Previously, we have shown that the transcutaneous application of carbon dioxide causes absorption of CO2 and increase the oxygen (O2) pressure in the treated tissue; it is expected that the application of CO2 may reduce scarring and pain caused by cancer treatment. We newly introduced the CO2 paste as a new CO2 application method, which does not need to use CO2 gas directly. In this study, we aimed to apply of CO2 paste to healthy people and to investigate its usefulness, safety and feasibility by analysing the increase in blood flow and frequency of adverse events.Scarring and pain are postoperative complications in patients after head and neck cancer treatment; however, there is no effective treatment. These complications are affected by local blood flow disorders, and it is well known that the transcutaneous application of carbon dioxide  significantly increased 60 seconds after application. In the surface layer of the lower leg, the SI was significantly increased 60 and 300 seconds after paste application. Although mild heat was noted after the paste application, no obvious adverse events occurred.We demonstrated the increase in SI by dynamic MRI at the site of the carbon dioxide paste application, which indicates the paste application is effective in improving the blood flow. In humans, people with sickle cell anaemia experience extreme pain during vaso-occlusive episodes, whereby sickle-shaped red blood cells obstruct blood vessels, resulting in tissue ischemia. Chronic ischemic pain is also reported in patients with peripheral arterial diseases. Chronic pain after neck dissection is considered to be related to local vascular disturbances other than surgical neuropathy. Various medications have been used to improve these postoperative neuropathic pains–7; however, they have some side effects and they insufficiently reduce chronic pain.,9 Therefore, none dramatically relieve postoperative suffering of cancer patients. Chronic postoperative pain may be resolved if the blood flow of scar tissue can be improved.The current main treatments for head and neck cancer are surgery, chemotherapy and radiotherapy. Postoperative complications, such as scarring and pain, which remain for a long time after these treatments, cause physical and psychological suffering for patients, even though the cancers are completely cured. Chronic pain, such as postoperative pain, is associated with vascular dysfunction, and there are many reports about microvascular disturbances in neuropathic pain animal models and humans with neuropathic pain.2 in a hydrogel as an absorption-promoting agent for healthy people and various animal models.–12 The transcutaneous CO2 application increased the number of mitochondria, increased muscle fibre switching, promoted vascularization, and improved the exercise performance in rats. In other studies on healthy people, the CO2 application improved the microcirculation and increased the transcutaneous oxygen causing an artificial Bohr effect. CO2 causes dissociation of oxygen from haemoglobin, promoting local oxygenation. However, it is difficult to apply this method to the head and neck area because it requires covering the application site and using CO2 gas. Focusing on the effect of the transcutaneous CO2 application as described above, we introduced a CO2 paste for a CO2 effect in the head and neck area. This new application mechanism does not directly use CO2 gas, but rather uses a paste that reacts with the water on the skin surface, which then generates CO2 gas. In this study, we aimed to apply of CO2 paste to healthy people and to investigate its usefulness, safety and feasibility by analysing the increase in blood flow and frequency of adverse events.Previously, we reported the effects of the transcutaneous application of COEleven healthy volunteers participated in this study. The subjects were 9 males and 2 females, aged 24 to 35 years . Subjects who met the following conditions were excluded; firstly, those allergic to drugs, secondly, those with peripheral artery disease, ischemia (Fontaine III-IV), thirdly, those with heart failure (NYHA class IV), fourthly, those who are pregnant or have the possibility to be pregnant, fifthly, those with severe respiratory disease, sixthly, those who have difficulty applying the paste, such as to large skin ulcers or those with significant skin diseases, seventhly, those with claustrophobia, and finally, those who were deemed inappropriate by the researcher or the attending physician. Each subject provided written informed consent before participating in this study. This study was approved and permitted by the Ethical Committee of Kobe University Graduate School of Medicine. The approval number is No.300013.2 paste for 20 minutes, and a post-observation period for 1 week. First, the screening of the subjects was performed. After the screening, we applied CO2 paste to the subject's skin. The CO2 paste was applied to the neck area and the lower legs to examine the effect to deep muscles. CO2 paste was applied only once with fingers to the skin of the lower leg and neck surface, the areas corresponding to the sternocleidomastoid and gastrocnemius muscle. Twenty minutes after the application, the paste was removed by wiping or rinsing. We then evaluated the effect of the CO2 paste by dynamic MRI. Subjective symptoms, such as pain, heat sensation, and discomfort, were evaluated by a Visual analogue scale (VAS). The patient's vital signs were also checked before, 10 minutes after and 1 week after the application of the paste, including the blood pressure and oxygen saturation (SpO2).This study is a single-arm clinical trial. After informed consent, the study period was for a total of 5 weeks, including a pre-observation period within 4 weeks, application of the CO2 paste invented by NeoChemir Inc. (“direCO2t”). The paste contains sodium bicarbonate and malic acid as components for generating CO2 gas. When we apply it to skin, the paste reacts with the water of the skin surface, generating CO2 gas. This CO2 paste was applied evenly on the skin of the neck and lower leg. Twenty minutes later, the pate was wiped off.In this study, we used COAll MR imaging was performed with a 3.0-tesla system  using a 32-channel cardiac coil. The BOLD MR imaging protocol was a single-shot multi-echo gradient-echo echo-planar imaging sequence with fat suppression with the following parameters: repetition time (TR), 1000 ms; echo time (TE), 4 echoes at 6.9, 19.5, and 44.5 ms; slice thickness, 4 mm; field of vision (FOV), 200 × 400 mm; and imaging matrix, 115 × 128. The slice position was set at the proximal quarter of the lower left leg and the neck area was taken at the centre of the sternocleidomastoid muscle. We performed dynamic measurement with a temporal resolution of one measurement for a consecutive series for 700 measurements of the whole phase. The paste was applied in the MR gantry with the first 30 seconds as a baseline. Imaging was performed for about 10 minutes after paste application.2 paste using the signal intensity ratio.We set regions of interest (ROI) in the MR images. In the neck area, the ROI was set at the centre of the sternocleidomastoid muscle. In the lower leg, the ROI was set in the three layers, superficial, middle and deep areas of the gastrocnemius muscle Fig. . The datU test. Subjective symptoms and vital signs were analysed by Wilcoxon signed-rank test. The level of statistical significance was set at P < .05.Statistical analyses were performed with BellCurve for Excel . The results of the signal intensity ratio were analysed using the Mann–Whitney Of 11 subjects, three were excluded due to body movement during MRI imaging that caused inaccurate imaging results. We analysed only data from 8 volunteers Table . An imprThe results of the signal intensity ratio of the eight subjects are shown in the following table. The average signal intensity ratio of the neck area at 60, 300, and 600 seconds after paste application are 106.1 ± 7.5%, 103.2 ± 5.5%, and 102.3 ± 3.8%, respectively. The average signal intensity ratio of the surface layer of the lower legs at each point are 101.9 ± 0.8%, 100.8 ± 1.5%, and 101.7 ± 1.5%. Those of the middle layer of the lower legs are 101.8 ± 2.2%, 101.0 ± 2.9%, and 101.6 ± 2.6%. In the neck and middle layer of the lower leg, a significant increase was observed in the signal intensity ratio 60 seconds after the paste application. In the surface layer of the lower leg, significant differences were observed 60 and 300 seconds after the application compared with the ratio before the application . There were no complaints of pain or discomfort in all eight subjects  in this study. Therefore, it is necessary to examine the effects of CO2 on actual patients with oral cancer because the effect of CO2 may differ from the results of this study. The CO2 paste used in this study is very safe, simple to use, and has been shown to be useful as a new CO2 transcutaneous absorption method applicable to the head and neck region. This paste is expected to be used clinically for the purpose of preventing skin flap necrosis, improving symptoms of wrinkles after radiotherapy and scarring after surgical treatment by utilizing its hypoxic environment improvement effect. This method may be applied to oral cancer patients, which may receive additional postoperative treatments such as radiotherapy and chemotherapy. It is also necessary to carefully study the influence of CO2 paste on tumours when combined with additional post-operative treatment.Surgical dissection of the neck and post-radiotherapy peripheral nervous system damage induce neuropathic pain.2 paste that can capture carbon dioxide percutaneously in tissue. No serious side effects were observed with the CO2 paste application, indicating its potential as a new treatment for scars and pain after head and neck treatment.In this study, an increase in blood flow was observed in dynamic MRI image evaluation by applying COhttps://en-author-services.edanzgroup.com/) for editing a draft of this manuscript.We thank Ashleigh Cooper, PhD, from Edanz Group (Conceptualization: Takumi HasegawaData curation: Daisuke Takeda, Izumi Saito, Nanae Yatagai, Rika Amano, Satomi Arimoto, Yasumasa KakeiFormal analysis: Katsusuke Kyotani, Tomohiro NodaFunding acquisition: Takumi HasegawaInvestigation: Daisuke Takeda, Izumi Saito, Nanae Yatagai, Rika Amano, Satomi Arimoto, Yasumasa KakeiMethodology: Takumi HasegawaProject administration: Masaya Akashi, Takumi HasegawaResources: Takumi HasegawaSupervision: Masaya AkashiValidation: Katsusuke Kyotani, Tomohiro NodaVisualization: Katsusuke Kyotani, Tomohiro NodaWriting – original draft: Nanae YatagaiWriting – review & editing: Takumi Hasegawa


Attention-deficit/hyperactivity disorder (ADHD) has been reported to be associated with primary chronic pain syndromes, such as fibromyalgia, migraine, and chronic low back pain. Although idiopathic orofacial pain (IOP) is classified as burning mouth syndrome or persistent idiopathic facial or dentoalveolar pain and as a primary chronic pain, the association between IOP and ADHD has not been investigated. This retrospective cohort study investigated the severity of ADHD symptoms measured using the ADHD scale and the effects of treatment using ADHD drugs and the dopamine system stabilizer aripiprazole. The participants were 25 consecutive patients with refractory IOP referred to a psychiatrist and diagnosed with coexisting ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-5. The ADHD scale scores were higher in patients with intractable IOP than those in the general population. Pharmacotherapy used in this study led to clinically significant improvements in pain, anxiety/depression, and pain catastrophizing. Intractable IOP and ADHD were shown to be associated. In the future, screening and pharmacotherapy for ADHD should be considered in the treatment of intractable IOP. Pain is usually persistent, moderately intense, non-localized, and described as dull, oppressive, or burning. IOP is further classified as burning mouth syndrome (BMS), persistent idiopathic facial pain (PIFP), or persistent idiopathic dentoalveolar pain (PIDAP). BMS is characterized by bilateral, superficial, persistent pain in the oral mucosa, with a predilection for the lingual apex, lingual border, and palate; it occurs more commonly in women than in men, especially after menopause2. PIFP is persistent facial and/or oral pain of unclear localization with various symptoms and female predilection3. PIDAP is a deep pain in the teeth and alveolar region with well-defined localization, relatively low age of onset, and little gender difference; 70–83% of incidences are triggered by dental treatment4.According to the International Classification of Orofacial Pain (ICOP), 1st edition, idiopathic orofacial pain (IOP) is defined as unilateral or bilateral intraoral or facial pain of unknown etiology in the distributions of one or more branches of the trigeminal nerve(s)5 and 0.03%6, respectively. However, in clinical settings, such as oral-facial pain clinics, the incidence is reportedly 7.72% for BMS7, 10–21% for PIFP at orofacial pain clinics3, and 2.1% for PIDAP at tertiary medical centers4.The incidences of BMS and PIFP, including PIDAP, in the general population, are 0.1–3.9%8, and tricyclic antidepressants (TCAs)9 and cognitive behavioral therapy10 are likely to be effective. IOP is a difficult disease to treat as its response to various therapies is inconsistent, with limited efficacy. IOP has a spontaneous remission rate of 3–4% even 5–6 years after the diagnosis is confirmed11, and patients with IOP may visit several dentists and doctors to understand the cause of their pain and for effective treatment. Although dental procedures may provide temporary improvement in the symptoms, they may subsequently reoccur in other teeth and the original locations, triggering a vicious cycle of further invasive procedures at the patient's request and despite the dentist's good intentions. Over the course of this process, the patient may lose multiple healthy teeth and experience pain in the entire orofacial region. Therefore, clinicians have great difficulty in managing patients with IOP12.The pathophysiology of all three disorders is unclear; however, psychosomatic factors and central nervous system dysfunction are reportedly involved8. In addition, the majority of the patients also had one or more other chronic pain symptoms, and almost all patients had other pain symptoms when they developed orofacial pain, suggesting that the three IOP disorders have common vulnerabilities to chronic pain and psychiatric disorders. IOP disorders are reportedly caused by dysfunction of the dopaminergic system, and it has been proposed that they are on the same neuroplastic pain spectrum, only with different degrees of disability13.It was reported that 41.3% of patients with IOP had a history of a mental disorder before the onset of pain, approximately half of the patients had long-term psychiatric disorders, and one-third had a psychiatric comorbidity at the time the survey was conducted, indicating that mental disorders show a chronic, long-term course. The most common psychiatric comorbidities were major depression, anxiety disorder, and Diagnostic and Statistical Manual of Mental Disorders-5 (DSM-5) anxious and fearful Cluster C personality disorders 14. The pathophysiology of ADHD is dysfunction of the dopaminergic and noradrenergic nervous systems. Psychostimulants that enhance dopamine neurotransmission, selective noradrenaline reuptake inhibitors, noradrenergic alpha-2 receptor agonists15, and dopamine system stabilizers16 can improve ADHD symptoms. Previous studies suggested that ADHD is associated with fibromyalgia22, migraine23, and chronic low back pain25. These pain disorders are classified as primary pain syndromes in the International Classification of Disease, Eleventh Revision26, suggesting that ADHD is likely to coexist with chronic primary pain. IOP is also classified as a type of primary chronic pain; however, although no previous reports on a connection between IOP and ADHD are available, similar to IOP, patients with ADHD are more likely to experience depression, anxiety disorders, and DSM-5 anxious and fearful Cluster C personality disorders than the general population27. As the neuropathology of ADHD is also thought to be caused by dopaminergic system dysfunction28, IOP and ADHD may coexist as they share common origins.Attention-deficit/hyperactivity disorder (ADHD), a developmental disorder, is also reportedly associated with chronic pain. ADHD is characterized by attention deficit, hyperactivity, and/or impulsivity, which persists for a relatively long period from childhood to adulthood and causes dysfunction in daily livingHerein, we conducted a retrospective cohort study of patients with intractable IOP referred to a psychiatrist by specialists in psychosomatic dental care due to difficulty in managing their symptoms to delineate the characteristics of refractory patients. This study focused on the severity of ADHD symptoms measured using the ADHD scale, and the effectiveness of treatment using ADHD drugs and the dopamine system stabilizer aripiprazole (APZ) in intractable IOP.This cohort study retrospectively investigated the ADHD scale scores and ADHD diagnoses in patients with refractory IOP during the initial visit to examine whether there is an association between intractable IOP and ADHD. The severity of ADHD symptoms was assessed using Conners' Adult ADHD Rating Scale (CAARS), and ADHD was diagnosed according to the DSM-5. The attending psychiatrist (S.K.) routinely performs the CAARS evaluation at the patient's first visit.We reviewed the clinical assessments of pain, mood, and catastrophic thinking conducted by the psychiatrist in every routine session, along with the medication algorithms followed by the psychiatrist in his usual practice, and evaluated the results of the practice through longitudinal analysis. Pain intensity was assessed using the Numerical Rating Scale (NRS), mood using the Hospital Anxiety and Depression Scale (HADS), and catastrophic thinking using the Pain Catastrophizing Scale (PCS), and compared before and after treatment. Dr. SK routinely evaluated patients using the "Pain NRS," the "HADS", and the "PCS”, and provided feedback on the scale scores to the patients at each visit.Thirty consecutive patients with refractory IOP were referred to a psychiatrist (S.K.) at the Pain Center of our university hospital between May 2016 and March 2020 with suspected somatic symptom disorder after it was determined that treatment would be difficult by a specialist in psychosomatic dentistry at a tertiary medical center. The diagnosis of IOP was made by a specialist in psychosomatic dentistry who referred the patient. The definition of intractable IOP is undefined; therefore, we defined this condition as a strong and lasting IOP that did not respond to psychoeducation, psychotherapy, and the use of three or more medications . These patients were treated by their dentist and referred to our university hospital because further treatment was difficult. This retrospective cohort study was conducted in accordance with the Declaration of Helsinki of the World Medical Association.Of the 30 patients with intractable IOP mentioned above, patients diagnosed with ADHD were included as the subjects in this study. Patients under 18 years of age or with impaired judgment due to severe psychosis, manic status, or depression were excluded from this study.30. The CAARS-S and CAARS-O have eight subscales and calculate the T-scores for each. Patients with a T-score greater than 65 on the CAARS-S or CAARS-O were classified as CAARS positive, indicating a clinically significant level of ADHD symptoms. The CAARS is widely used as a measure of ADHD symptoms in adults aged ≥ 18 years.All participants and their families were instructed to answer the long version of the Connors' Adult ADHD Rating Scale Self-Report (CAARS-S) or the observer-version (CAARS-O) at the time of their first medical examination in this study14. The diagnosis was verified using the semi-structured Diagnostic Interview for ADHD in Adults 2.0 (DIVA 2.0)31 conducted on the first visit as well. DIVA 2.0 provides typical examples of dysfunction in the 18 diagnostic criteria for ADHD and in five domains  caused by the ADHD symptoms in daily life from childhood through adulthood, and is an aid to ADHD diagnosis. According to the DSM-5 diagnostic criteria, ADHD in a person aged > 17 years is diagnosed if at least five of the nine inattention symptoms or at least five of the nine hyperactive/impulsive symptoms are present. ADHD is classified into three types: predominantly inattentive, predominantly hyperactive-impulsive, and combined.Diagnosis of ADHD was made by a psychiatrist (S.K.) at the time of the first visit according to the criteria of the DSM-532, an 11-point pain rating scale, with 0 indicating no pain and 10 indicating the highest pain. The NRS assesses the maximum, minimum, and average pain intensities of patients. The minimum clinically important difference (MCID) was a −1 point (or −15.0%) decrease on the NRS. A reduction of −2 points (or −33.0%) or more on the NRS is considered an optimal improvement33.Pain duration (months) was defined as the period from the onset of IOP to the patient’s first visit to our pain center. Pain intensity was evaluated using the NRS34. The HADS is a validated assessment scale for screening psychological distress in non-psychiatric patients in clinical practice consisting of 14 questions, seven of which form a subscale for assessing anxiety (HADS-A), and the remaining seven form a subscale for assessing depression (HADS-D). All items were scored on a 4-point scale ranging from 0 to 3, with 21 points each for HADS-A and HADS-D as the highest score. HADS-A/D results of 8 points or higher on each subscale were considered clinical manifestations of anxiety and depression35. Based on previous studies, the MCID of the HADS was set to 1.536.Anxiety and depression were evaluated using the HADS37. More intense catastrophic thinking increases the intensity of pain and daily life disability and increases the likelihood of the pain becoming chronic38. PCS is a self-administered questionnaire comprising 13 items; the scores for each question range from 0 to 4, with a possible total score of 0 to 52 points. A total of 30 points on the PCS corresponded to the 75th percentile of PCS score distribution in patients with chronic pain. Patients with a score above the 75th percentile were at high risk of developing chronic pain39. MCID for PCS was between 38 and 44%40.Catastrophic thinking associated with pain was evaluated using the PCS30. The results of the two-tailed independent samples t-test were expressed as mean differences and 95% confidence intervals (CIs). The changes in outcome variables from an individual baseline to the endpoint were analyzed using paired-sample tests. The points and percent improvement in pain NRS per dental diagnosis were evaluated using one-way analysis of variance and Tukey’s test for post-hoc analysis. The statistical significance level was set at P < 0.05 for convenience; however, considering the risk of type 1 error, its interpretation should be limited to that of a reference to observe the overall trend only. In addition, P values adjusted by the Bonferroni method are provided as corrected P values.Statistical analyses were performed using the JMP Pro version 16 . Since CAARS separates Japanese standardized groups for men and women, the CAARS subscale scores for IOP patients with ADHD were analyzed separately for men and women with the Japanese standardized group15. In cases where MP did not result in sufficient improvement or with intolerable adverse effects, the patient underwent combination therapy with MP and the selective norepinephrine reuptake inhibitor atomoxetine (ATX)15 or switched to ATX. In cases where ATX administration did not result in sufficient improvement or with intolerable adverse effects, the patient underwent combination therapy with APZ or switched to APZ. APZ is a partial agonist of dopamine D2 receptors; it is also called a dopamine system stabilizer as it suppresses excessive dopamine activity, or activates it when dopamine is underactive15. APZ is thought to improve ADHD16, chronic pain41, and IOP43. In cases where APZ administration did not result in sufficient improvement or with intolerable adverse effects, the patient underwent combination therapy with clonidine, a noradrenergic alpha 2 receptor agonist that is effective for ADHD15, or switched to clonidine. The therapeutic effects on pain NRS, HADS, and PCS were judged 2 months after the prescription was revised with sufficient improvement, in the absence of any side effects that prevented the patients from continuing the drug.The medication algorithm used by Dr. SK in his usual practice is shown in Fig. This study was approved by the Research Ethics Committee of Tokyo University Hospital . Informed consent was obtained orally from all subjects on the occasion of clinic visit, and all subjects provided written informed consent for participation in and publication of this study. Furthermore, the participants were guaranteed the opportunity to withdraw or refuse participation and informed that they could opt out of this study through the University of Tokyo Hospital website homepage.To elucidate the clinical characteristics and treatment methods of intractable IOP with ADHD, of the 30 consecutive IOP patients referred, 25 patients with both IOP and ADHD (83.3%) were included in our analyses.In the IOP subcategory, 14 patients had BMS, six had PIDAP, and five had PIFP. Table Among the 25 patients, 19 (76.0%) had a history of psychiatric treatment, with somatic symptom disorder in nine (36.0%), depression in 10 (40.0%), anxiety disorders in five (20.0%), bipolar disorder in one (4.0%), post-traumatic stress disorder in one (4.0%), dissociation disorder in one (4.0%), and suicide attempt in one patient (4.0%). All 19 patients with a history of psychiatric treatment underwent psychiatric pharmacotherapy; however, there was no improvement in the symptoms of chronic orofacial pain.The number of items of the diagnostic criteria for ADHD in the DSM-5 (inattention/hyperactivity-impulsivity) that each patient met is shown in Table 30 is also shown in Table The mean scores of the eight subscales (A-H) of the CAARS-S and CAARS-O in patients with IOP are summarized in Table Among the eight subscales of the CAARS, subscales E, F, and G assess the extent to which a patient's ADHD symptoms meet the criteria of DSM-IV; subscale H, called the ADHD index, indicates the extent to which a patient's ADHD symptoms require treatment. Except for the CAARS-S subscale E for men, which was not significantly different from the standardized sample, both male and female patients with intractable IOP in this study had significantly higher scores on subscales E, F, and G on both CAARS-S/O compared with standardized samples. On subscale H of the CAARS-S/O, both male and female patients with intractable IOP scored significantly higher than the standardized sample on the CAARS-S/O.P = 0.01), CAARS-O subscale E , CAARS-O subscale F , CAARS-O subscale G , and CAARS-O subscale H .Furthermore, although not shown in Table Five of the 25 patients with IOP diagnosed with ADHD did not undergo pharmacotherapy . The changes in the pain scale scores before and after treatment for the 20 patients  who underwent pharmacotherapy according to the treatment regimen used in this study are shown in Table P = 0.059); however, there was a significant difference in the percentage of improved NRS   = 5.50 P < 0.05), and post-hoc analysis (Tukey’s test) showed a significant difference in PIDAP vs. PIFP (P < 0.05).The administered dose of each medication and the percentage improvement in the average NRS for pain are shown in Table This study demonstrated that a high percentage (83.3%) of the 30 patients with intractable IOP had ADHD, and the CAARS-S/O DSM and ADHD index scores for patients with refractory orofacial pain were higher than those for the general population in almost all cases. Moreover, the pharmacotherapy used in this study, consisting of ADHD medication and a dopamine system stabilizer, may result in significant clinical improvements in pain, anxiety, depression, and pain catastrophizing.In this study, 25 of the 30 patients with refractory orofacial pain  were diagnosed with ADHD. To the best of our knowledge, no previous surveys have investigated the incidence of ADHD in patients with IOP. This study revealed that ADHD occurs frequently in patients with refractory IOP. Therefore, we believe that the results of the present study provide a new perspective on the clinical care of and research on patients with IOP. However, given the specific referral source and small sample size in this study, the rate of ADHD comorbidity in patients with intractable IOP should only be viewed as an indication of the overall trend.44. In addition, Young et al. reported that 80% of patients with fibromyalgia had ADHD19. The findings reported in these studies are similar to that of the present study. In contrast, other studies21 reported that the incidences of ADHD among patients with fibromyalgia were 25% and 29.5%, respectively, indicating large discrepancies between the studies. There are cases in which the patient does not recognize the symptoms of ADHD; thus, assessments by family members and other third parties are important. However, in a previous survey of ADHD on patients with fibromyalgia, the Wender Utah Rating Scale45 or the Adult ADHD Self-Report Scale-V1.146 was used, and in both cases, only the patient himself/herself was expected to answer the questionnaire. In contrast, the CAARS used in this study instructed the patients and their families to answer the questionnaire. To ensure the accurate clinical assessment of ADHD, it is important to obtain information from multiple sources, and it is preferable to collect information from both self-reports by the patient and observer reports by family members and other third parties29. It is preferable to refer to the findings obtained from family members on the CAARS-O when diagnosing ADHD using the structured interview of the Conners’ Adult ADHD Diagnostic Interview for DSM-IV47. Furthermore, in clinical interviews, it is easier to extract information that contributes to the diagnosis by asking the patient questions by referring to the answers to each CAARS question by the patient and his/her family29. Therefore, we believe that it is important to screen for and diagnose ADHD using both the CAARS-S and CAARS-O.A study of 153 patients with chronic pain, including lower back pain and widespread pain, reported the coexistence of ADHD in 72.5% of the cases49. A study on ADHD subtypes comorbid with fibromyalgia in adults reported that approximately one-third of the cases were inattentive and about two-thirds were combined50. Therefore, comorbidities with chronic pain may more likely present in the combined subtype than in other ADHD subtypes. Based on our experience, the characteristic feature of ADHD in patients with IOP is difficulty in continuing with time-consuming treatment; that is, they tend to opt for risky treatments and on not experiencing improvement immediately, they tend to go from doctor to doctor, displaying impulsive behavior. The symptoms of inattention are being prone to derailed and uncoordinated conversations.The ADHD subtypes identified in the present study were inattentive (12.0%), hyperactive (8.0%), and combined (80.0%). Although there are no reports on ADHD subtypes in adults in the general population, surveys on children reported the ratio of inattentive: hyperactive-impulsive: combined as 3.5: 1.3: 2.2Among our 25 patients, 16 (64.0%) screened positive for both the CAARS-S/O, 23 (92.0%) screened positive for the CAARS-S or the CAARS-O, and two (8.0%) screened negative for both. Among all patients, only one had been previously diagnosed with ADHD. However, even when using the stricter criteria for a positive result on the CAARS-S and CAARS-O, 64.0% of the patients tested positive for ADHD, indicating that screening for adult ADHD is required when examining and treating patients with refractory IOP.Except for CAARS-S subscale E for men, both men and women with intractable IOP in this study had significantly higher scores for subscale E (DSM-IV Inattentive Symptoms) and subscale F (DSM-IV Hyperactive-Impulsive Symptoms) on both CAARS-S/O than the standardized sample. Thus, men and women with intractable IOP experienced both inattention and hyperactivity-impulsivity symptoms at a greater intensity than the standardized sample did. This is consistent with the finding that 80% of the patients in this study had combined type ADHD.In terms of subscale H, both men and women scored significantly higher than the standardized sample on both the CAARS-S/O. The CAARS-O subscale H, that is, the ADHD index, exceeded a T-score of 65 for both men and women; therefore, the ADHD symptoms of patients with refractory IOP from the perspective of the family were considered to be at the level requiring psychiatric treatment.Comprehensive observation of the eight subscales of the CAARS-S/O indicates that in the CAARS-O, both men and women with intractable IOP scored significantly higher on all eight subscales than the standardized sample. When we examined CAARS-O scores for all 25 patients with IOP , we found that on all scales except for the F scale, the T-score was > 65, and ADHD symptoms in patients with IOP from the perspective of the family were at the clinical psychiatric level.33. Among the 20 patients in the present study who underwent pharmacotherapy, pain improved by an average of 47.4%, indicating that the degree of pain improvement exceeded the optimal MCID. The MCID for HADS-A/D is 1.5 points36. In the present study, the HADS-A and HADS-D did not show statistically significant differences in the before vs. after treatment comparison; however, HADS-A showed an improvement of 1.6 points and HADS-D showed an improvement of 2 points, indicating that both achieved MCID. The MCID for PCS has been reported to improve by 38%40. In the present study, the PCS of patients who underwent pharmacotherapy improved by 39.5%, indicating that MCID was attained. The above findings suggest that the pharmacotherapies in the present study that utilized ADHD medication and the dopamine system stabilizer APZ are capable of achieving clinically significant improvement in refractory IOP with ADHD and symptoms related to pain such as anxiety and depression.The optimal MCID for the degree of improvement in chronic pain NRS was 33% on an averageThe pain NRS improvement % of patients with PIDAP was significantly lower than that of those with PIFP. The improvement in pain NRS in the three IOPs could be due to the following reasons: first, PIFP does not require dental procedures to be undertaken, whereas dental procedures in PIDAP tend to make treatment more difficult iatrogenically; this may explain the difference in the improvement between the two groups. Second, the number of patients with PIDAP was small (only three), and although PIDAP in patients No. 5 and 6 showed significant clinical improvement, the patients were unaware of their improvement, which was not reflected in the improvement of their pain NRS scores.51. Stimulants used as ADHD medication have been reported to improve the pain symptoms of fibromyalgia52, and ATX improves the cognitive disorder of fibromyalgia known as “fibro-fog”15 and atypical odontalgia53. In addition, ADHD medications (MP and/or ATX) have been reported to improve average pain NRS associated with chronic pain in patients suspected of somatic symptom disorder by 3.5 ± 2.1 points44.Young reported that chronic pain is associated with ADHD-related attention deficit, and that improving attention with ADHD treatments could activate the inhibitory filtering system and improve pain15. Theoretically, low phasic dopamine activity is associated with increased pain through the decreased release of μ-opioids54; therefore, APZ could have improved IOP by activating phasic dopaminergic transmission resulting in the release of μ-opioids.APZ is an atypical antipsychotic that exhibits properties of a partial agonist of Dopamine D2 and serotonin 5-hydroxytryptamine (5-HT) 1A receptors and a potent antagonist of 5-HT 2A receptors, resulting in enhanced dopamine neurotransmission55. Hence, it has been applied in pain management via intravenous and intrathecal administration in the perioperative period56. However, no previous studies have reported the effects of orally administered clonidine on chronic primary pain, and this is the first report of such a study. Furthermore, α2 receptors are abundantly distributed in the prefrontal cortex, and clonidine is regarded as an ADHD drug, as it can improve inattention and hyperactivity/impulsivity15. Therefore, clonidine is a potential treatment option for patients with IOP comorbid with ADHD, especially those with elevated blood pressure. Patient No. 18 in this study was hypertensive; 300 mg of clonidine improved her BMS, ADHD, and hypertension.Clonidine is a partial agonist of noradrenergic α2 receptors, and its action on α2 receptors in the spinal cord and peripheral nerves produces analgesia comparable with or better than that of acetaminophen57. Dopaminergic and prefrontal dysfunction based on ADHD can cause such central sensitization58. Dopamine plays a central role in pain perception and the descending pain suppression pathways, and reduced dopamine levels may increase pain59. ADHD is also assumed to have dopaminergic dysfunction28 and is a vulnerability to chronic pain. The prefrontal cortex is also functionally coupled to the descending pain inhibitory pathways and can act as a virtual filter to reduce unpleasant stimuli, such as pain and itching60. The prefrontal cortex performance follows an inverted U-shaped curve with respect to dopamine and noradrenaline activation and is maximized when the concentrations of both transmitters are moderate61. However, since ADHD assumes impaired dopamine and noradrenaline neurotransmission as pathophysiology, this filter does not function adequately, and ADHD is thought to be vulnerable to pain. As shown in this study, ADHD medications and the dopamine system stabilizer may activate the descending inhibitory system and reduce pain by moderately modulating the dopamine and noradrenaline transmission in the reward system and prefrontal cortex.IOP, as with other chronic primary pain syndromes, is caused by central sensitization due to central nervous system dysfunction9 due to their serotonin and noradrenaline reuptake inhibitory effects15. However, TCAs increase the dopamine and noradrenaline levels in the prefrontal cortex, since there are few dopamine transporters in the prefrontal cortex and there is a reuptake of dopamine by the noradrenaline transporter15. Thus, TCAs can improve ADHD symptoms to the same degree as ADHD medications62. If the higher comorbidity of ADHD and intractable IOP in the present study can be generalized to IOP in general, the following hypotheses can be considered: the effectiveness of TCAs for IOP may be due in part to TCAs improving ADHD comorbid with IOP by improving dopamine and noradrenaline neurotransmission, similar to the ADHD medications and the dopamine system stabilizer used in this study.TCAs are effective in the treatment of IOPThis study has two limitations. First, the participants were patients who were referred by a dentist at a tertiary medical center. The participants were special cases in which treatment was difficult even when they underwent specialized treatment, and the sample size was small; therefore, caution is required when attempting to apply the results of this study to patients with IOP treated at general dental clinics. Second, the therapeutic effect in the present study cannot be attributed simplistically to the ADHD medication or APZ. Because the participants in this study were often taking antidepressants and analgesics, there is a possibility that the interaction of these drugs with ADHD treatments and APZ provided improvement. Therefore, care should be taken when interpreting the results of this study.26. The neurocognitive traits of ADHD may be responsible for these emotional disorders and dysfunction in activities of daily living.This study reported on persistent IOP with ADHD comorbidity. But as mentioned above, it has been reported that ADHD is also associated with chronic primary pain such as fibromyalgia, migraine, and chronic back pain. Further, chronic primary pain is associated with extreme emotional distress, such as anxiety, depression, and anger/frustration, and is also associated with functional disabilities in activities of daily living and decreased participation in social rolesIn the future, when examining and treating fibromyalgia, migraine, chronic low back pain, IOP, and other types of chronic primary pain, ADHD screening should be conducted, and effective pharmacotherapies should be considered, provided the patient satisfies the diagnostic criteria. There remains a need to further study the relationship between chronic pain and ADHD by conducting surveys in more common clinical settings and controlled interventional studies.Supplementary Table S1.


Sacroiliac joint injection aims to provide pain relief, improve work status, and early return to work. We aimed to investigate the role of corticosteroid and anesthetic mixture to provide short- and long-term pain relief in patients with sacroiliac joint pain. This prospective observational study included 27 patients with sacroiliac joint dysfunction who received a combination of triamcinolone and ropivacaine for sacroiliac joint injection followed by three scheduled visits at four weeks, eight weeks, and six months. The pain was assessed using visual analogue scale (VAS), physician's assessment on the number of positive provocative tests, and patients' self-reported assessment to evaluate their functional outcome. At the four weeks and eight weeks follow up evaluations, the mean VAS reduced from 5.85 (±1.03) at baseline to 3.30 (±1.77) at four weeks, 3.30 (±1.86) at eight weeks, and 3.00 (±1.86) at six months. At each interval, improvement in terms of clinical assessment using a series of provocative tests was seen with a mean of 1.37 (±1.33), 1.63 (±1.31), and 1.48 (±1.05) at four weeks, eight weeks, and six months, respectively. For the functional effectiveness parameters (Roland-Morris questionnaires), the sacroiliac joint (SIJ) injected with these drugs combination showed a more significant improvement in symptoms and function, baseline (13.56±3.36), at four weeks (9.04±3.33), at eight weeks (9.07±4.13), and six months (8.26±4.92). Using the one-way repeated measures ANOVA, the SIJ pain, provocative test, and functional outcome significantly improved over time after injection with triamcinolone and ropivacaine (p<0.001). No complications of the administration of these medications were noted. Our findings support the intermediate-term (six months) effectiveness and safety of a combination of corticosteroid and anesthetic injection for patients with SIJ dysfunction who failed conservative treatment. Low back pain (LBP) is a common musculoskeletal condition. The incidence of low back pain is reported to be between 10% and 63%, with a median of 37% in several studies. In a suburban community survey in Malaysia, the incidence of low back pain was around 12%. There was a higher prevalence of approximately 60% in the population at risk  [Pain around the SIJ causes work restrictions, reduction in productivity, and causing impairment in quality of life. A presumptive diagnosis of SIJ pain can be made by clinical history, physical examination, and radiological test, as there is no standard test available to diagnose this pathology -6.Treatment of SIJ pain includes conservative treatment, which consists of physiotherapy , manipulSacroiliac joint (SIJ) injection has proved effective in providing short-term pain relief in managing SIJ pain . Our curThis prospective observational study was conducted at Hospital Perempuan Zainab II, Kelantan, Malaysia, from June 2018 to July 2020. The patients were recruited from the outpatient spine clinic. Patients aged between 18 years and 70 years old diagnosed with sacroiliac joint dysfunction based on their history, clinical examination, and radiological findings were included in this study. Other inclusion criteria include chronic pain at the sacroiliac joint for more than 12 weeks, with a pain score of four or more on the visual analogue score (VAS). Our patients received NSAIDs and other analgesics and physiotherapy as pre-treatment but failed to achieve the desired level of pain control. Therefore, we can conclude that the conservative treatment failed in these patients, and SIJ injection can be helpful to elevate the pain. Patients with coagulation disorder, connective tissue disorder, and pain due to infective origin were excluded from this study. Participation was voluntary. All the participants gave their informed consent. The National Medical Research Register (NMRR) and Medical Research and Ethics Committee (MREC) approved this study (ID number: NMRR-18-2676-43284).The patient underwent pre-injection clinical evaluation. Collected patient demographic data included age, gender, height, and weight. The intensity of SIJ pain felt is recorded using a visual analogue score (VAS), presented by a 10 cm horizontal line representing the patient's pain intensity. Zero represents "no pain" while the upper limit (10 cm) represents the "worst pain imaginable" .The clinical evaluation includes pain or local tenderness at the affected SIJ, flexion, abduction, and external rotation (FABER) test, Gaenslen's and Fortin finger test ,13. ThesPatients were subsequently evaluated using a plain radiograph. X-rays were reviewed by a senior consultant and were graded based on the New York Classification . Based oPatients were also required to answer Roland-Morris Disability (RMD) questionnaire as a pre-injection functional status assessment. This questionnaire consists of 24 questions describing different movements and functions for which patients tick those that apply to them daily. This questionnaire aimed to identify physical problems and not psychological or social problems, therefore adopted in the study. Even though we are using the English version, this questionnaire is easy to understand and consists of yes or no answers - an explanation given whenever is needed. The total score is the number of questions with a positive response (yes). A reduction in four or more scores indicates that the treatment has achieved its goal .The procedure is performed using fluoroscopy . The SIJOur study included intra- and periarticular injections as both techniques have proven effective in treating sacroiliac joint pain . Next, aPost-injection evaluation was performed at four weeks, eight weeks, and six months. The primary outcome variable was a reduction in pain scores. The second variables' efficacy measures include the number of positive provocative tests to reproduce pain at the affected SIJ and RMD questionnaires measures during visits.All the data  were entered into a computerized database. For a continuous variable, a one-way repeated measures ANOVA was conducted to compare pain scores post-SIJ injection at baseline (before injection) and follow-up at four weeks, eight weeks, and six months. Data were analyzed using a one-way repeated measure ANOVA test after its normal distribution was confirmed. All assumptions of the test were also checked and met. P-values of less than 0.05 are considered statistically significant. Data were presented in mean and standard deviation for numerical data; frequencies and percentages were used for categorical data.There were a total of 31 patients involved in this study. Twenty-seven patients completed the six months follow-up. Four patients did not complete the six months follow-up, which was considered a protocol violation; therefore, the patients were excluded from the analysis. Of the 27 patients, 20 patients received unilateral SIJ injection  and seven (25%) patients received SIJ injection on bilateral sit  experienced pain relief at four weeks, 81% (n=22) at eight weeks, and 74% (n=20) at six months. Recurrence of pain was observed in five patients (three at eight weeks and two at six months). The mean pain score pre-treatment was 5.85 ± 1.03, the mean pain score at four weeks was 3.30 ± 1.77, at eight weeks was 3.30 ± 1.86, and at six months was 3.0 ± 1.86, therefore it shows a significant reduction as compared to baseline (p<0.001). Continuous assessment with repeated one-way ANOVA shows significant changes in pain score over time (p<0.001) . In addition, a trend toward more remarkable improvement in clinical assessments was observed at eight weeks (p<0.002) and six months (p<0.001) as compared to baseline.The mean RMD score of the 27 patients pre-treatment was 13.56 ± 3.36, while on the subsequent follow-up at four weeks was 9.04 ± 3.36, at eight weeks was 9.07 ± 4.13, and at six months was 8.26 ± 4.92. These scores show significant improvement at each follow-up interval (p<0.001). The continuous analysis also shows a significant effect of time on the provocative test and RMD score with p<0.001 , which is similar to a previous study by Luukainen et al. . AnotherIn an earlier study by Maugars et al., the efficiency of SIJ injection shows 85.7% improvement at one month following injection, 62% at three months, and 58% at six months . Their rMost of the previous studies emphasize the intra-articular nature of SIJ injection compared to us, who accept both intra- and periarticular injection ,18,20. ISymptom description in sacroiliac joint pain can be dissimilar for each patient. Clinical observation of pain shows that the pain arising from the sacroiliac joint can be reproduced by provocative tests . ReductiThe previous studies did not include the assessment for the functional outcome, which is more important in understanding the effect of injection on a patient's daily living. The functional status is one of the factors which can determine the successful treatment provided to the patient. Several tools are available to assess sacroiliac joint pain. This tool includes the visual analogue scale , OswestrIn this study, we used Roland-Morris questionnaires to assess the functional status of patients receiving sacroiliac joint injections. The scoring system did not indicate the patients' pain directly but evaluated pain related to daily activity. From our findings, SIJ injection with anesthetic and corticosteroid mixture provide adequate pain relief and improve patient's function, which is shown by the decreased RMD score, which is significant up to six months. This finding is comparable to the previous study by Liliang et al., which shows significant pain improvement with an average observation period of 45.4 weeks .This prospective observational study is conducted in a single center that reflects actual population clinical practice. This study, however, did not have a control group, thus may pose selection bias. The lack of a comparison group in this current study can be explained in several ways. First, recruitment was difficult. Secondly, due to ethical issues, depriving patients of receiving appropriate treatment when the treatment is accessible can cause unnecessary pain, disturbing their daily living.Informed consent and patients who were not easily convinced of the benefit of this study posed a hurdle in recruitment. Further study with larger sample size, different study designs with a control group, and randomization, followed by a longer follow-up duration, may be required to validate these findings.Our findings demonstrate pain relief following SIJ injection with a combination of corticosteroid and anesthetic mixture in patients with SIJ pain. This improvement is significant for a short-term duration and, at the same time, shows a significantly longer-term positive response (up to six months) for patients satisfaction. Reduction in pain also indirectly improves a patient's functional status, as shown in our result. From this study, we think that SIJ injection is a reasonable approach to treating persistent SIJ pain. However, further randomized controlled trials can be designed to assess long-term side effects, disease progression, and the efficiency of this technique.


The findings of this study show that cognitive status, measured with MoCA, and emotional status, measured with the Depression, Anxiety, and Stress Scale (DASS-21), significantly influence the reduction in pain intensity and adherence to pharmacotherapy. The results suggest that cognitive and emotional status may be potential predictors of treatment success. This finding points to the importance of a biopsychosocial approach in the treatment of chronic pain, where an important emphasis can be placed on the psychosocial determinants of pain.This prospective study aimed to determine the cognitive and emotional status among patients with chronic pain and to examine the potential influence on the treatment success, measured by the reduction in pain intensity and adherence to pharmacotherapy. A total of seventy patients were followed for two months. The results of the comparison between patients who did and did not follow the physician’s instructions regarding adherence to pharmacotherapy showed a significant difference in cognitive status and a reduction in pain intensity. Patients who followed the physician’s instructions on taking analgesics had significantly higher scores on the Montreal Cognitive Assessment (MoCA) of cognitive status and a substantially higher reduction in pain intensity. Scores on the MoCA test provide statistically significant indications regarding patients’ decision to follow instructions regarding adherence to pharmacotherapy. Scores on the MoCA test, anxiety, age, and pain intensity  on admission were identified as potential predictors for the reduction in pain intensity. The linear regression model was statistically significant ( The treatment of chronic pain (CP) requires a multimodal and multidisciplinary approach, where pharmacotherapy and analgesics are cornerstones in treatment ,2,3. ChrMoreover, pain evaluation strongly depends on cognition, as it requires learning and the recall of previous experiences . PatientTherefore, this study aimed to determine the cognitive and emotional status regarding the level of anxiety, depression, and stress among patients with chronic pain and to examine the potential influence on the treatment success, measured by the reduction in pain intensity and adherence to pharmacotherapy.The study was conducted at the Department of Pain Management, University Hospital Centre Osijek, over two months, from June to the end of August 2021. At the beginning of the study, the patients had their first physician’s examination  to assess the intensity of pain on a numerical rating scale (NRS) and received instructions by the physicians for further treatment and pharmacotherapy. They were then referred to a psychologist for a brief assessment of cognitive status using the Montreal Cognitive Assessment (MoCA) and of anxiety, depression, and stress using the Depression, Anxiety, and Stress Scale (DASS-21). At the control physician’s examination , pain intensity was reassessed and adherence  to the physician’s instructions on taking the prescribed analgesics was assessed .All patients who attended their first physician’s examination  in this period were included. Inclusion criteria were: Chronic non-malignant pain (pain ≥ 3 months), >18 years old, who understood the Croatian language and script, and voluntary participation in the study. According to the pain diagnosis, 39 patients with low back pain, 14 patients with cervical pain, 9 patients with joint pain, 4 patients with headache, 3 patients with trigeminal neuralgia, and 1 patient with diabetic polyneuropathy were identified from the total sample.For the assessment of the intensity of pain, a numeric rating scale (NRS) was used , which is a widely used screening instrument . The NRSFor the assessment of the patient’s cognitive status, the Montreal Cognitive Assessment (MoCA) test was used. The MoCA is a brief screening tool for cognitive impairment, scored from 0 to 30. It is a one-page protocol that assesses eight cognitive domains  . The oriFor the assessment of the patients’ emotional status, the Depression, Anxiety, and Stress Scale (DASS-21) was used. The Depression, Anxiety, and Stress Scale is a measure of self-assessment that examines the frequency and severity of negative emotional states of depression, anxiety, and stress over the past seven days. The scale consists of 3 measures of associated negative affective states classified into 3 subscales, with a total of 21 items . The patFor the assessment of the adherence to pharmacotherapy, physicians asked the participants at the control examination (second measurement point) whether they took the pharmacotherapy medication according to the physician’s instructions for a period of two months. Physicians recorded answers as “followed” or “did not follow” in medical documentation.® statistical software, version 20.026 .For statistical analysis, we used standard statistical methods. All collected categorical data are presented with absolute and relative frequencies, while numerical data are presented with median, interquartile range, and total range, distributed within parameters that did not follow a normal Gaussian distribution. Differences between two independent sets of numerical data were tested with the nonparametric Mann–Whitney U test, while differences between two dependent sets of numerical data were tested with the nonparametric Wilcoxon test. Differences between categorical data were tested with the Chi-square test. Exploratory logistic regression and multiple regression were used to identify potential predictors regarding adherence to pharmacotherapy and reductions in pain intensity. The strength of the relationship between pairs of measurements was tested with the nonparametric Spearman’s correlation test or Kendall’s Tau correlation test. The level of statistical significance was set at α = 0.05. Statistical data analysis was performed with MedCalcThis study was approved by the Ethics Committee (R2-13170/2020) of the authors’ institution, following the principles of the 1983 revised Helsinki Declaration guiding research on human subjects. All patients gave their written informed consent for participation in the study.This study included 70 patients. Demographic characteristics, adherence to pharmacotherapy, MoCA, and DASS-21 scores are shown in In 20.0% of patients, a decrease in pain intensity was noted for one score, while in 11.4% it was noted for two scores at the control examination after two months (second measurement point) .p < 0.001) and a significantly higher reduction in pain intensity  compared to those who did not follow the physician’s instructions. There was no significant difference found regarding gender , NRS at first visit , NRS at control visit , or DASS-21 depression , anxiety , and stress  subscale scores . The model was statistically significant , explained between 28.4% (Cox and Snell) and 39.0% (Negelkerke) of variance regarding adherence to pharmacotherapy, and correctly classified 75.7% of all cases (p < 0.001). However, age was not identified as a significant contributor in this model, even though there was a significant difference in age between patients who followed instructions and patients who did not (p < 0.001) and age highly influenced the scores on the MoCA test, with R2 = 0.338 .Scores on the MoCA test made statistically significant contributions to patients’ decisions to follow instructions regarding adherence to pharmacotherapy  and NRS at the baseline visit , while a negative, moderate, statistically significant correlation was found with the anxiety DASS-21 score . There was no correlation found between the reduction in pain intensity and cognitive status, depression, or stress DASS-21 score . The model was statistically significant , explained between 43.5% (Cox and Snell) and 61.1% (Negelkerke) of variance regarding the reduction in pain intensity, and correctly classified 82.9% of all cases  patients had a reduction in pain intensity. Scores on the MoCA test, patient’s age, and level of anxiety made statistically significant contributions to the reduction in pain intensity  and depression .There was no significant correlation found between the MoCA test and each DASS-21 test, or between patients’ ages and each DASS-21 test. However, there was a significant, moderate, positive correlation between NRS at first visit and DASS-21, for both anxiety  in terms of pain intensity. Nevertheless, the logistic regression analysis suggests an interesting result. Even patients who did not consistently follow the physician’s instructions showed a decrease in pain intensity. There are probably some factors that were not identified by this research which may have an influence on the reduction of pain intensity. Additionally, it may be necessary to consider that the research was performed with a small sample. Therefore, this result should be taken as preliminary data. Observing the age variable, studies indicate that older adults show a lower level of adherence ,41, whicIn this study, the results suggest a significant pain reduction. This result was significantly negatively correlated with anxiety and positively with patients’ age, but not correlated with mental status. However, the logistic regression model has identified mental status as a potential predictor for pain intensity reduction. Shuchang et al. showed that comorbidities such as depression and anxiety could impact pain perception . ResearcAdditionally, our results demonstrate a significant positive correlation between pain intensity at first visit and depression and anxiety. The conclusions of several studies indicate that depression and anxiety are predictors of worsening chronic pain over time and that this relationship is reciprocal . Due to The limitations of this study were the small sample size, the predominant older age group, the lack of data on the type of prescribed analgesics, and the study being conducted in one health institution. Therefore, the plan is to repeat this study on a larger sample with a control group to examine cause-and-effect findings. Additionally, we can investigate which interventions would help patients with cognitive deficits to more easily follow their physician’s instructions about taking pharmacotherapy. This is a significant issue because a large number of patients with chronic pain are members of the elderly population, with many other comorbidities. Furthermore, another limitation was the impossibility of objectively verifying the patients’ answers regarding compliance with the instructions received from the physicians. In the following study, it will be necessary to include a standardized questionnaire to assess adherence. Lastly, it is important not to ignore the fact that all questionnaires have biases.Despite some limitations, the results of this study highlight the importance of procedures that reduce the risk of the improper use of pharmacotherapy. Considering that cognitive status is a potential predictor of adherence, by identifying it, we have the possibility to influence adherence by adjusting interventions.The findings of this study showed that cognitive status measured with the MoCA, and emotional status measured with the Depression, Anxiety, and Stress Scale (DASS-21), significantly influenced the reduction in pain intensity and adherence to pharmacotherapy among patients. The results suggest that cognitive and emotional status may be potential predictors of treatment success. This finding points to the importance of a biopsychosocial approach in the treatment of chronic pain, where an important emphasis can be placed on the psychosocial determinants of pain.


Lack of assessment of 90-d perioperative morbidity in elderly patients after radical cystectomy and pelvic lymph node dissection (PLND) using a standard reporting methodology, and the Clavien–Dindo classification (CDC) does not accurately reflect the burden of complications. We aim to report the 90-d complications of elderly patients after radical cystectomy, and to compare the validity of the Comprehensive Complication Index (CCI) and CDC.Retrospective review of 280 patients aged ≥75 years who received radical cystectomy between 2006 and 2021. The 90-d complications of elderly patients after radical cystectomy were reported by implementing the EAU criteria. The CDC and CCI were both used for grading complications. The Spearman rank correlation coefficient was used to estimate the correlation between postoperative stay and CDC/CCI. Logistic regression was used to identify the risk factors for major complications. The sample size for a fictive superiority trial was calculated for different endpoints.A total of 225 (80.36%) patients suffered from 528 complications. The cumulative CCI had a more accurate prediction of postoperative stay than the CDC . The need for sample size could decrease when CCI was used for the primary endpoint. More risk factors for major complications were identified when CCI ≥33.7 was defined as the endpoint of major complications.CCI is better than CDC for grading the severity of complications in elderly patients after radical cystectomy and PLND. Radical cystectomy is recommended by evidenced-based guidelines as the gold standard treatment for patients with recurrent high-grade non-muscle-invasive bladder cancer and local muscle-invasive bladder cancer . BecauseThe Clavien–Dindo classification (CDC) was recommended as a severity grading system for postoperative complications . HoweverThe aims of the present study are threefold: (1) to assess the 90-d complications of elderly patients after radical cystectomy and PLND based on EAU guideline of complication reporting, (2) to compare CCI with CDC in elderly patients, and (3) to explore the risks of major complications after operations according to CDC and CCI.Retrospective analysis of data from chart review was performed in this study. We defined the following inclusion criteria: (1) patients who received radical cystectomy with urinary diversion from January 2006 to October 2021 at Peking University First Hospital and (2) patients aged ≥75 years. The exclusion criteria were as follows: (1) PLND was not performed (n = 130) and (2) patients received neoadjuvant chemotherapy or radiotherapy before surgery (n = 4). Finally, a total of 280 consecutive patients were enrolled in this study. Ethical approval for this study was obtained from the clinical research ethics committee of Peking University First Hospital, Beijing, China.https://www.assessurgery.com. The cumulative CCI and non-cumulative CCI were calculated based on all complications and the highest complication, respectively. The intraoperative complications were reported separately. This study complied with the EAU guideline of complication reporting , and postoperative stay, were collected in this study. The Charlson comorbidity index was used to assess the comorbidity of patients . The lasp values were two-sided. p < 0.05 was considered to be statistically significant. R (version 3.6.3) was used for visualization of correlation analyses, and Prism 6.0  was used for graphing.The Spearman rank correlation coefficient was used to estimate the correlation between variables. Logistic regression was used to identify the risk factors for major complications for all patients, which included the variables that showed a univariate relationship with major complications or that were considered clinically relevant. The sample size for a fictive superiority trial was calculated when the presence of any CDC complication, the presence of a major CDC complication, or the cumulative CCI were used as the primary endpoints. We assume a 30% relative risk reduction for the incidence of any complication and the incidence of major complications, a difference of 10 points for the cumulative CCI, a power of 80%, and an α-error of 0.05. A difference of 10 points on the cumulative CCI reflects one grade difference of CDC . The staA total of 280 elderly patients who underwent radical cystectomy and PLND were enrolled in this study. The clinical and pathological characteristics are depicted in A total of 225 (80.36%) patients suffered from complications after operations, and the total number of all postoperative complications was 528. The detailed summary of categories, grading (according to CDC), number and proportion of all types of complications are depicted in p < 0.001). A total of 139 (49.6%) patients developed more than one complication after radical cystectomy and PLND. With increasing CDC grade, patients had a higher number of complications .The correlations of postoperative stay with cumulative CCI and CDC were analyzed Figure 2In order to compared sensitivity of CCI and CDC to identify the difference of postoperative morbidity caused by treatment. The sample sizes were calculated when the presence of any CDC complication, presence of major CDC complication, and cumulative CCI were used for the primary endpoint. The assumptions for the fictive superiority trial are depicted in p = 0.002) and higher ΔHb  were identified as risk factors for major complications in elderly patients after radical cystectomy. While not only Charlson comorbidity index ≥3  and higher ΔHb  but also preoperative renal insufficiency  and higher time of operation  were associated with major complications, when the endpoint of that was referred to CCI ≥33.7 .The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Total urinary frequency decreased from 14.00  to 9.00  (p < 0.05), and all the other secondary endpoints also showed a statistically significant improvement. Eleven patients improved by ≥3 pain points in VAS, meaning that 65% of patients that ended the study protocol achieved clinical significant improvement or, in the full analysis set, that 55% of the 20 initial patients improved significantly. Fourteen (82%) decreased by ≥2 micturitions/day. Overall, the cohort’s stress coping was low. Conclusions: Silodosin can be an effective and well-tolerated treatment for refractory BPS/IC female patients.Purpose: Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) is a bladder-related chronic inflammatory disease. Data indicate that stress enhances the excitability of bladder nociceptors through the stimulation of alpha1A-adrenoceptors. Stress is known to play a crucial role in BPS/IC patients. We aimed to assess the efficacy and safety of daily silodosin in refractory BPS/IC female patients and its correlation with stress coping. Materials and Methods: An open-label trial was conducted with 20 refractory BPS/IC patients. Evaluations occurred at baseline and the 8th and 12th weeks. Primary endpoint was bladder pain evaluated by visual analogue scale (VAS). Secondary endpoints included daily frequency, nocturia and maximum voided volume obtained from a 3-day bladder diary, the O’Leary–Sant Symptom Score, and two questions accessing stress coping. Patients initiated daily doses of 8 mg silodosin, which could be titrated to 16 mg. Median values with percentiles 25 and 75  were used. Wilcoxon signed-rank test was used for comparisons. A minimally important difference of 3 points for pain was established to define clinically relevant improvement. Results: Median age was 56 years. Median pain score decreased from 8.00  at baseline to 4.00  ( Primary Bladder Pain Syndrome/Interstitial Cystitis (BPS/IC) is a chronic disease. Suprapubic pain associated with bladder filling is the cornerstone symptom and is associated with urinary symptoms such as frequency, nocturia and persistent urge to prevent/relieve pain . EffectiA-Ars enhances the responses of nociceptors, such as transient receptor potential cation channel subfamily V member 1 (TRPV1) [Increasing evidence suggests that stress plays a crucial role in BPS/IC ,6. Sympt (TRPV1) , resulti (TRPV1) ,11,12. I (TRPV1) ,14. More (TRPV1) .A-ARs by silodosin, although not altering NE levels, normalized the abdominal pain threshold and bladder function of rats subjected to WAS [In a recent pre-clinical experiment, adult female mice developed an equivalent of a BPS/IC phenotype after being subjected to an early-life water avoidance stress test (WAS). In this model, the lower abdominal mechanical pain threshold was decreased and the frequency of bladder voiding contractions during filling cystometries was increased, while urinary NE levels were multiplied by a factor of 20. Interestingly, the blockade of α1d to WAS .A-ARs, limiting cardiovascular events [Silodosin has a safe profile, conferred by its high selectivity for α1r events . With thThis study was approved by the local ethics committee  under protocol number 338-21: “Efeito da Silodosina nos doentes com Síndrome Doloroso vesical aos 3 meses”. The trial occurred in a tertiary university hospital with expertise in BPS/IC. Oral and written consent was obtained from patients after explaining the off-label drug use. Patients were informed that silodosin is licensed for the treatment of male LUTS. The rationale for this use was understood. We also stated that the side effects of this drug were extensively known.Previously, a small cohort of patients outside the study, refractory to every other previous therapy , showed a good response to silodosin.Twenty women with BPS/IC refractory to previous therapies were enrolled between 2019 and 2020. As a pilot study, without any available data to predict the potential efficacy, power calculations were not carried out.During the previous follow-up, patients had been advised to adjust their diet, increase physical activity, avoid stressful events, and stop smoking. Patients under any oral treatment in the last two months, other than simple oral analgesia (such as acetaminophen or ibuprofen), were excluded. Patients who received intravesical treatments in the previous six months were also excluded.We designed a 12-week single-arm exploratory study to evaluate the efficacy of silodosin against BPS/IC symptoms.Patients were evaluated at baseline, at week 8 (8w), and at week 12. The primary outcome was the pain intensity at 12w, assessed by a 0–10 VAS score (in which 10 was the worst pain ever). The secondary outcomes included the daily urinary frequency, the nocturia, and the MVV recorded in a 3-day bladder diary; the OSS problems and symptoms index ; and the QoL evaluated with the question used in the IPSS questionnaire . For the definition of a relevant clinical improvement, we considered a decrease in 3 points in the VAS score as the minimally important difference (MID). Decreases of 2 micturitions in total daily urinary frequency and 1 micturition in nocturia were defined as the MID to consider a relevant improvement in these parameters.Does stress aggravates or initiate BPS/IC symptoms?”, and a second question, “I have a relaxed personality, coping well with stress“, could be answered on a scale from 1 to 5, with 1 being “I totally disagree with it” and 5 being “I totally agree with it”. After consenting to enter the study, patients began with an 8 mg daily oral dose of silodosin. This dose could be titrated to 16 mg at 8w. Adverse events were assessed and recorded.Two questions were addressed to the patients at the beginning of the study in order to assess their capacity to cope with stress: the first question was answered yes/no, “p < 0.05) were considered statistically significant. The analysis was carried out per-protocol, comparing the data from the baseline with that from 12w in patients completing all 12 weeks. The primary end-point was also evaluated, taking into account the dropouts. Patients who left the study before the 12w were excluded from the final analysis but were included for safety exploration.Data analysis was performed with the statistical package for social sciences (SPSS version 28.0). Data are presented as medians, with the 25 and 75 percentiles . Differences assessed by a non-parametric Wilcoxon signed-rank test  years old. Three patients presented Hunner lesions at cystoscopy. Fifteen of them had previously received at least one treatment of intra-trigonal injection of onabotulinum toxin A six or more months before. Dose escalation to silodosin 16 mg was requested by four patients at 8w.A total of three patients abandoned the study. Two patients abandoned therapy at week 8 due to lack of effect, without trying dose escalation despite the clinician’s effort to try medication until the 12th week. The third patient was excluded due to the diagnosis of a UTI during the study period, which caused a symptomatic flare up. Two patients failed to attend the 8w visit due to the COVID-19 pandemic but were observed at 12w.p = 0.001). A total of 11 out of 17 patients (65%) had an improvement of 3 or more points from baseline to 12w, as seen in per-protocol analysis. When evaluated taking into account the full analysis set, the percentage of clinically significant improvement was 55% (11/20).The characteristics of the population at baseline are shown in p = 0.01). A total of 14 patients out of the 17 (82%) achieved the MID of a decrease of at least two micturition from baseline to 12w. The total urinary frequency variation per patient result is shown in At 12w, the total urinary frequency decreased to a median of 9.0 , which was significantly lower than the baseline median of 14.0  micturition (non-parametric Wilcoxon signed-rank test p = 0.01). A total of 13 (76%) patients achieved an MID of one episode per night between baseline and 12w.Nocturia decreased to 2.0  at 12w, with the baseline being 4.0  micturition per night, and this is a statistically significant difference  presented this simultaneous improvement, as shown in p = 0.03; OSS p = 0.01 and QoL p = 0.04) shown in When it comes to the other secondary endpoints, at 12w the median MVV increased to 250 mL  mL; OSS total score decreased to 19.00  with a and QoL decreased to 3.00 . All these data were statistically significant when compared to baseline values through the non-parametric Wilcoxon signed-rank test (MVV p = 0.001). Moreover, at this earlier time point, the total frequency had already significantly decreased to 10.0  micturition when compared to baseline (non-parametric Wilcoxon signed-rank test p = 0.03) , indicating a significantly early pain reduction (non-parametric Wilcoxon signed-rank test  = 0.03) .In an exploratory attempt to find possible predictors of a positive response to silodosin, we compared the demographics between patients who presented an improvement of more than 3 points in the VAS pain intensity and the patients who did not reach this improvement. The compared demographics were: age, pain intensity, urinary frequency, nocturia, MVV, OSS, and QoL. The results and the comparison between groups are presented in Of the 17 patients, 13 answered to the question “Does stress aggravate or initiate BPS/IC symptoms?” with yes, as opposed to 4 patients who denied an association between stress and symptoms worsening. The median answer to the second question “I have a relaxed personality, coping well with stress” was 2.0  from 0 to 5, which means that patients tend to have a low capacity for coping with stress.No adverse events were registered, not even in the dropouts.A-Ars with silodosin, at a dose of 8 to 16 mg daily, induced a substantial improvement in pain, the primary endpoint. Although the endpoint was defined at 12 weeks, relevant improvement in pain intensity was also observed at week 8. In addition, secondary outcomes such as daily voiding frequency and bladder functional capacity were also substantially improved after 12 weeks of therapy. All these findings certainly contributed to the marked improvement in QoL observed. The effect of silodosin is also in agreement with a previous finding of this group, which consisted of the demonstration of an exaggerated sympathetic activity and high levels of urinary NE excretion [The most important finding of the present pilot study was the clinical confirmation that the blockade of α1xcretion .We statistically evaluated the cohort with medians comparisons and with individual treatment responses given the low number of enrolled patients. This way, we weakened the bias that great responses could have in lower responders and at the same time evaluated responses through MID, assuming that a complete resolution of complaints would be unrealistic; rather, a satisfying level of improvement was sought.All the parameters evaluated improved significantly. This could indicate that silodosin could have a place in the oral pharmacology treatment for BPS/IC patients. These improvements were obtained both in objective and subjective parameters.In total, 11 out of 17 patients achieved an MID of 3 points of pain in the VAS score, which is a significant result since the main complaint of this condition is bladder pain. These results could be biased by the single-time evaluation of pain, a parameter that could fluctuate over time. When comparing the demographic parameters between responders and non-responders, none of these parameters were found to be helpful in identifying a possible characteristic or predictor of positive results, as seen in per patient, using the MID, evaluated the most bothersome features for these patients: pain and urinary frequency. Fifty-nine per cent (10 out of 17) of the patients significantly improved simultaneous in terms of pain and urinary frequency, and this study could strongly support a future randomized clinical controlled trial (RCT), which we are planning to perform. According to the calculations, a total of 70 patients (35 per group) should be randomized to placebo or silodosin in a ratio of 1:1.The analysis of treatment response A-ARs [A-ARs could enhance bladder pain through the pain receptor TRPV1 by increasing the amount of ATP released to bladder distension, suggesting the existence of crosstalk between the sympathetic nervous system and nociceptive pathways.The present clinical data support previous experimental observations. Matos et al. showed in rodents that bladder pain, voiding bladder contractions, and histologic bladder, features similar to those seen in BPS/IC patients, could be triggered by the systemic administration of an alpha-adrenergic agonist, and that such effect could be prevented by α1A-ARs ,15. MoreIn addition, in the WAS model of stress, Dias et al. showed increased levels of noradrenaline in the urine of rodents . The WASB-AR lowers the risk of dizziness or orthostatic hypotension. In women, we confirmed the safety of silodosin use, even when escalated to 16 mg. Two patients abandoned the study before week 4 at a very early phase of the treatment, eventually indicating that the effect of silodosin on pain is not immediate.Silodosin is a very safe drug. The absent effect on α1This single-arm study has obvious limitations: the lack of a control group and not being blinded. The number of enrolled patients was small, with three of them dropping out. Intrinsic to this condition, pain is a subjective symptom which depends on different variables, and its intensity can fluctuate over short periods. This last one is specifically true in chronic pain conditions, which can present unprovoked flares. Another limitation was the assessment of self-perception of stress coping, which was based on two questions, and the answer was always modulated by the feeling at that moment.In conclusion, daily silodosin could be an effective and well-tolerated treatment for refractory BPS/IC females. The treatment effect was sustained for 12 weeks. Personality type does not seem to be an independent factor for treatment response. More robust studies should be conducted to assess the role of silodosin in BPS/IC patients.


They also had significantly shorter times to the injection order  and the injection occurrence . In this study, more efficient care for patients with back and/or leg pain was delivered in the MSC setting, which was evidenced by the shorter times to the injection order and occurrence. The impact of the MSC approach on patient satisfaction and health-related quality-of-life outcome measures warrants further investigation.Chronic back and leg pain are leading causes of disability worldwide. The purpose of this study was to compare the care in a unidisciplinary (USC) versus multidisciplinary (MSC) spine clinic, where patients are evaluated by different specialists during the same office visit. Adult patients presenting with a chief complaint of back and/or leg pain between June 2018 and July 2019 were assessed for eligibility. The main outcome measures included the first treatment recommendations, the time to treatment order, and the time to treatment occurrence. A 1:1 propensity score-matched analysis was performed on 874 patients (437 in each group). For all patients, the most common recommendation was physical therapy (41.4%), followed by injection (14.6%), and surgery (9.7%). Patients seen in the MSC were more likely to be recommended injection ( Back and leg pain are leading causes of disability worldwide. Low back pain is the most common musculoskeletal disorder ,2,3,4 anMultidisciplinary approaches have allowed clinicians to treat complex conditions, including spinal disorders, more efficiently . For patNonetheless, data on multidisciplinary teams that evaluate patients with back and/or leg pain during the same office visit are limited. At our institution, patients referred to spine surgeons for back and/or leg pain are seen either by the surgeon alone (unidisciplinary spine clinic (USC)), or in a separate multidisciplinary spine clinic (MSC) that includes a co-located cross-disciplinary team of neurosurgeons, orthopedic surgeons, pain-management physicians, and physiatrists. Patients can be evaluated by any of the team members during the same visit. In this manuscript, we compare the differences in the treatment recommendations, the time to the treatment order, and the time to the treatment occurrence for patients seen in a USC versus a MSC setting.This is a retrospective cohort study. After institutional-review-board approval (IRB 2019-10657), eligible patients were identified through local healthcare surveillance software  and an electronic-medical-record (EMR) review. We included adult patients (age 18+) initially presenting to orthopedic spine or neurological spine surgeons for back and/or leg pain at our institution between 1 July 2018 and 30 June 2019. Patients were excluded if they previously sought care for their chief complaint from another spine specialist at our institution, including Emergency Room visits, or if their chief complaint was cervical spine pathology or myelopathy.Our institution’s central call center is responsible for scheduling all spine surgery visits, and for allocating patients to the USC or MSC, which are both located in close proximity in the Bronx, New York. Appointments are assigned on the basis of next availability alone, but the USC has a larger capacity and, thus, a higher number of patients were seen there initially. At the USC, patients are evaluated only by the spine surgeon, and they can receive a specific treatment recommendation, a treatment order, or they can be referred to another specialist within our system. In contrast, the MSC includes four specialties on site: neurosurgery, orthopedic surgery, pain medicine, and physiatry. At the MSC, spine surgeons discuss the case with other team members on site, and patients can be seen by multiple specialists during the same clinic visit, if deemed appropriate.The index visit (baseline) was defined as the initial visit with the spine surgeon during the study period at either the USC or MSC. We collected demographic data on age, gender, race/ethnicity, medical insurance, the Charlson Comorbidity Index (CCI) score, and the diagnosis at baseline. Data were identified and collected in the form of ICD-9 codes.Differences in the first treatment recommendations; this had six possible categories : injection, physical therapy, surgery, medically cleared, lost to follow-up, or no recommendation. Each category was analyzed separately. The “injection” category included epidural steroid injection (ESI), radiofrequency ablation, and/or nerve block. Patients were labelled as “no recommendation” if no treatment recommendation was made within 180 days. Patients were considered lost to follow-up if they did not return to either the MSC or the USC within 180 days of their last visit. If patients received multiple treatment recommendations throughout one year from the index visit, only the initial treatment was used in our analysis. All references to “treatment” in this manuscript hereafter refer to the first treatment that was recommended by the surgeon;Time to treatment order; defined as the time from the index visit to the date when the treatment was ordered in the EMR. The date of treatment was recorded for patients recommended injection and surgery. We could not analyze PT treatment because many patients received PT outside our institution/network. Some treatment orders may not have occurred at day zero if further imaging or insurance authorization was required, for example;Time to treatment occurrence; defined as the time when the ordered treatment was delivered.We assessed the clinical outcomes up to 180 days after the index visit, as this was considered sufficient time for patients to receive a treatment recommendation. Outcomes included:p < 0.05. Analyses were conducted in SAS 9.4 and R 3.5.1.A 1:1 propensity score-matched analysis was performed. The propensity score was nonparsimonious and was estimated from a logistic regression model with all the baseline covariates . Matching was performed without replacement and with a caliper width of 0.2. Patient characteristics were compared between the USC and the MSC by using Wilcoxon rank sum tests for continuous variables, and Pearson’s chi-squared tests or Fisher’s exact tests for categorical variables. Pearson’s chi-squared tests or Fisher’s exact tests were used to compare the rates of treatment recommendations between the USC and the MSC. Kaplan–Meier survival curves were plotted for time analyses, and log-rank tests were used to compare the curves. Treatment  rates and lead times were analyzed similarly. Statistical significance was specified a priori as A total of 1738 patients with a chief complaint of back and/or leg pain were seen by a spine surgeon between 1 July 2018 and 30 June 2019. There were 1004 patients (57.8%) seen at the USC, and 734 at the MSC (42.2%). The diagnoses included low back pain (73.5%), radiculopathy (10.3%), spinal stenosis/neurogenic claudication (4.5%), and others (11.7%).p = 0.332); over two-thirds of the patients in both groups were female . There were significant differences in the race distribution between groups, with a lower proportion of White and Black patients seen at the USC compared to the MSC (p = 0.002). On the other hand, a higher proportion of patients in the USC had Medicaid or were uninsured compared to the MSC (p = 0.001). The average CCI score was significantly lower in the USC clinic .The baseline patient and socioeconomic characteristics are summarized and compared in p = 0.880). The proportion of females in the USC was 64.1%, and it was 58.4% in the MSC (p = 0.096). The racial distribution (p = 0.432), the insurance distribution (p = 0.162), and the average CCI scores (p = 0.671) were no longer significantly different between the two groups.These differences warranted a propensity score-matched analysis, in which 437 patients in the USC were matched to 437 patients in the MSC; the results are summarized in p < 0.001), and a significantly lower proportion of patients were recommended surgery as their first treatment .For all patients, the most common recommendation was physical therapy (41.4%), followed by injection (14.6%), and surgery (9.7%). The differences in the treatment recommendations and the timing are summarized in p < 0.001)  .p < 0.001)  . The tim< 0.001) .Longer times to care delivery have been associated with suboptimal outcomes and decreased patient satisfaction for patients with chronic pain ,11,12. IThe most common initial treatment recommendation for patients seen at both clinic settings was physical therapy. The most common recommended intervention was injections in 14.6% of cases, followed by surgery in 9.7% of cases. Patients seen at the MSC were more likely to be recommended an injection and were less likely to be recommended surgery as a first treatment, compared to patients seen at the USC. Although the exact reason is unknown, the fact that the pain medicine clinician and physiatrist can both see the patient at the same visit may account for this finding. These specialists can offer patients nonsurgical treatment options and can further discuss cases with the surgeon in real time. The most noteworthy finding, however, was the significantly shorter times to the treatment order and the actual treatment occurrence that were seen after patients were evaluated in the MSC, and specifically for injections.Epidural injections, radiofrequency ablation, and nerve blocks are part of the armamentarium that is used by physicians to treat chronic back and/or leg pain. A survey of 314 practitioners who treated patients with back and radicular pain showed that over 77% recommended lumbar interlaminar injections, and over 97% recommended transforaminal injections . The eviTimely access to treatments, such as injections, is of the upmost importance for patients who suffer from debilitating back and/or leg pain. In the present study, a significant benefit in the time to the injection order and the injection occurrence was seen for patients evaluated in the MSC setting. Surgery is rarely recommended on the first visit to a spine clinic, and our study suggests that multidisciplinary approaches may decrease surgical recommendations further during the index visit. Having a multidisciplinary team available to discuss a case may allow for the exploration and recommendation of other treatment options.Commensurate with our findings, other studies have shown significant benefits in the time to care when multidisciplinary approaches are employed in patients with spinal disorders ,19,20. WA recent single-center prospective cohort study also evaluated the effect of the SSP on patients with low back pain . The autDrymalski and Agha described their experience creating the MU (University of Missouri) Comprehensive Spine Center . In theiNamiranian et al. also describe their experience with a multidisciplinary spine board for patients with low back pain . The autThe retrospective nature of this study and the lack of other objective health-related quality-of-life outcome measures are important limitations. Although age, sex, race, insurance, and CCI were used for the matching analysis, unmeasured covariates may also impact treatment recommendations and the time to care. A single-center institution is also subject to selection bias, and the population that it treats may not necessarily represent other populations with back and/or leg pain. Nevertheless, the first step was to evaluate whether or not the care was more efficient in the MSC setting; this was evidenced by significantly shorter times to the injection recommendation and occurrence. Given that only the initial visit was examined, whether treatment recommendations or times differed after a second or third visit is also unknown. This also means that the success rate for each of the initial treatments is unknown. Future prospective studies are currently planned to address these limitations.Multidisciplinary approaches allow for more efficient healthcare delivery for patients with complex health conditions. Nonoperative care still remains the first-line treatment for patients with chronic back and/or leg pain without any red flags. In this study, patients evaluated in an MSC received more efficient care, which was evidenced by the shorter times to the injection order and the injection occurrence. Our approach is unique in that patients are seen by multiple specialists at the same time, and it does not require referrals or multiple visits. The impact of the MSC approach on patient satisfaction and quality of life warrants further investigation.