding musculature that is accompanied by pain and movement limitation . Most TMAntinuclear antibody (ANA) and rheumatoid factor (RF) are laboratory tests applied to identify potential autoimmunity along with basic studies including complete blood cell count, acute phase reactants, and comprehensive metabolic panel . ANA posCurrently the diagnosis of TMD is limited to radiographic and clinical examinations and there is a general lack of indices that may be applied to predict a patient’s prognosis . There iThe data of a total of 257 consecutive patients  who visited the Orofacial Pain Clinic of Seoul National University Dental Hospital complaining of TMD symptoms from May, 2013 to July, 2015 were analyzed. Patients were diagnosed as TMD according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) . The cliThose with a history of other pain disorders within 6 months prior to the study, history of psychiatric or immune diseases, medication intake within 4 months prior to the study that could affect the results, history of recent trauma and orthognathic surgery, clinical history of other joint involvement, presence of inflammation or infection in other body parts were excluded from the study. Assessment was based on comprehensive screening and blood tests done before the RDC/TMD examinations. Patients with ANA and/or RF (ANA/RF) positivity were first referred to the department of rheumatology of Seoul National University Hospital and those who were diagnosed with a rheumatologic disease were also excluded. The included patients were divided into 2 groups according to the presence or absence of ANA/RF.All patients completed the RDC/TMD axis II questionnaire and a comprehensive interview concerning demographic and medical features including age, gender, pain-related characteristics , general conditions , and comorbidities of TMD .Clinical examination based on RDC/TMD included clinical parameters such as comfortable mouth opening (CMO), maximum mouth opening (MMO), pain on palpation of masticatory and cervical muscles and TMJ capsule, pain on mouth opening and eccentric mandibular movements (protrusion and laterotrusion). Overall TMD pain intensity was scored by the patient on a 0–10 numeric rating scale (NRS).Pain-related disability level and the psychological status of patients were assessed by RDC/TMD axis II  and SympPlasma samples of all patients were obtained from the antecubital vein and stored in Lavender tubes coated with ethylenediaminetetraacetic acid . The plasma was immediately centrifuged (3000 rpm) for 10 min at 4 °C, and analyzed. ANA was measured by indirect immunofluorescent methods using HEp2 cells . ANA titers of 1:40 or higher were considered as positive. RF was determined through enzyme-linked immunosorbent assay by detecting the presence of autoantibodies that react to the Fc portion of polyclonal IgM .Inflammatory markers including C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were analyzed. Plasma concentrations of CRP were analyzed by means of a highly sensitive immunoturbidimetric assay autoanalyzer . Comprehensive laboratory assessments included complete blood cell counts with white blood cell differential, red cell indices, and blood chemistry. The person conducting serological analysis was blind to patients’ identity.Following the initial examination all patients were educated about their TMD problems and instructions concerning the control of contributing factors  of TMD were given. Demonstrations for self-exercise  and physp < .05. All statistical analyses were performed with the SPSS 19.0 software program .The Kolmogorov-Smirnov and Shapiro-Wilk test was applied to check for normality of the data. Non-parametric tests were applied when data were not normally distributed. Differences according to ANA/RF presence were analyzed by Mann-Whitney and Chi-square test. Correlations of each dimension of TMD clinical parameters, psychological profile and laboratory findings were analyzed by Spearman’s correlation coefficient. Results were considered statistically significant at a probability level of Two hundred fifty-seven patients completed assessment procedures at baseline and 6 months follow-up. Thirty-nine patients  showed ANA/RF positivity.p = 0.033) and MMO(p = 0.016) ranges of ANA/RF positive male TMD patients were significantly smaller compared to ANA/RF negative male TMD patients before treatment initiation. ANA/RF positive male TMD patients had significantly more neck muscles that showed tenderness on palpation compared to ANA/RF negative male TMD patients. ANA/RF positive male TMD patients also had longer pain duration, higher pain intensity, and more disability days due to pain. The NRS before treatment was higher and a larger portion of patients reported a NRS higher than 5 compared to ANA/RF negative male TMD patients. ANA/RF positive male TMD patients more frequently reported pain during mouth opening and eccentric movement of the jaw. More masticatory muscles and TMJ capsule areas showed a positive response to palpation in ANA/RF positive TMD male patients although the differences were not statistically significant. The same tendencies of a higher pain level and resulting disability based on subjective and objective indices were identified in women TMD patients and the patient group as a whole but none of the differences was statistically significant according to ANA/RF positivity (Table The CMO(MOp = 0.06 ranges p = 0.024) and more ANA/RF positive female TMD patients reported pain during mouth opening (p = 0.022) compared to ANA/RF negative TMD patients. The significant differences in mouth opening range and number of positive neck muscles to palpation observed before treatment in male ANA/RF positive TMD patients had resolved to an insignificant level. However, mouth-opening ranges were still smaller and more patients reported pain on palpation of the capsule, neck and masticatory muscles compared to ANA/RF negative male TMD patients  and TMD patients as a whole group (p = 0.037) had a significantly higher ESR level compared to their ANA/RF negative counterparts. This difference was not significant in female TMD patients. ANA/RF positive male TMD patients had lower red blood cell counts, hemoglobin levels, and higher CRP levels compared to ANA/RF negative patients although the difference was not statistically significant , NRS before treatment , CMO , number of positive muscles on palpation of cervical muscles , CMO at 6 months after treatment (γ = 0.323 p < 0.05), and MMO at 6 months after treatment . Hemoglobin concentration showed significant correlation with MMO at 6 months after treatment . ESR showed significant correlation with pain duration  and NRS before treatment  and CRP with NRS before treatment  (Table Significant correlation was shown between RBC with pain intensity (γ = − 0.297, The results of this study showed that male TMD patients with ANA/RF positivity were associated with higher pain levels and more clinical dysfunction followed by worse long-term treatment outcomes. This study provided evidence of a possible role of autoimmunity in the pathogenesis of TMD pain in a certain patient subgroup. RF positivity has been reported to be found in around 4%  while ANThe ANA/RF positive TMD patients also showed higher scores of anxiety and depression. An intimate association between autoimmunity and depression has been demonstrated  and repoANA/RF positive male TMD patients of this study had lower red blood cell counts and hemoglobin levels showing an anemic tendency. Patients with autoimmune disorders have been reported to show altered hematologic conditions. Autoantibodies may bind to antigens expressed on RBC surfaces and initiate their destruction through the complement system. An example is immune hemolytic anemia which is a disorder characterized by decreased RBC or RBC-related indices due to autoimmune destruction . AutoimmESR is a non-specific measure of inflammation which is increased in inflammatory states. In our study, ANA/RF positive men showed significantly higher ESR levels. Increased ESR may represent a chronic inflammatory condition associated with elevated pro-inflammatory cytokine levels. Such inflammatory conditions can directly result in various pain-related TMD symptoms  since inCorrelations among hematological and TMD pain-related indices were revealed in the male TMD patients. Among them, RBC was most closely associated with TMD pain-related indices. Decreased RBC levels were related to increased pain levels and impaired mandibular function. This may reflect the relationship among autoimmunity, anemia, and pain since higher hemoglobin concentrations were also significantly related to larger CMO values after 6 months’ of treatment in ANA/RF positive male TMD patients.Most autoimmune disorders are significantly more common in women , 33. FemMany studies discuss the pathophysiology of TMD but the complexity of the underlying mechanism hinders complete understanding and a consensus concerning this issue is yet to be reached. So the diagnostic process of TMD is usually based on empirical evidence and is mostly constituted of interviews, physical examinations, and imaging . HoweverAt the baseline, most clinical indices of TMD patients with ANA/RF positivity were significantly worse compared to ANA/RF negative subjects. However, after 6 months of conservative therapy TMD pain levels also improved in ANA/RF positive patients and the difference in symptom severity was no longer significant between the two groups. This may reflect the effectiveness of conservative treatment in controlling TMD symptoms. TMD patients with autoimmune tendency may have a more painful functional disorder but they also responded well to conservative therapy. So the application of conservative treatment could be advised regardless of ANA/RF positivity. But the dysfunction level of ANA/RF positive patients were still higher in spite of long-term treatment. This may suggest the possibility of using ANA and RF in predicting patient response to conservative treatment at the initial evaluation, allowing for more active measures to be taken at an earlier stage for certain TMD patients that may not respond well to conservative approaches. However, the results of this study have certain limitations.First the small sample size of ANA/RF positive patients could have lowered statistical power resulting in insignificant results. Further studies of a larger scale and longer duration must be conducted to evaluate the reliability of ANA and RF as diagnostic indices in TMD. Secondly comorbidities are known to affect TMD pain levels , 39 but This study evaluated differences in clinical symptoms of TMD according to ANA/RF positivity and the results suggest a possible role of autoimmunity and inflammation in the pathophysiology of TMD pain and resulting dysfunction. It might not be possible to apply these results to all patients but a certain group of TMD patients may show an autoimmune disposition that is associated with pain of a higher level and more dysfunction followed by poor treatment outcomes. Such results may be considered in the diagnosis and prognosis prediction process of chronic TMD pain and hematologic indices such ANA and RF should be further evaluated.


This study assessed the effects of a lactobacillus-based medication on pain intensity scores in womenwith endometriosis.®and placebo groups.Lactobacillus capsules or placebo were administrated orally once a day for 8 weeks. Patients were assessed for painseverity using Visual Analogue Scale (VAS) scores for dysmenorrhea, dyspareunia and chronic pelvic pain at baselineand after 8 and 12 weeks post-intervention.The present randomized pilot placebo-controlled trial was done on eligible women whowere surgically and pathologically diagnosed with endometriosis. Thirty-seven participants who had not receivedhormonal treatment in the last three months, were enrolled and randomized into LactoFem®and control groups were compara-ble. All patients had stage 3 and 4 of the disease based on revised American fertility society (AFS) classification of endome-triosis. Mean initial pain scores for dysmenorrhea, dyspareunia and chronic pelvic pain were 6.53 ± 2.88, 4.82 ± 3.76 and4.19 ± 3.53, respectively in the LactoFem®group and 5.60 ± 2.06, 3.67 ± 2.64 and 2.88 ± 2.80, respectively for the controlgroup; the two groups had comparable scores in this regard. There was more decrease in pain scores for both dysmenorrheaand the overall pain after 8 weeks of treatment in LactoFem®group compared to the control group. The scores for dysmen-orrhea were 6.53 ± 2.88 and 5.60 ± 2.06 in the LactoFem®and control groups, respectively, before intervention but, after8-week treatment, these values were 3.07 ± 2.49 and 4.47 ± 2.13 (P=0.018), respectively. The changes in overall pain scorein the LactoFem® and control group during this period were 7.33 ± 7.00 and 4.11 ± 1.68, respectively (P=0.017).Mean age of participants and mean body mass index (BMI) for the LactoFemThis study showed some beneficial effects of lactobacillus administration on endometriosis-related pain(Registration number: IRCT20150819023684N5). Endometriosis, characterized by abnormal presence of endometrial tissue outside the uterus, is a major cause of discomfort in women . This disease which occurs primarily in women of reproductive ages, seems to be an estrogen-dependent phenomenon (1-3). Although clinical symptoms are not seen in all women, the impact of endometriosis on physical, psychological and social performance is obvious in many other women (4). Endometriosis-associated pain includes dysmenorrhea, dyspareunia, dyschezia and dysuria, as well as chronic pelvic pain. Endometriosis patients at some time points endure debilitating pain which is worse than the pain experienced by women suffering from cancer (2). Moreover, ovarian endometriosis may have clinical and paraclinical manifestations of ovarian carcinoma (5). The mainstay of treatment of endometriosis consists of surgery accompanied by ovarian suppressive therapy . Full consultation with patients and use of various types of analgesics, oral contraceptive pills, progestins or gonadotropin-releasing hormone agonists (GnRHa) are often required (8-12). There is sufficient evidence showing the efficacy of progestins and GnRHa against endometriosis-associated pain , however, their side effects and patient tolerance, particularly in the long term, should not be overlooked . Based on molecular studies, changes in the function of immunologic cells like monocytes, macrophages, natural killer cells (NK), cytotoxic T cells and B cells have been detected in the peritoneal fluid of women with endometriosis. This alteration of immunologic defense which is not capable of removing the ectopic endometrial cells, leads to implantation of endometriosis lesions. Furthermore, the paramount role of NK cells was highlighted in many studies (15-20). According to Oosterlynck et al. (17), decreased activity of NK cells is remarkably associated with the severity of endometriosis. Previous studies led to the hypothesis that lack of ectopic endometrial clearance by NK cells in the peritoneal fluid contributes to the development of the disease. Therefore, any agent that stimulates the immune cells or increases the cytotoxicity of NK cells could be beneficial in treatment of endometriosis (21-24). Lactobacillus acidophilus, Lactobacillus plantarum, Lactobacillus fermentum and Lactobacillus gasseri, constitute the predominant normal microbial flora of genitourinary and gastrointestinal (GI) tract of healthy individuals. The effectiveness of these probiotics in maintenance of the normal pH of vagina and prevention of genital infections has been well-studied (27). Host immunity modification and interference with colonization of external pathogens are considered their main mechanisms of action . There is also evidence that alterations in the normal flora within the gastrointestinal (GI) tract caused by administration of probiotics, antibiotics or even transplantation of feces into the GI tract, could result in pain relief by affecting neurologic pathways (30). In this regard, some recent studies indicated the use of lactobacillus-mediated medications in the treatment of endometriosis-related lesions . Considering the hypothesis that lactobacillus may have immunogenic properties, the present study was conducted to assess the efficacy of oral lactobacillus-based pills on pain relief in patients diagnosed with endometriosis. Sashihara et al. (21-23) showed that a kind of lactobacillus called Lactobacillus gasseri (OLL2809), which is of probiotic type, stimulates the production of interleukin 12 (IL-12) from murine spleen cells. IL-12, a cytokine secreted by antigen presenting cells, triggers the production of cytotoxic lymphocytes by activating NK cells and T cells . Lactobacillus species including This was a pilot randomized triple-blind placebo-controlled trial carried out in a referral center for endometriosis in a university-based hospital in Tehran, Iran from October 2016 to October 2017. Enrolled participants were women with endometriosis (diagnosed based on pathologic report) who had undergone laparoscopic surgery due to pain and were randomly allocated into one of the two groups at a 1:1 ratio. The study was approved by the Institutional Review Board of Iran University of Medical Sciences (IUMS) by the Ethical Committee number IR.IUMS.REC1395.9311290013. All participants were patients with stage 3 and 4 of endometriosis (according to the revised American fertility society (AFS) classification of endometriosis (33). Patients were between 18 to 45 years old with menstrual cycle ranging from 21 to 35 days, with initial overall pain score higher than 4 [based on the visual analogue scale (VAS) scoring system]. The overall pain score was defined as the sum of dysmenorrhea, dyspareunia, chronic pelvic VAS pain scores. A scale of 0 (without any pain) to 10 (most severe pain), by the use of a 10-cm ruler in the questionnaire filled by the physician at the initial visit and each follow up visit at 8 and 12 weeks post-treatment, was used in the VAS scoring. Patients had at least 3 months interval from surgery and in this period, they were not supposed to use hormonal treatment; also, the participants were asked not to take any pain-killer medications other than NSAIDs which have short-term effects and do not have interference with lactobacillus effects. Those with history of hormonal replacement after surgery, hepatic or renal disturbances, cancer, diarrhea after taking dairy products, or consuming any type of probiotic products were excluded. Written informed consent was obtained from all patients eligible for the trial. Data including demographic findings, medical history and medication use were recorded in questionnaires by a physician in the first visit and completed in the follow-up visits at 8 and 12 weeks post-treatment visits. The participants were asked to mention any kind of excessive GI upset, nausea, vomiting, or any other non-specific side effects.®, Zist Takhmir Co. Tehran, Iran (one capsule per day) or placebo (as the control group). Each LactoFem® capsule contains 109 colony of four different lactobacillus strains . The lactobacilli contents and placebo contents were packed in the similar packing with 30 capsules in each pack by the manufacturer; two packs were given to each patient in the first visit, to be used during the 8 weeks. The lactobacilli packs and placebo packs were named A or B by the manufacturer. After completion of the analysis, the manufacturer revealed which one was lactobacilli or placebo.The present study was a pilot placebo-controlled randomized clinical trial which recruited 20 patients for each arm . After exclusion of 3 patients, thirty-seven patients with endometriosis were randomly assigned (by simple randomization method using table of random numbers) to one of the two groups receiving either LactoFemAll women had undergone complete laparoscopic removal of endometriosis lesions including deep infiltrating endometriosis (DIE). The procedures had been performed with similar extent of resection including ovarian cystectomy (endometrioma), salpingectomy, ureteral dissection, uterosacral ligament ablation or DIE removal. The interval between surgery and commencement of intervention was at least 3 months. At the beginning of the study, patients were evaluated for the intensity of pelvic pain, dysmenorrhea, and dyspareunia based on the VAS score rated from zero (no pain) to 10 (the most severe pain). Patients in the two groups continued taking medication for 8 weeks and then, the pain intensity was evaluated again 8 and 12 weeks following intervention by a follow-up visit or a phone call. During the time of follow-up, patients were allowed to use NSAIDs only as the rescue therapy. Patients who were not willing to continue the trial due to personal reasons were excluded from the study. This study was conducted as a triple-blind trial in which the researcher, the subjects, and the statistician were all unaware of the allocation of the two groups. Results are presented as mean ± SD for quantitative variables and as absolute frequencies and percentages for categorical variables. Normal distribution of data was assessed using the Kolmogorov-Smirnoff test. Categorical variables were compared using chi-square test or Fisher’s exact test. Quantitative variables were also compared using t test or Mann U test. ANOVA test was also used to analyze more than two means. For statistical analysis, the statistical software SPSS version 20 for windows  was used. P.0.05 were considered statistically significant. The main outcome of the study was the mean pain score  after 8 and 12 weeks of intervention as assessed by VAS scoring system. The secondary outcome was the change in VAS scores during the first 8 weeks of intervention and from 8 to 12 weeks post medication.The two groups were comparable regarding mean age (P=0.955), body mass index (BMI) (P=0.14), history of infertility (P=0.669), irregular menstrual cycle (P=0.264), underlying disorders (P=0.307), and history of medications (P=0.600). Demographic characteristics of the subjects are demonstrated in Table 1. All patients had undergone laparoscopy beforehand and endometriosis was pathologically diagnosed in all participants. According to revised American fertility society (AFS) classification of endometriosis (33), stage III was found in 25 and 0% and stage IV was observed in 75 and 100% of intervention and control groups, respectively (P=0.101). ® group was significantly larger than that of the control group during 8 weeks of treatment . The decreases in mean pain scores from week 0 to 12 and from week 8 to 12 were not however statistically significant (P=0.051 and 0.191 respectively). Concerning chronic pelvic pain, the mean pain score decrease from week 0 to 8 was 3.35 ± 2.18 for the LactoFem® group and 3.03 ± 0.37 for the placebo group (P=0.119). The decrease in chronic pelvic pain score from week 0 to 12 was not significant (P=0.458). The change in pain scores from week 8 to 12, however, was significantly larger in the control group . Concerning the overall pain scores, the mean pain score decreased significantly in the LactoFem® group during 8 weeks of intervention in comparison to the placebo group . Moreover, the change in pain scores between week 8 and 12 was statistically different between the groups (P=0.015). No serious side effects following ingestion of these capsules were reported.As shown in Table 2, the mean pain scores at baseline as well as 8 and 12 weeks after intervention were not different between the groups. Using ANOVA analysis, the trend of the changes in pain intensity for dysmenorrhea, dyspareunia, and chronic pelvic pain during 12 weeks were evaluated. Concerning dysmenorrhea, the mean pain score decrease observed in the LactoFemThe aim of this study was to assess the therapeutic effects of oral lactobacillus on endometriosis-associated pain . Few studies were conducted until now on the effects of lactobacilli on pain complaints related to endometriosis. A review of these few studies indicated the beneficial impact of lactobacilli on endometriosis . This possible effectiveness could result from increases in interleukin-12 levels and NK cells activity (15-18). Also, decrement of the activity of natural lethal cells seems to be related to the severity of endometriosis, and the inability to clear the ectopic endometrial lesions by the NK cells in the peritoneal space, contributes to development of disease  which could be prevented by the use of probiotics. In a study done by Uchida and Kobayashi (32), lactobacillus therapeutic effect was evaluated in animal models following four weeks of treatment. It was finally observed that administration of lactobacillus was associated with a significant reduction in the volume of induced endometriosis in rats. Lactobacillus gasseri used by Itoh et al. (31). Although the mean pain scores for two groups (according to VAS) after 8 weeks and 12 weeks were comparable, a larger decrease in dysmenorrhea intensity and the overall pain scores in the LactoFem® group was seen after 8 weeks of treatment. This improvement in pain after 8 weeks was not significant for chronic pelvic pain and dyspareunia comparing with dysmenorrhea and overall pain scores. Quite interestingly, during the four weeks following cessation of LactoFem® (i.e. from week 8 to 12), the mean pain scores related to chronic pelvic pain and the overall pain intensity increased significantly compared to the control group. This increase could be due to the withdrawal effects of the LactoFem® and the fact that the efficacy of the lactobacillus is limited to the treatment duration only. Our study was the first randomized trial using lactobacillus-based medication on stage 3 and 4 of endometriosis regarding three common pain types in such patients. Given the progressive nature of endometriosis and unbearable pain episodes related to this disorder, any intervention that could mitigate its symptoms, is certainly invaluable. Compared to other conventional medical therapies used for endometriosis-associated pain, LactoFem® capsules have no remarkable side effects such as weight gain, flushing or abnormal uterine bleeding and no serious side effects following ingestion of these capsules were reported in our experiment.In another study (31), 33 patients with clinical diagnosis of endometriosis were given Lactobacillus gasseri capsules for 12 weeks. It was shown that 2 and 3 months post-treatment, use of lactobacillus was associated with significant improvements in pain intensity during menstruation in comparison with placebo. This finding was consistent with ours. The difference in pain scores during the first 8 weeks were apparently more in the mentioned study (31), and this was due to the lower initial pain scores post-surgical treatment in the present study. In both studies, no significant relief in non-menstrual pain was achieved. In our study, diagnosis of endometriosis was based on pathologic report and not just based on complaints of dysmenorrhea or other types of pain, which could be a strength of the present study. Furthermore, surgical staging was done based on the revised AFS classification. All the subjects had gone through laparoscopic surgery because of intolerable pain. An interval of at least 3 months was given to each patient before prescribing lactobacillus, to evaluate the effects of the surgical treatment. Lactobacillus-based medication used in our study consisted of four different strains of Lactobacilli including ® capsules are readily available in our country at a reasonable price. The finding that the remedial outcome of LactoFem® was not as significant as expected could be due to the limitations of our study. The first limitation was the small sample size which was not large as many patients had received hormonal therapy during 3 month interval before initiating the study. Also, some patients were not able to refer to the clinic for participation in the study. Another limitation that should be mentioned was the lower initial pain scores of the patients, due to the surgical treatment, which could affect both the sample size and the results. This trial was designed as a pilot study and we believe that in a larger study population, more robust results could be achieved. The dosage of lactobacillus capsules administered could be another limitation. Maybe at higher doses, more declines in pain scores could have been resulted. Moreover, changes in microbiome caused by lactobacilli were not evaluated which could be another limitation of this study. It should also be mentioned that it was not possible to design a cross-over study because of the limited time that many of the patients agreed to participate in the study, since many of them planned for in vitro fertilization (IVF) or pregnancy in the near future. Also, there was no similar study conducted within a longer time of follow-up to be sure how long the effect of lactobacilli could remain on pain suppression, therefore to avoid a bias in this field, we preferred a non-cross over design.Furthermore, these capsules modify microbiota of urogenital and GI tract and prevent from infections by improving immune system function. LactoFemIt seems that lactobacilli have some beneficial effects regarding endometriosis-associated pain including dysmenorrhea and chronic pelvic pain. Regarding the dysmenorrhea, the best results happened after 8 weeks of the lactobacilli consumption, which also caused a significant decrease in the overall pain over the course of lactobacilli use in our study. The findings of our research may be used for sample size estimation for further randomized trials to better evaluate the impact of lactobacilli on endometriosis and its related symptoms.


P < 0.05). The amelioration of 3 common symptoms, namely, limb pain, limb numbness, and insomnia, was evident, and the major response of common symptoms at month 6 including limb pain, insomnia, and limb coldness was significantly increased compared with the results at month 3 (P < 0.05). Moreover, 2-hour postprandial blood glucose (2hPG) level decreased from 10.77 ± 1.29 mmol/L at baseline to 9.66 ± 0.60 mmol/L at month 6 (P < 0.05). No serious adverse events occurred throughout the treatment period. The modified HGWD was effective in the treatment of moderate and severe pDPN and can thus be offered as a new alternative treatment option for pDPN patients who failed to respond to regular pharmaceutical therapies.Painful diabetic peripheral neuropathy (pDPN) is a debilitating complication of diabetes. The aim of this retrospective study was to investigate the effectiveness of a Chinese herbal medicine regimen—the modified Huangqi Guizhi Wuwu Decoction (HGWD)—in the treatment of moderate-severe pDPN. The primary objective was to estimate the improvement in neuropathic pain severity. The secondary objective was to assess the response of common symptoms to the treatment. The change in patients' blood glucose level during the whole treatment was also evaluated. By searching through our medical records of all the diabetic patients from January 2006 to January 2012, we identified and enrolled 30 moderate and severe pDPN patients in the study, for whom the treatment of neuropathic pain by regular pharmacotherapies had failed. The modified HGWD treatment was administered orally twice a day for 6 months. The numerical rating scale (NRS) level at month 6 was 2.57 ± 2.30, significantly improved compared with the baseline level of 6.03 ± 1.83 ( Diabetic peripheral neuropathy (DPN), one of the most common complications of diabetes mellitus, is defined as the presentation of symptoms and/or signs of peripheral nerve dysfunction in patients with diabetes after the exclusion of other causes . It has Traditional Chinese medicine (TCM), which has a thousand years of history in China and other Asian countries, is one of the major systems of complementary and alternative medicine. As the predominant branch of TCM, Chinese herbal medicine (CHM) is currently widely applied in the treatment of many diseases. The flexible modifications of herbal medicines, with various functions performed by each prescription, and the essential holistic theory of TCM allow CHM to reduce drug-drug and drug-condition interactions . RecentlTreatise on Cold-induced Febride Diseases in the Han Dynasty (3rd century AD). As a commonly used CHM formula able to stimulate blood circulation and enhance body motility, HGWD has been widely used in DPN for decades [Huangqi Guizhi Wuwu Decoction (HGWD), which was first recorded in a famous Chinese medical classic named  decades . We have decades . To furtThis study was a retrospective case series. Data for the study were obtained from the medical records of all diabetic patients who consulted our outpatient clinic of the Endocrinology Department in the Guang'anmen Hospital between January 2006 and January 2012. The study was approved by the Ethics Committee of Guang'anmen Hospital (Identification No. 20190614).Diabetic patients with moderate or severe neuropathic pain were enrolled in the study based on the following inclusion criteria: (1) pDPN diagnosed before patients were treated with modified HGWD, as determined by the patients' previous medical records; (2) failure of the treatment of neuropathic pain by regular pharmacotherapies such as pregabalin, duloxetine, or other therapeutic interventions; (3) discontinuation of all these interventions before treatment with modified HGWD in our outpatient clinic; (4) moderate or severe neuropathic pain present when they first received our modified HGWD treatment, with pain score at least 4 according to the numeric rating scale (NRS) ranging from 0 to 10, where 0 = no pain and 10 = worst possible pain ; (5) modQi and invigorating blood circulation. The basic formula consisted of 6 herbs: Astragali Radix (Huangqi in Chinese), Cinnamomi Ramulus (Guizhi in Chinese), Spatholobi Caulis (Jixueteng in Chinese), Paeoniae Radix Alba (Baishao in Chinese), Polygoni Multiflori Caulis (Shouwuteng or Yejiaoteng in Chinese), and Glycyrrhizae Radix (Gancao in Chinese)  . If the On the basis of the patients' preference, modified HGWD was administered in the form of decoction due to their trust in a traditional decoction method. The Chinese medicine material crude slices used for decoction were supplied and quality controlled by Kangmei Pharmaceutical Co., Ltd. , which were conformed to meet the standard of China Pharmacopoeia (2015 edition) . All herData from the patients' medical records were manually collected and examined manually by two researchers from our outpatient clinic. The demographic and clinical characteristics of the pDPN patients were recorded at baseline, including age, sex, body mass index (BMI), and diabetes history . The effectiveness of the modified HGWD treatment was recorded and evaluated at 3 and 6 months compared with baseline, based on the primary and secondary objectives. Additional telephone interviews were conducted when needed to supplement the data obtained from the medical records.The primary objective was to estimate the improvement in neuropathic pain severity in these pDPN patients. Neuropathic pain severity was measured by the score of the numeric rating scale (NRS) as reported in the medical records.The secondary objective was to assess the response of common symptoms, where “major response” referred to improvement by 50% or more, “minor response” referred to improvement less than 50%, and “no response” referred to no improvement or worsening. The response rate was defined as the sum of the major response rate and minor response rate. The reproducibility of the rating method was demonstrated by a separate, blinded grading by two researchers on the patients' medical records.The change in patients' blood glucose during the whole treatment was also evaluated, including glycated hemoglobin level (HbA1c), fasting blood glucose (FBG), and 2-hour postprandial blood glucose (2hPG). The measurements were carried out in the laboratory of Guang'anmen Hospital.P values < 0.05 were considered statistically significant.All data were analyzed using the SPSS 20.0 software . Regarding demographic and clinical characteristics at baseline, quantitative variables were reported as the mean ± standard deviation (SD) and qualitative variables as frequencies and percentages. The severity rate of neuropathic pain measured by the NRS score was presented as the mean ± SD. Common symptoms were defined as the 10 symptoms most frequently occurring in our cohort at baseline, month 3, and month 6. HbA1c, FBG, and 2hPG levels were reported as the mean ± SD. Since some patients neglected to undergo laboratory examinations at the time of return visits, missing data were processed by deleting the records with too many missing variables, then interpolating with the mean values to replace missing values in the remaining records. One-way ANOVA was used to compare NRS scores among the groups, and one-way ANOVA followed by a LSD (Least Significant Difference) post hoc test was used to compare HbA1c, FBG, and 2hPG levels among different times. A chi-square test was used to compare the response rate of common symptoms between months 3 and 6. 2  were eligible according the inclusion and exclusion criteria and were enrolled in this study. The mean age of the included patients was 59.00 ± 12.28 years (range: 20 to 75 years). Twenty-nine patients (96.67%) had been diagnosed with type 2 diabetes and only one (3.33%) with type 1 diabetes. The mean duration of diabetes at the time of diagnosis was 10.32 ± 7.50 years (range: 0.5 to 40 years), and the mean BMI was 23.60 ± 3.39 kg/mP < 0.05). After 6 months of modified HGWD treatment, compared with baseline, 8 patients recovered from moderate neuropathic pain, 10 patients turned from moderate to mild neuropathic pain, 1 patient turned from severe to mild neuropathic pain, and 6 patients with severe pain turned to moderate pain, while only 5 patients remained unchanged. The mean NRS level at month 6 was 2.57 ± 2.30, and the improvement was statistically significant compared with both baseline (P < 0.001) and month 3  and 8 were evaluated to have severe neuropathic pain (26.67%) at baseline. The mean NRS score was 6.03 ± 1.83. All patients had received regular pharmacotherapies for treating neuropathic pain without satisfactory results before visiting our outpatient clinic. After being treated with modified HGWD for 3 months, 2 patients recovered from moderate neuropathic pain and did not require further medical attention, 8 patients turned from moderate to mild neuropathic pain, and 2 turned from severe to moderate neuropathic pain, while 18 patients (12 with moderate and 6 with severe pain) remained unchanged. The mean NRS level was 4.20 ± 2.41, and the difference with baseline was significant (P < 0.01), and the major response of limb coldness at month 6 was also significantly increased after 3 months (P < 0.05). However, the response rate of common symptoms, which was the sum of the major response rate and minor response rate between months 3 and 6 showed no obvious difference . The mean FBG level was 8.37 ± 2.65 mmol/L at baseline and decreased to 7.01 ± 1.14 mmol/L at month 6, but there were no significant differences comparing baseline, month 3, and month 6 (P > 0.05). The 2hPG level was 10.77 ± 1.29 mmol/L at baseline and decreased to 9.66 ± 0.60 mmol/L after 6 months of treatment; the difference with both baseline and month 3 was statistically significant (P < 0.05)  .During the 6 months of treatment, there was no report of any serious adverse events, and none of the patients progressed to diabetic foot ulceration or amputation.In the present retrospective case series study, we investigated the efficacy of modified HGWD treatment on pDPN by analyzing and evaluating the medical records of 30 pDPN patients with moderate or severe neuropathic pain. The study applied NRS to measure the neuropathic pain level of the pDPN patients. NRS is one of the widely accepted pain rating scales which are commonly used in judging neuropathic pain in DPN. Compared with other scales, NRS has greater sensitivity and is the choice of most people in clinical practice . Our resTo our knowledge, the present study is one of the very few clinical studies showing a promising effect on pDPN patients with moderate and severe peripheral neuropathic pain by the oral administration of complementary and alternative medicine, with the added advantage of providing a comprehensive, multitarget effect on various clinical manifestations of pDPN. Other complementary and alternative medicine practices, such as acupuncture  and acupoint injection, were also shown to lead to pain improvement in DPN –26. TopiQi deficiency to appear at this time. According to TCM, the movement of Qi is a significant factor in maintaining health during the whole lifespan, as it promotes blood circulation [Qi is consumed and gradually becomes deficient, leading to blood stasis. Many herbs and minerals were confirmed to have the function of invigorating Qi and blood movement. However, TCM practitioners often use a combination of multiple herbs or minerals to compose CHM formulas based on TCM principles, instead of a single herb or mineral, an approach that focuses on enhancing clinical efficacy by targeting complex pathogenetic mechanisms. In Tong's outpatient clinic, he applied the principle of nourishing Qi and promoting blood circulation to treat pDPN patients and chose the HGWD regimen including some herbs with the specific function of relieving neuropathic pain [DPN usually occurs in mid- or late-stage diabetes, and TCM theory considers culation . During hic pain , 32.Qi, and Qi deficiency is considered a primary factor for the occurrence of neuropathic pain [Qi deficiency diseases. It has been proved that the active component of Cinnamomi Ramulus, cinnamomi acid, exerts an analgesic action against neuropathic pain by inhibiting spinal pain transmission, and the mechanism may be related to its agonist action on transient receptor potential ankyrin 1 (TRPA1) [α-glucosidase and fatty acid synthase (FAS) activity [HGWD, a classic CHM formula, has been used by TCM practitioners for the clinical treatment of DPN for a long time. There are evidences that HGWD improves DPN clinical symptoms and ameliorates nerve conduction velocity while decreasing the plasma viscosity of DPN patients , 34. A phic pain . Pharmachic pain , 38. Cin (TRPA1) , 40. Spa (TRPA1) , 42. Pae (TRPA1) . Another (TRPA1) . Polygon (TRPA1) . Studies (TRPA1) . The extactivity , 48.The present study has some limitations. First, due to its retrospective nature and its reliance on past medical records, some important data were inevitably missed or difficult to obtain. Second, the study did not have a control group because it is rather difficult for us to enroll moderate to severe pDPN patients who have not taken Chinese medicine in the clinic, so we could not present a comparison of pDPN patients with and without modified HGWD treatment. Moreover, long-term outcomes and quality of life were not observed, because the follow-up was limited. Despite these limitations, we believe the present study is of value since it is the first clinical study to explore the effect of oral administration of complementary and alternative medicine on pDPN patients with moderate to severe neuropathic pain. The study can lay a foundation for later researches of complementary and alternative medicine in the treatment of DPN patients who suffers intolerable neuropathic pain.In order to obtain evidence of higher quality on the efficacy of modified HGWD in the treatment of pDPN, our team has conducted a prospective, double-blinded, randomized controlled trial to further explore the curative effects, safety, and feasibility.In summary, modified HGWD appeared to be effective and safe in the treatment of DPN with moderate or severe neuropathic pain, thus presenting a new alternative option for pDPN patients who failed to respond to regular pharmaceutical therapies. During our 6 months of study, pain relief and improvement of common symptoms were clearly shown. However, further studies like randomized clinical trials are inevitably needed to obtain higher quality evidence on the effects of modified HGWD on DPN, particularly in the long term.