It seems that magnesium (Mg) sulfate can be helpful in controlling the acute pain caused by the stone passing from the ureter by reducing ureter smooth muscle contractions. The present study has been designed with the aim of assessing the role of Mg sulfate in controlling the renal colic pain in emergency department (ED).This double blind randomized clinical trial was performed on 18 to 60 year-old patients with acute renal colic presenting to the ED of a teaching hospital during 1 year. Patients were allocated to one of the 2 groups receiving either IV morphine or IV Mg sulfate using block randomization method and were then compared regarding pain control characteristics and probable side effects.th minute and reached 100% on the 30th minute for both groups. The number of cases that were pain-free on the 20th minute was significantly higher in the morphine groups . However, on the 30th minute both groups experienced a similar condition in this regard . None of the patients in the 2 groups experienced the studied side effects.90 patients with the mean age of 37.34 ± 12.10 (18 – 60) years were divided into 2 equal groups. The 2 groups were in a similar condition regarding mean age (p = 0.168), sex distribution (p = 0.267), underlying disease (p = 0.414) and alcohol and drug abuse (p = 0.524). Mean pain scores of the patients based on VAS were not significantly different between the 2 groups on admission and 20, 30, 60, 120, and 180 minutes after drug administration. Success rate in reducing the pain by at least 3 points on VAS was equal and 91.1% for both groups on the 20It seems that Mg sulfate, as a muscle relaxant agent, can be considered as a safe adjunct medication in controlling the pain of renal colic patients in the ED. Pain is one of the most common causes of patients visiting emergency departments (EDs) and pain control is one of the important responsibilities of the specialists in this department . In the Choosing an efficient drug with easy administration, few side effects, and rapid acting in pain management of these patients, is of great interest.Main drugs used in managing renal colic pain are categorized into 2 major groups of non-steroid anti-inflammatory drugs (NSAIDs) and opioids. It seems that tocolytic drugs such as magnesium (Mg) sulfate can be helpful in decreasing the pain caused by the stone passing from the ureter by reducing ureter smooth muscle contractions. By preventing calcium from entering through the cell membrane of smooth muscles, Mg sulfate can reduce calcium, which is required for muscle contraction , 4. In aThe results of the study by Delavar Kasmaei et al. regarding comparison of Mg sulfate and ketorolac in controlling migraine headaches were indicative of similar effects of both drugs in the acute phase and better performance of Mg sulfate 1 hour and 2 hours after drug administration . AdditioStudy design and settingThe present double blind randomized clinical trial was performed on patients with acute renal colic presenting to the ED of Shohadaye Tajrish Hospital, Tehran, Iran, from March 2017 to March 2018. Protocol of the study was approved by the ethics committee of Shahid Beheshti University of Medical Sciences under the number SBMU.MSP.REC.1396.2548 and was registered on the Iranian clinical trial registry under the number IRCT20171206037774N1. The researchers adhered to research ethics and confidentiality of patient data based on the recommendations of Helsinki Declaration. Informed consent was obtained from the patients for participating in the study.ParticipantsPatients with acute renal colic in the age range of 18 – 60 years were studied without any sex limitation. Patients with known arrhythmia or heart block; cardiac failure, myocardial injuries; kidney failure; hepatitis; cardiac glycoside recipients; those consuming alcohol, opioid drugs, anti-anxiety medications, barbitorates, anti-depressants, anti-psychotic and sleep medications, and calcium channel blockers; those affected with myasthenia gravis and other neuromuscular diseases; pregnant women or those suspected with pregnancy; those having underlying bradycardia (heart rate less than 60 /minute) and long QRS interval; patients who did not sign the consent form; and cases with sensitivity to morphine or Mg sulfate were excluded from the study. In addition, those who had received any kind of analgesics or sedatives during the 6 hours prior to presentation to the ED were also excluded.InterventionAfter history taking and clinical examination, pain score of the patients was evaluated based on visual analogue scale (VAS) and morphine sulfate with 0.1 mg/kg dose was intravenously injected for all the patients via the median cubital vein during 1 minute. If the pain persisted 10 minutes after receiving morphine with a pain score over 6 and considering the inclusion and exclusion criteria, patients were allocated to either intravenous (IV) Mg sulfate  or IV morphine (0.1 mg/kg dose) groups via block randomization using random numbers table. Double dummy method was used for blinding, which means that recipients of injected morphine simultaneously received 100 ml normal saline and those receiving Mg also received IV distilled water with the same volume and speed as morphine.The whole mentioned process was done under constant cardiac, respiratory and blood pressure monitoring and pulse oximetry under the supervision of the senior emergency medicine resident who was in charge of performing the study but was blind to the type of drug administered.Considering the random method, injectable drugs were prepared in advance in syringes with the same color and with the same volume by a nurse who helped in performing the study and was blind to the pain severity and other characteristics of the patients on admission. Pain severity of the patients was reevaluated and recorded 20, 30, 60, 120, and 180 minutes after drug administration. If the patients’ pain was not controlled after being allocated to a study group and receiving the allocated medication, patients received reminder doses of morphine and were excluded from the study, but they were included in the statistical analyses in order to adhere to the intention to treat method.Data gatheringBaseline characteristics of the patients, pain severity based on VAS on admission and 20, 30, 60, 120, and 180 minutes after drug administration and probable side effects such as nausea, vomiting, vertigo, shortness of breath, allergy, and respiratory depression were gathered and recorded for all patients by the senior emergency medicine resident in charge of the patient and under supervision of the attending physician on duty using a pre-designed checklist.In this study, 3 or more points drop in the pain score based on VAS was considered as treatment success. Suspicion to renal colic was made by the senior resident in charge of the patient based on clinical symptoms including acute and sudden pain with a colic nature and its radiation to the groin or the lower part of the abdomen and also the testes with or without nausea, vomiting, sweating, paleness, burning urine, frequent urination, urinary urgency, and blood in urine, and was confirmed using ultrasonography or abdominal and pelvic computed tomography (CT) scan as well as urinalysis at the first possible opportunity that the patient could bear it.Pain score was assessed using VAS. This scale consists of a 10-cm ruler on which 0 indicates absence of pain and 10 indicates the most severe pain possible.OutcomesThe studied outcomes included success in pain management and probable side effects due to prescription of drugs.Statistical analysis For statistical analysis, SPSS software version 20 was used and for comparing the results between the 2 groups, t-test, Mann-Whitney, Chi square, or Fisher’s exact tests were applied. The findings were reported as mean and standard deviation (SD) or frequency and percentage. P value less than 0.05 was considered as level of significance. The person performing statistical analyses was also blind to the drugs received by the groups.Baseline characteristics of the studied patientsFinally, 90 patients with the mean age of 37.34 ± 12.10 (18 – 60) years were randomly allocated to one of the 2 groups receiving either Mg sulfate (45 patients) or morphine sulfate (45 patients) . Table 1Outcomesth minute and was 91.1% (41 out of 45 patients in each group) and reached 100% on the 30th minute for both groups. The number of cases that were pain-free (pain severity of 0) on the 20th minute was significantly higher in the morphine groups . Of course, on the 30th minute both groups experienced a similar condition in this regard .None of the patients in either group experienced any side effects including hypertension, allergy, drop in respiratory rate or reduced arterial blood oxygen saturation, and respiratory depression.Based on the findings of the present study, Mg sulfate showed a similar effect and an equal success rate in relieving the acute pain caused by renal colic in the patients presenting to ED when compared to morphine sulfate. However, it seems that the time interval to reach a pain-free status is a little longer for the group receiving Mg sulfate. None of the patients in either group experienced side effects in the prescribed doses in this study.Findings of the present study were similar to the results of Jokar et al. study in 2016, which evaluated and compared Mg sulfate with ketorolac in management of pain caused by renal colic and expressed that Mg sulfate can reduce the pain of patients with renal colic and decrease the need for additional morphine . Kocman Mg sulfate has been identified as a safe and efficient drug in dilation of the bronchi in patients with severe asthma . Mg sulfOn the other hand, a study carried out on women giving birth via cesarean section showed that intraspinal injection of 5% bupivacaine and Mg sulfate did not have much effect on elongation of analgesia. However, IV injection of Mg sulfate along with intraspinal injection of 5% bupivacaine showed better results .In the present study, adding Mg sulfate to the standard treatment of patients with acute renal colic led to a decrease in pain severity and reduced need for additional morphine. In the future, Mg sulfate might be considered for establishing pain control protocols and sedation induction in patients with acute renal colic in the ED. However, we should not forget that prescription of Mg sulfate is very dose-dependent; therefore, choosing the proper dose is very important for maximum efficiency and minimum toxicity.On the other hand, Mg sulfate should not be used in patients with known cardiac block, myocardial injury, severe kidney failure, hepatitis, and Addison’s disease and it is not recommended for use in patients with decreased kidney function, those who receive cardiac glycosides, patients with myasthenia gravis and other neuromuscular diseases, and when giving birth.Yet, in cases that there is an acute pain not responding to available medications or they are banned for use or are not available in ED, we might be able to consider Mg sulfate as a proper alternative with few side effects.Considering the obtained results and not seeing any significant side effect when using Mg sulfate drug as well as its easy administration, and on the other hand the problems caused by prescribing opioids, Mg sulfate can be used for adjunct treatment of patients with acute renal colic in ED to decrease patients’ pain severity. In addition, through simultaneous use of Mg sulfate, the rate of administration of other opioid drugs and their possible side effects can also be reduced.Not homogenizing patients regarding size and location of stone could be counted as a limitation of the present study. In addition, by increasing sample size, various subgroup analyses based on sex or drug and alcohol abuse and etc. can be performed.Based on the findings of the present study, Mg sulfate showed a similar effect and an equal success rate in relieving the acute pain caused by renal colic in the patients presenting to ED when compared to morphine sulfate. However, it seems that the time interval to reach a pain-free status is a little longer for the group receiving Mg sulfate.


Drug dependence, which can exist concurrently with chronic pain, is seen as one of the major causes of rapidly increasing medical expenses. However, drug dependence in patients with chronic pain has not been evaluated. The aim of this study was to identify the risk factors for drug dependence in patients with chronic noncancer pain.This retrospective study included 151 patients with chronic noncancer pain . Low back pain (LBP) occurred in 96 patients, whereas 22 had shoulder pain, 8 had hip pain, and 77 had knee pain. Patients were divided into drug dependence and nondrug dependence groups based on the Severity of Dependence Scale (SDS) scores. Patients with SDS scores ≥5 and <5 were classified into drug dependence and nondrug dependence groups, respectively. All patients completed self-report questionnaires. Factors that predict drug dependence were identified by performing univariate and multivariate analyses.Sixty (40%) of the 151 patients met the SDS criteria for drug dependence. Significant differences were found between patients with and without drug dependence for the LBP, hip pain, number of medications, and for the Numerical Rating Scale, Pain Disability Assessment Scale (PDAS), Hospital Anxiety and Depression Scale, and Pain Catastrophizing Scale (PCS) scores. Multiple regression analysis identified LBP, hip pain, PCS, and PDAS scores as factors related to drug dependence in patients with chronic noncancer pain.Drug dependence tends to differ in patients based on the location of their chronic pain. Pain catastrophizing and disability indicated a greater tendency for drug dependence. Thus, PCS and PDAS scores are useful screening tools for predicting drug dependence in patients with chronic pain. As nonsteroidal anti-inflammatory drugs (NSAIDs) have a limited effect in patients with chronic neuropathic pain, it is necessary to treat these patients with other drugs such as pregabalin or tramadol/acetaminophen.,7Although pain is a major complaint among patients visiting the hospital, it is often undertreated. Therefore, higher number of visits to health services are reported for patients who experience persistent pain and long-term disability. the potential for abuse is much lower for NSAIDs, acetaminophen, and analgesic plasters. However, the undertreatment of patients with persistent chronic pain can lead to a strong desire for oral medication. Drug dependence in patients is a chronic condition of the brain that results from compulsive drug use. Even though the user is aware of the negative consequences, a lack of self-control results in the compulsive drug use. The 3 symptoms that characterize drug dependence are as follows: psychological dependence in which patients have a compulsive desire to ingest more of the drug to obtain a desired effect; physical dependence characterized by an inability to perform normal activities and functions of daily life, as well as the occurrence of withdrawal symptoms when they stop using the drug; and tolerance, in which patients need to consume increasing amounts of a drug to obtain the desired effect. Although opioid addiction has frequently been reported during treatments for back pain, to the best of our knowledge, drug dependence in patients with chronic pain has not been analyzed in detail. Therefore, the purpose of this study was to investigate drug dependence in patients with chronic noncancer pain.Although the abuse of opioids can lead to drug dependence,2The present retrospective study was performed at the authors’ institution. All patients provided written, informed consent to participate in the study. Ethical approval was obtained from our institution's Institutional Review Board. This study recruited 151 patients  with chronic pain. Inclusion criteria included persistent pain for ≥3 months, conservative treatment for pain for ≥1 month, and the patient's agreement to complete questionnaires. Exclusion criteria included dementia, heavy users of alcohol, illicit drug users, or other conditions that would make it difficult to complete self-report written questionnaires. Patients were also excluded if they had a severe chronic disease such as cardiovascular disease or renal failure that would interfere with the treatment. The 5 multiple-choice items used by the SDS can be easily changed to modify references to the named drug or specific time span, respectively, thereby making it possible to cover different drugs and time frames. All items are explicitly concerned with the psychological components of dependence. Scores for each of the items range from 0 to 3, with a total scoring range of 0 to 15. Higher scores indicated a greater degree of dependence on the drug in question. Although earlier work with the SDS suggested that a cutoff score of 4 or 5 was indicative of dependence, this has yet to be statistically validated. In the present study, we judged a SDS score of 5 or more points to indicate drug dependence. In addition to the SDS score, data were collected on the patients’ demographic and clinical backgrounds.The mean age of the participants at the time of examination was 72 years , with a mean duration of pain from the onset of symptoms of 52 months . Table 2.1To measure the intensity of chronic pain, the Numeric Rating Scale (NRS) for pain self-assessment is a widely used, valid, and reliable tool. NRS scores range from 0 to 10, with 0 representing no pain and 10 representing the worst pain imaginable.2.2 The 20 items used for PDAS are rated on a 4-point Likert scale, with scores ranging from 0 to 60 points. Clinicians who require a multidimensional measure of the effects of pain have used the PDAS to examine a patient's daily routine.The items used for the Pain Disability Assessment Scale (PDAS) are designed to assess the negative effects of pain on broad-spectrum pain interference domains.2.3 Patients with physical illness can be easily assessed for anxiety and depression by using the HADS. The HADS is a 14-item scale, with 7 items assessing anxiety and 7 assessing depression. Each item is rated from 0 to 3 on a 4-point Likert scale. The overall scores for anxiety or depression range between 0 and 21, with higher scores indicating a greater severity of symptoms.The Hospital Anxiety and Depression Scale (HADS) was used to assess anxiety and depression.2.4 The PCS, which is a broad measure of pain catastrophizing, is composed of 13 items rated from 0 (never) to 4  on a 5-point Likert scale. The maximum score for the PCS is 52, with higher scores indicating greater pain catastrophizing levels. High levels of catastrophizing are defined by a score of >24. The items on the PCS are divided into the following 3 subscales: rumination, helplessness, and magnification. Rumination (items 8–11) “refers to the fact that the patient cannot get the idea of pain out of his/her head and cannot stop thinking about the pain.” Helplessness (items 1–5 and 12) “refers to the estimation that the person has not been able to do anything to influence the pain.” Magnification  “refers to the exaggeration of the threatening properties of the painful stimulus.”The Pain Catastrophizing Scale (PCS) is used to assess self-reported pain catastrophizing due to chronic pain.2.5t test. Nonnormally distributed variables were compared using the Mann–Whitney U test. Chi-square analysis was performed for categorical variables. Values of P < .05 were considered significant. Factors predicting drug dependence were identified by multivariate analysis (multiple regression). Potential predictive variables were included in the multivariate model if values of P < .05 were obtained on univariate analysis. A multiple regression model and 95% confidence intervals (CIs) were used to identify the risk factors that influence drug dependence. Statistical analysis was conducted using SPSS software version 22.0 for Windows .Patients with SDS scores ≥5 and <5 were classified into drug dependence and nondrug dependence groups, respectively. Univariate analyses were then conducted between the groups to compare age, sex, duration of pain, number of medications, pain complaints, and the NRS, PDAS, HADS, and PCS scores. Normally distributed variables were compared using a Student 33.1P = .35), mean age and duration of pain were significantly higher in the Both versus the LBP group . As shown in Table P = .02), and significantly lower PDAS (P = .02), PCS (P < .01), HADS (P < .01), and SDS scores (P < .01) in the Joint pain group compared with the other 2 groups. However, the NRS scores were significantly higher in the Both pain group compared with the other 3 groups (P < .01).In this study, 96 patients had LBP, 22 had shoulder pain, 8 had hip pain, and 77 had knee pain. Patients were divided into 3 groups. The LBP group consisted of 50 patients with LBP only , the Joint pain group consisted of 55 patients with joint pain only , and the Both pain group consisted of 46 patients with both LBP and joint pain  (Table 3.2P < .01). No significant associations were found between the drug dependence and mean age (P = .14) and the sex (P = .15). Among the drugs used in this study, pregabalin was administered at significantly higher rate in patients with drug dependence than without drug dependence (P < .01). Significant differences were observed for all of the other variables (P < .01) with the exception for shoulder pain (P = .73) and knee pain (P = .84).Among all of the patients, 60 40%) met the criteria for drug dependence according to their SDS scores. The 60 patients in the drug dependence group were composed of 21 males and 39 females, whereas the 91 patients in the nondrug dependence group were composed of 22 males and 69 females. Table 0% met th3.3y) were positively correlated with LBP (x1), hip pain (x2), and the PCS (x3) and PDAS scores (x4)  Table . These r4The results of this study revealed that drug dependence, as defined by SDS scores, was present in 40% of the patients with chronic noncancer pain. Drug dependence differed according to the site of pain, and was higher among chronic LBP patients versus chronic joint pain patients. Furthermore, among the chronic joint pain patients, drug dependence was higher in patients with hip pain than in those with pain in other joints. Multiple regression analysis revealed that high PCS and PDAS scores were associated with an increased risk of drug dependence. These findings suggest that these factors are useful indices that can be used when setting up treatments for patients with chronic noncancer pain.,16 Thus, none of the patients included in the present study were alcohol misusers or illicit drug users. Furthermore, iatrogenic substance abuse or addiction needs to be differentiated from preexisting substance abuse or addiction. A previous study reported that the prevalence of drug dependence predating the onset of back pain was 77%. Another study reported that 94% of patients had substance abuse problems before the onset of their back pain. These reports suggest that most substance abuse or addiction problems may predate chronic back pain and related opioid treatment. Chronic pain and addiction can coexist either on a continuum or as separate comorbid conditions. In pain management, controlled substances are viewed as either a problem or a solution depending on the healthcare professional's training and perspective. Only a few pain training programs are known to offer significant experiential and didactic training in drug abuse and addiction, even though chronic pain and addiction often coexist. There is a low risk for iatrogenic abuse or addiction in patients with no previous history of substance abuse or addiction in short-term treatment for noncancer-related back pain. Even so, the undertreatment of chronic pain cannot be ethically justified in well-selected patients. Therefore, it is important that clinicians be able to recognize the difference between true addiction and similar conditions. Opioid-seeking behaviors are known to increase in patients when chronic pain is left untreated or undertreated. In the present study, 21.2% of the patients with chronic noncancer pain were treated with NSAIDs only. As it has been reported that NSAIDs have only limited effects in chronic pain patients, a weak opioid analgesic such as tramadol should be considered as an alternative treatment. However, other studies have found that the long-term efficacy of opioids for chronic pain may be limited.,23When assessing drug dependence in patients being treated for chronic pain, it has been reported that heavy users of alcohol or illicit drug user need to be excluded. Moreover, a decreased incidence of adverse drug reactions has been reported when a combination of individually ineffective doses of tramadol and acetaminophen are used to provide adequate pain relief through the actions of multipathways. However, in the absence of a clear treatment policy, this could introduce the risk of increased dosage levels.As most pain conditions involve various pathways, analgesic therapy using a single agent may be inadequate for relieving chronic pain. It has been suggested that more effective pain relief for a broader spectrum of pain could be achieved by using combination analgesics with 2 or more agents that have synergistic analgesic effects. Psychological factors are one of the causes of this change. It has also been reported that depression and sleep disorders, which cause functional impairment, can lead to reduced pain thresholds. Therefore, patients receiving prolonged pain management tend to have persistent pain. The present study found that many patients with drug dependence also had depressive conditions. Thus, the results of our study suggested that the dominant factors that influenced drug dependence were pain catastrophizing and disability. Cognitive behavioral therapy has been widely accepted for use in patients with alcohol and drug dependence. We believe that multidisciplinary approaches, including physical therapy are necessary to treat patients with pain catastrophizing and disability. A recent study reported that patients treated for chronic intractable pain at a pain liaison clinic showed significant improvement in pain catastrophizing and anxiety after 6 months of treatment. We also believe that drug dependence is “a family illness,” as a patient's family plays a crucial role in recovery because the drug dependent patients lack insight into their disease. Therefore, cognitive behavioral therapy with the patients’ families has been recommended.Pincus et al examined the transition to chronic pain status and reported finding strong evidence for the role of negative mood (distress or depression). Patients with neuropathic pain show higher ratings of pain intensity, and tend to be intractable than nociceptive pain. As neuropathic and nociceptive components contribute to chronic pain, these components require different pain management strategies because of their different pathogeneses. There is a possibility that drug dependence could be examined in more detail by classifying chronic pain patients according to type of pain. Despite these limitations, this study does provide new knowledge on drug dependence. Patients with LBP and hip pain were at a higher risk of drug dependence versus patients with shoulder or knee pain. Trials that have tried to visualize chronic pain using functional magnetic resonance imaging (fMRI) have been actively carried out in recent years. The application of techniques such as fMRI and brain imaging are expected to result in further developments and improvements in identifying and treating patients with drug dependence. In addition, based on the correlation we found for the PCS and PDAS scores with drug dependence, these scores might be beneficial screening tools that can be used at the time of the first examination in order to prevent drug dependence. The results of this study could very well lead to improvements in the treatment of patients with chronic pain.There were some limitations for the present study. Firstly, the sample size of this study was small. This study examined drug dependence in patients with chronic noncancer pain according to different pain locations, which included the lumbar area, shoulder, hip, and knee. However, there were only 8 patients with hip pain included due to its low morbidity rate. Moreover, we analyzed which drug could induce drug dependence using univariate and multiple regression analyses. However, analyses of the 9 different drugs made it even smaller-size study. This small number of patients is considered the weakness of this study. Second, we did not classify patients based on the nature of the chronic pain. The results of this study indicated that patients with LBP were found to be more dependent to drugs. Generally, 64.7% were found to have possible neuropathic pain in an unselected cohort of chronic LBP patients.Conceptualization: Tomoko Tetsunaga, Tomonori Tetsunaga, Keiichiro Nishida, Hirotaka Kanzaki, Toshifumi Ozaki.Data curation: Tomoko Tetsunaga.Formal analysis: Tomoko Tetsunaga, Tomonori Tetsunaga.Investigation: Tomoko Tetsunaga.Methodology: Tomoko Tetsunaga, Tomonori Tetsunaga, Keiichiro Nishida, Hirotaka Kanzaki, Tomoyuki Takigawa, Yasuyuki Shiozaki, Toshifumi Ozaki.Supervision: Tomonori Tetsunaga, Haruo Misawa, Tomoyuki Takigawa, Yasuyuki Shiozaki.Writing—original draft: Tomoko Tetsunaga, Tomonori Tetsunaga.Writing—review and editing: Tomoko Tetsunaga, Tomonori Tetsunaga, Keiichiro Nishida, Hirotaka Kanzaki, Haruo Misawa, Tomoyuki Takigawa, Yasuyuki Shiozaki, Toshifumi Ozaki.


In multivariable analysis, alcohol abuse , prescription drugs abuse , functional pain , head and neck pain , MEDD  ≥ 200 mg/day , and ongoing litigation  were significant predictors of OrCC. In conclusion, the break-out of OrCC in CNCP in South Korea was comparable to those in countries with high opioid consumption, such as the United States, regardless of the country’s opioid consumption rate.Opioid consumption has increased worldwide, which carries the risk of opioid use disorder (OUD). However, the literature on OUD and opioid-related chemical coping (OrCC) in chronic noncancer pain (CNCP) is heterogeneous, with most studies conducted in the United States. We performed a multicenter, observational, cross-sectional study to address OrCC in long-term opioid therapy (LtOT) for CNCP in South Korea. The objectives were to determine the frequency and predictors of OrCC. We included 258 patients. Among them, fifty-five (21%) patients showed OrCC. The sample had high pain catastrophizing , moderate-severe insomnia , low resilience (68 points), and high suicidal ideation (67%). OrCC patients had greater pain interference (85.18% vs. 58.28%,  Chronic pain is a devastating disease that is often treated inadequately . Among aMany clinicians are reluctant to prescribe opioids due to the risk of opioid use disorder (OUD) secondary to the induced reward responses to the drug . In chroThe literature on OUD and OrCC is heterogeneous, and an overwhelming majority of the studies took place in the U.S. ,17,18,19Given the above, we performed a national, multicenter, observational study to address OrCC, the intermediate status of OUD, in LtOT for CNCP in S. Korea, a country with moderate opioid consumption rates . The objThis national, observational, cross-sectional study was conducted in eight tertiary university-based hospitals in S. Korea between April 2017 and January 2018. The study was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Institutional Review Boards (IRB) in each hospital. The protocol of the study was registered and openly shared in ClinicalTrials.gov (NCT03161795) to stress in the transparency of the research conduction. Eleven pain specialists, one neuropsychiatrist, and one oncologist took part in the study. Written informed consent was obtained from each participant prior enrollment. All methods and results have been reported according to the STROBE recommendations .Inclusion criteria: (1) age ≥18 years; (2) diagnosis of chronic pain defined by the International Association for the Study of Pain (IASP) as persistent or recurrent pain lasting longer than 3 months or past the time of normal tissue healing ; (3) patExclusion criteria: (1) patients with a cancer diagnosis and/or receiving ongoing cancer treatment, palliative care, or end-of-life care; (2) patients who received opioid therapy for <3 months or intermittently; (3) patients with serious systemic diseases or acute psychiatric disorders that required inpatient management , which compromised their safety or the completion of the study; or (4) patients with intellectual impairment and unable to answer the survey questions.The evaluation of OrCC was discussed by eleven anesthesiologists, one neuropsychiatrist, and one oncologist in the initial expert meeting. The presence of OrCC was determined through a questionnaire that contained seven behaviors related to OrCC. The questionnaire was based in a previous study of OrCC  and the Patients’ sociodemographic data were obtained from the electronic medical record (EMR) including educational level (<high school or ≥high school) and religion , pain characteristics ) , co-morbThe risks of LtOT were assessed through a survey in the outpatient setting of each pain clinic. After obtaining written, informed consent, the patients received a patient’s booklet and responded to the following questionnaires and forms: (1) Cut down, Annoyed, Guilty, Eye-opener Adapted to Include Drugs (CAGE-AID) ; (2) BriOn the survey day, after answering the patient’s booklet, each patient attended a routine visit with a pain specialist. Once the patient exited the room, the specialist answered the questionnaire to assess the patient’s OrCC  includedThe precision/absolute error and the significance level were set at 5% and 95%, respectively . According to a published study by Kwon et al. , the pret-tests or Wilcoxon rank sum tests were performed to compare two independent groups. A paired t-test was used to compare two means from the same group. Categorical data were analyzed using Pearson’s χ2 test, Fischer’s exact test or Chi-square test. The normality distribution for continuous variables was assessed with the Kolmogorov–Smirnov test. The independent t-test was used to compare normal distribution and the Mann–Whitney U test was used for non-normal distribution.Depending on the data distribution, independent p-value < 0.1 in univariable analysis were considered for multivariable analysis. The multivariable regression analysis was conducted by manual forward stepwise selection, and variables with a p-value < 0.05 were retained.Univariable analysis was performed to explore variables associated with OrCC, using the presence of OrCC as a dependent variable and clinical variables that included sociodemographic data, pain characteristics, opioid information, scores of CAGE-AID, K-IADL, PCS, and BPI-SF, as independent variables. Clinical variables with a p-values are two-tailed, and p-values < 0.05 were considered statistically significant. Statistical analyses were performed using SPSS version 22.0. .All parametric data were presented as mean ± standard deviation (SD) and nonparametric data as percentage (%) or odds ratio (OR) with a 95% confidence interval (95% CI). All A total of 258 CNCP patients receiving LtOT, in six of eight hospitals, were included in the study . Patientn = 55) and control group (n = 203)). p = 0.038) and with an education level greater or equal to high school level . Although the reduction of NRS pain score from the initial to final visit was significant within each group (p < 0.001 in controls and p = 0.048 in copers), it was less than 1 point in both groups. Pain in the head and neck, functional pain syndrome, and mixed pain were more common in copers . Alcohol and/or medication abuse, and prescription drug use with alcohol within one year, were remarkably frequent in copers when compared to non-copers . More copers had co-morbid depression  and reported ongoing litigation . Additionally, an overwhelming 66.7% of the sample (n = 172) had suicidal ideation related to their chronic pain.The patients were divided into two groups according to a positive OrCC . The average MEDD (mg/day) was significantly higher in the copers than the non-copers . Patients with MEDD ≥100 and ≥200 mg/day were more frequent in the coping group . The number of annual visits to an opioid prescriber and the number of patients who visited the ER seeking for opioids was significantly higher in the copers than non-copers . The first opioid prescriber was not significantly different between groups; and in 81% of the sample, the first opioid prescriber was a pain specialist.The opioid information is shown in p = 0.054). The PCS was over 30 in both groups, indicating a “catastrophic” appraisal of pain. The “worst” NRS item of the BPI-SF was higher, and the general activity, mood, and sleep interference were worse in the copers than the non-copers . The K-IADL score and percentages were higher in the coping group . Both groups reported high anxiety and depression in HADS, moderate clinical insomnia in the ISI, and low resilience in the K-CD-RISC.n = 24, 44% vs. n = 44, 22%; p = 0.002). The PGIC was similar in both groups. There were no differences in the adverse or undesirable effects between groups, and 62% of the patients reported at least one event. The most frequent was constipation  followed by somnolence  and nausea .About 74% of the subjects were extremely or somewhat satisfied with their LtOT, and the percent of patients unsatisfied was significantly more prevalent among copers vs. non-copers (p = 0.016); (2) alcohol abuse (OR = 6.84 (95% CI = 2.26–20.69), p = 0.001); (3) functional pain syndrome (OR = 12.96 (3.47–48.45), p < 0.001); (4) head and neck pain (OR = 2.48 (95% CI = 1.05–5.88), p = 0.039); (5) MEDD ≥ 200 mg/day (OR = 3.48 (95% CI = 1.43–8.48), p = 0.006); and (6) ongoing litigation (OR = 2.33 (95% CI = 1.01–5.39) p = 0.047). Additionally, age < 55 years (OR = 2.17 (95% CI = 0.99–4.76), p = 0.052) and BPI-SF mood interference ≥ 8 (OR = 1.84 (95% CI = 0.90–3.77), p = 0.096) remained in the multivariable model.This study evaluated the rate of OrCC and patient characteristics in a group of CNCP patients receiving LtOT. The frequency of OrCC was 21%, which indicates that about one out of every five CNCP patients used opioids to cope with emotional distress. There is a scarcity of research regarding the frequency of OrCC, with the except of one study  which rep = 0.005). In our study, younger patients had higher level of education and conversely older patients had lower than high school education level. A recent report found that 66% of Koreans, between the age of 25 and 34 years, attained tertiary education, while only 8% of Korean women aged 55–64 years did it [Regarding patients’ demographics, previous studies reported that young age and male sex are common risk factors for OUD and dependency ,46. In ts did it . Therefon = 52, 20.2%) without significant differences between the groups. Those patients have more risk factors for pain, including higher rates of psychiatric and substance use disorders [p = 0.039), and functional pain disorders increased 13 times the risk of OrCC (p < 0.001) in our multivariable analysis. Functional pain syndromes typically concur with anxiety, depression, and chronic fatigue syndrome [In terms of the pain characteristics, the overall patients in this study complained of moderate to severe pain with the NRS pain score of >7 at their initial visits. Despite LtOT, however, their pain improvement on the last measurement was trivial with only 8.6% reduction in the pain severity. In addition, the prevalence of posttraumatic stress disorder in the study’s sample was relatively high  and 19 times (p = 0.016) the risk of OrCC in our results. The concomitant use of alcohol and opioids is associated with OUD, OrCC and worse outcomes [p = 0.002). Therefore, CNCP patients with alcohol and/or prescription drug abuse history require special attention due to an increased risk of OrCC, opioid toxicity, and poor outcomes.Major depression and alcohol or drug abuse are known risk factors for OUD and OrCC ,54,55 whoutcomes , which ip = 0.006) in this study. Interestingly, doses of 100–200 mg/day were not different among the groups (p = 0.878). However, dosages ≥200 mg/day almost quadrupled the risk of OrCC (p = 0.002). Another study from the U.S. also found increased OUD rates with dosages ≥200 mg/day, without differences at 100 or 120 mg/day [p = 0.001 and p < 0.001 respectively). Therefore, although pseudo-addiction should be initially discarded as a cause of opioid seeking [Similar to previous studies in OUD ,60, pati0 mg/day . Therefo0 mg/day ,63,64. A0 mg/day ,66, our  seeking , frequenThe BPI-SF showed increased pain interference, and the K-IADL indicated an increased compromise of daily activities in the copers. Our results suggest that decreased functionality and high pain interference constitute risk factors of OrCC ,69. Ongop = 0.054). Interestingly, CAGE-AID positives were found in 66.5% of the controls, whereas 20% negatives were copers. This result infers that CAGE-AID is a predictive, but not a diagnostic tool for OUD with a low specificity [Contrary to previous studies on chemical coping ,67, in tcificity ,74. Morecificity , as in ocificity . Converscificity . Additiocificity ,78. AccoAnother remarkable finding in this study is the absence of illicit drug abuse reports. This result may be secondary to deep-rooted cultural and social stigmatization of illicit drugs in Asia . Historin = 258); however, a broad CI of some OrCC risk factors in our multivariable analysis, such as prescription drug abuse (OR = 19.32 (95% CI = 1.75–213.81)) or functional pain syndrome (OR = 12.96 (95% CI = 3.47–48.45)), would be a limitation. Another drawback is that the study’s data depended on statements from patients. Although there was assurance of confidentiality, patients’ responses may not always be reliable. Finally, urine drug test (UDT) and opiate immunoassay, which are considered “gold standards” to assess OUD [There are several limitations to be addressed. First, this study took place only in tertiary hospitals. This may be associated with biases for generalization since the patients in this study may have more challenging pain syndromes than those in primary institutions. Second, the questionnaire used to evaluate OrCC was a result of an expert meeting, however, it is not a validated tool. In addition, although there were three consensus and educational meetings prior to patient enrollment, there might be detection biases between pain specialists. Nonetheless, OrCC is a clinical phenomenon accurately assessed by experienced providers , thus, aApproximately 21% of the CNCP patients receiving LtOT are chemically coping with opioids, carrying high intensity of pain, and experiencing severe interference in daily activities. The high rates of OrCC found in this study suggest that the break-out of OUD in CNCP of S. Korea is comparable to those in countries with high opioid consumption, such as the U.S., regardless of the country’s opioid consumption rates. Therefore, we should be vigilant about OUD in CNCP patients with LtOT. The independent risk factors of OrCC are prescription drugs and alcohol abuse, functional pain syndrome, pain in the head and neck, MEDD ≥ 200 mg/day, and ongoing litigation. Although further validation studies are warranted, the assessment of OrCC may prompt the identification of patients at high risk for severe OUD. Finally, although our result has suggested that there is no benefit of LtOT in CNCP, more research is needed to establish the rationale of evidence-based opioid prescription that should be limited to short-term use as much as possible.


To assess the effects of virtual reality on patients with musculoskeletal disorders by means of a scoping review of randomized controlled trials (RCTs). The databases included PubMed, IEEE, and the MEDLINE database. Articles involving RCTs with higher than five points on the Physiotherapy Evidence Database (PEDro) scale were reviewed for suitability and inclusion. The methodological quality of the included RCT was evaluated using the PEDro scale. The three reviewers extracted relevant information from the included studies. Fourteen RCT articles were included. When compared with simple usual care or other forms of treatment, there was significant pain relief, increased functional capacity, reduced symptoms of the disorder, and increased joint angles for the virtual reality treatment of chronic musculoskeletal disorders. Furthermore, burn patients with acute pain were able to experience a significant therapeutic effect on pain relief. However, virtual reality treatment of patients with non-chronic pain such as total knee replacement, ankle sprains, as well as those who went through very short virtual reality treatments, did not show a significant difference in parameters, as compared with simple usual care and other forms of treatment. Current evidence supports VR treatment as having a significant effect on pain relief, increased joint mobility, or motor function of patients with chronic musculoskeletal disorders. VR seems quite effective in relieving the pain of patients with acute burns as well. Virtual reality (VR) of players using body movement to interact with a computer is a new form of treatment in rehabilitation settings. It generates a virtual world in three-dimensional space through a computer simulation that stimulates user senses, such as sight and hearing, making users feel as if they are immersed in it. VR has three elements: Interaction, Immersion, and Imagination . It can However, its greatest obstacles lie in the lack of space, time, support staff, appropriate customer and customer incentives, therapist knowledge, and management support. The clinical use of VR often depends on the motivation and attitude of the therapist ,4.In the clinical investigations on the VR experience and perception of physical therapists (PTs) and occupational therapists (OTs) in Canada conducted by Levac et al., it was found that VR treatment is most commonly used for stroke 25.8%), brain injury 15.3%), musculoskeletal disorder 14.9%), cerebral palsy 10.5%), and neurodevelopmental disorders 6.3%) [%, muscul.8%, brai.3% %, m,8,9,10. %, cerebr.5%, and According to the World Heath Organization (WHO), musculoskeletal conditions affect muscles, bones, joints and associated tissues such as tendons and ligaments. To patients, musculoskeletal conditions are typically characterized by pain and limitations in mobility or functional ability.... Pain and restricted mobility are the consistent features of the range of musculoskeletal conditions. Musculoskeletal conditions are the second largest contributor to disability worldwide . HoweverSo far, there are no integrated and first-rate studies that explore which musculoskeletal disorders are suitable for VR treatment. The comparison of the effects of VR games and other treatments  on patients with musculoskeletal disorder is inconclusive. Therefore, this article integrates the results of studies made in recent years into a scoping review to: (1) Compare the effectiveness of VR and other treatment interventions for patients with musculoskeletal disorder; (2) further explore whether there is any consistency in the VR treatment of patients with musculoskeletal system disorder, so as to give recommendations based on the highest level of evidence. This review only contains RCT articles with a PEDro Scale score ≥5 points.http://www.pedro.org.au/). When reference materials could not be found on the PEDro website, scores were independently made by two authors who have completed the PEDro Scale training tutorial on the Physiotherapy Evidence Database.The methodology of this scoping review was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines because the main aim of this work is mapping all the available literature in the musculoskeletal field . The useWhen the scores were different, the clinical physiotherapist with more than five years of experience, and who completed the PEDro assessment training, was asked to conduct another assessment. When issues such as disagreement or ambiguity arose, they were resolved through discussions. Finally, literature with very low PEDro scores (<5/10) was excluded. The search process is shown in Initially, the two authors completed the abstract review independently. When it was not possible to know whether an article could be included in the scoping review from its abstract, an assessment of the full article was made. All of the articles that had been included were reviewed in full. After sorting, the following were investigated: (1) Whether VR treatment improved the musculoskeletal system as compared with other treatments; (2) whether there was any consistency in the musculoskeletal disorder of patients that received VR treatment. The selected articles were summarized and analyzed with descriptive statistics. The author, publication year, subject, intervention, outcome measures, and mean between-group differences  were extracted from the references by the two authors of this study. A consensus was reached through discussion when the authors had different opinions.A database search was made to exclude articles with a PEDro score of less than 5 and non-English publications. A total of 14 articles were included. These 14 articles were included in this scoping review .The quality of included studies was presented in Each article abstract  is organized in Virtual Reality was applied using several resources. In the 14 studies, one study used Kinect ; 5 studiThe outcome could not be pooled into meta-analysis due to the following reasons. Clinical heterogeneity  can be cp < 0.05) [In the articles included, a total of twelve studies compared the effects of VR treatment and other intervention on orthopedic conditions . The res < 0.05) . However < 0.05) . In the  < 0.05) . A study < 0.05) .In the included articles, four articles discussed the therapeutic effects of VR and no intervention on chronic cervical pain, burn wound, low back pain, and ankle sprains . When apDuring the dressing application of patients with burn wounds, patients undergoing VR treatment received significantly lower doses of Entonox  compared with those in the standard distraction group. However, there is no significant reduction in patient pain . For patAlthough associated pain is not itself part of the root disorder, managing the pain of musculoskeletal disorders is a major part of general practice. Of the 14 musculoskeletal studies included, six were for acute pain, including the dressing of the burn wound ,28, threMost virtual reality treatment research applications still focus on the VR treatment of central nervous system problems, such as stroke and cerebral palsy, while only a little research explores the therapeutic effect of VR treatment on patients with musculoskeletal disorders. At present, there is no research on the integration of virtual reality for patients with various musculoskeletal disorders and an analysis of its effects. Therefore, this scoping review searched and integrated multiple musculoskeletal disorders in VR applications. Analysis showed which patients with musculoskeletal disorders had better results after VR treatment.In general, chronic pain usually lasts for more than 12 weeks, while acute pain usually lasts for 4 to 6 weeks . TherefoGenerally, patients suffering from chronic pain have lower levels of fitness than healthy people. This is because pain can affect the motor control strategies of people. Individuals tend to move in the least painful way; however, the least painful way is usually to refrain from moving. This causes a decrease in muscle size and strength; it repeatedly increases pain and stress, eventually producing to a vicious circle . In the In addition, this result lasted for one month . AnotherThe results of this study show that VR treatment with a hand joystick significantly reduces the pain score of patients when removing dressings from patients with acute burns, or it will reduce the use of analgesics ,28. ThisIn summary, VR treatment can reduce pain in acute burn wound care and chronic musculoskeletal disorders. It can effectively distract patients with chronic pain, and allow them to ignore the cumbersome rehabilitation training, consequently improving treatment motivation. In addition, VR treatment may be helpful in the psychological level and the establishment of confidence. For example, patients with burns or chronic disability may have a tendency to fall into depression because of the long course of the disorder. The use of VR can release psychological stress and reduce their fear of pain .Virtual reality is also helpful in the control and perception of muscle movements. This systematic review includes the hard to control PFM, as well as waist and neck movements. The PFM training research included in this article  recommenDepending on the different facilities which possess different visual perception methods, Virtual Reality can be divided into four types: (a) Desktop VR: Mouse, trackball, and joystick are the main computer transmission devices and a common PC screen was used as its output; (b) Simulator VR: In a specific environment, machines and equipment, added to an image screen, provided the Users simulation results; (c) Projection VR: With a large projection screen, several projectors, and stereo sound output devices, simulation scenes were projected around the user; (d) Immersion VR: Specific Input and output devices, such as helmet display, etc., were used in this type of simulation . The resBecause this system review includes first-rate RCT studies, fewer articles that compare the effects of VR therapy with other interventions on patients with musculoskeletal disorders are available. In some articles, the lack of raw numeric data makes it impossible to calculate the mean difference between the experimental and control groups. During the article retrieval process, language was also restricted; therefore, some language bias might exist. In addition, very few articles contain the minimal clinically important difference (MCID) on various parameters; hence, further discussion was not made.VR treatment appears to have a significant effect upon pain relief, increased joint mobility, or the motor functions of patients with chronic painful musculoskeletal disorders. VR seems quite effective in relieving the pain of patients with acute burns as well. However, there is insufficient evidence in the current literature; hence, more research is needed to explore the therapeutic effects of VR treatment on musculoskeletal disorders. In the future, VR games maybe used for more patients with chronic musculoskeletal injuries. As to whether different types of VR would affect the effectiveness for rehabilitation results in musculoskeletal disorder patients, this should also be further investigated.


Significant differences were also observed when TAC levels between high-intensity pain patients and controls were compared, as well as between DD patients and controls. In logistic regression analysis, higher levels of TAC were related to DD  and to high-intensity pain . We also found that morning SC was positively correlated with antioxidant parameters in TMD patients. Our data suggest compensatory mechanism as response to higher level of stress. This stress could be extrinsic and lead toward TMD, or intrinsic, emerging from established TMD, or could be both. The intensity and the source of pain should be considered important factors in future investigations evaluating salivary OS markers in TMD patients.Temporomandibular disorders (TMD) have been associated with altered salivary oxidative status, but the relation with pain source and pain severity isn’t clarified. With the aim to assess their interaction with TMD, we compared levels of selected salivary oxidative stress (OS) markers , uric acid, 8-hydroxydeoxyguanosine, malondialdehyde) and salivary cortisol (SC) as a stress indicator, between 20 TMD patients and 15 healthy control subjects. In order to record differences relating to pain source and severity, patients were respectively classified according to specific diagnoses ), and pain intensity (high or low). TAC was significantly higher in TMD patients than in controls (morning  Oxidative stress (OS) has been implicated in the pathophysiology of many diseases, including oral diseases .Different biospecimen, including saliva , are useBecause pain-related TMD impact individual’s daily activities, psychosocial functioning, and quality of life, it is important to understand their pathophysiology and the mechanisms involved in provoking pain and determining its intensity in order to determine factors predictive for disease severity and enhance therapeutic strategies for these patients. Advances in our understanding of the disorder and the mechanisms of pain allow the possibility of providing personalized care for TMD patients .Several studies suggest that OS plays a role in the TMD and the experience of pain related to TMD. The aim of our study was to compare the levels of selected salivary OS markers and salivary cortisol (SC) between patients with chronic pain-related TMD and healthy controls and to assess differences relating to the source (muscle or joint) and the intensity (low or high) of pain. We also evaluated the relationship between OS markers and SC, a biological marker for stress response, since it is suggested that TMD patients have biological predisposition for enhanced stress reactivity . On the We hypothesized that we would encounter higher salivary oxidant levels and lower salivary antioxidant levels in TMD patients than in control group, depending on the source and intensity of pain, and that salivary OS markers would correlate with SC concentrations.This case-control study was performed at the School of Dental Medicine, University of Zagreb. The study was approved by the Ethics Committee  and conducted in accordance with the Helsinki Declaration. All subjects were informed of the procedures involved in the study and provided written consent. Recruitment of participants was performed between May 2017 and April 2018.Power analysis, performed to estimate sample size, was based on the data from the pilot study . MinimalParticipants were recruited from patients seeking treatment for TMD and orofacial pain. Inclusion criteria were painful disc displacement (DD) or myofascial pain (MP) according to the diagnostic criteria for TMD (DC/TMD)  and repoExclusion criteria were other orofacial pain conditions including dental pain, smoking, poor oral hygiene, gum swelling, periodontitis, oral lesions, chronic medical conditions , pregnancy, use of supplements and medications known to affect the results of our tests. Patients displaying combined MP and DD and patients with degenerative joint disease were also excluded. Twenty TMD patients and 15 healthy age matched control subjects were included. All participants were women. Different groups relating to pain source (10 DD and 10 MP) were formed in order to explore its interaction with OS.Characteristic pain intensity (CPI) was assessed using the graded chronic pain scale by computing the means of three items  and multiplying them by 10. CPI < 50 was considered to be low-intensity pain (LIP), and CPI ≥ 50 was considered to be high-intensity pain (HIP). Subsequently, we formed another division of TMD patients according to pain severity (10 HIP and 10 LIP).The methods of sample collection and analysis were described in detail and validated by our group in a prior study . The subSaliva samples were used to analyze the following OS markers: 8-hydroxydeoxyguanosine (8-OHdG), malondialdehyde (MDA), TAC, glutathione peroxidase (GPX), superoxide dismutase (SOD), and uric acid (UA). For these assays, analytical performance, including intra- and inter-assay variability, was assessed. The data and a detailed description of the methodology is available in our previous study .Free SC was analyzed using a competitive ELISA kit . The intra- and inter-assay variabilities of this assay kit are 5.8 and 6.4%, respectively, according to the manufacturer. All results were normalized to the total protein concentration. Sample analysis was performed at the Department of Laboratory Diagnostics, University Hospital Center Zagreb.p < 0.05. Data distribution was tested using the Shapiro-Wilk test. Student’s t-test was used for comparison of two groups (TMD vs. controls) and analysis of variance (ANOVA) for comparison of three groups (controls vs. TMD subgroups), for the normally distributed data (age and CPI). Mann-Whitney U test and Kruskal-Wallis test were used for comparison of two and three groups, respectively, if the data were not normally distributed (OS markers and SC).Analyses were performed using SPSS 17.0  with the alpha set at Spearman correlation evaluated the association between salivary OS products and antioxidative enzymes with SC. Logistic regression analysis determined the association between each marker, which were the independent variables, and the groups, for which the dependent variables were study groups (TMD and controls), source of pain (MP or DD), and pain intensity (LIP or HIP).p = 0.175) nor between the control subjects and the TMD subgroups of 10 MP (42.6 ± 12.65) and 10 DD (36.00 ± 11.10) subjects . The mean CPI of MP subjects (46.03 ± 15.92) and DD subjects (45.4 ± 19.77) were not statistically different . Five MP and 5 DD subjects had LIP . The difference between groups was non-significant . Similarly, no significant difference  was shown between 5 MP and 5 DD subjects with HIP . Therefore, patients were pooled in pain intensity subgroups regardless of the source. Conversely, patients were pooled in pain source subgroups regardless of pain intensity.No statistically significant age differences were noted between 20 TMD subjects (39.30 ± 12.07) and 15 controls (34.33 ± 7.86) . The levels of salivary TAC were significantly higher in TMD patients compared to the controls . Morning SC was significantly higher  in the TMD group than in the control group. Differences in salivary OS markers and SC between the control group and TMD subgroups are presented in Table 1.The levels of salivary GPX among TMD subjects were significantly lower than among the controls . Among control subjects, no significant correlation was found between SC and OS markers.In TMD patients, antioxidant parameters were positively correlated with morning SC .TAC was positively associated with TMD  and in the afternoon  were positively associated with DD. No such association was found for MP. Higher TAC was also related with HIP .When evaluating the association between each salivary OS marker and the source of pain, higher levels of TAC in the morning (OR: 1.66, 95%CI: 1.05–2.64, The results of our study did not confirm lower levels of salivary TAC in TMD patients as we expected, based on the results of previous studies . On the The mechanisms by which OS may modulate pain in TMD are not known but are probably diverse. Number of subjects and high variability of OS markers clearly represent study’s limitations, and demand caution in the interpretation of results. Nevertheless, results encourage research on the relationship between OS and TMD, aiming to better understand the disturbed antioxidative/oxidative balance and TMD, either as the consequence or the cause of one another. In conclusion, both the intensity and source of pain as well as time of saliva sampling should be considered in future investigations to determine the diagnostic utility of OS markers in the saliva of TMD patients.The datasets generated and analyzed during the current study are not publicly available, because this is a pilot study and further study will include more TMD patients who are still being recruited. However, all data from this study is available from the corresponding author on reasonable request.EV and LV collected the samples and wrote the manuscript. IZA designed the study, analyzed the data, and wrote the manuscript. IL measured the samples and co-wrote the manuscript. DR contributed substantially to the concept and design, and measured the samples. AAR collected the samples and coordinated specimen storage. DI analyzed and interpreted the data. DKZ collected the samples and analyzed the data. TB planned the analyses and collected the samples. IA designed the study and critically reviewed the manuscript.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.


The primary objective was to investigate the prevalence of neuropathic-like pain in patients with psoriatic arthritis (PsA). Secondary outcomes were to investigate whether mood, fatigue, pain, disease severity and fibromyalgia are associated with neuropathic-like pain in PsA patients.PsA patients were assessed for fatigue, mood, pain, disease activity and fibromyalgia using questionnaires. Neuropathic-like pain was assessed by PainDetect.p < 0.05). PainDetect score correlated with measures of disease activity, fatigue, depression, anxiety, Widespread Pain Index and Symptom Severity Scale . Most patients (71%) with neuropathic-like pain fulfilled American College of Rheumatology 2010 fibromyalgia criteria. Patients with ‘possible neuropathic-like pain’ had scores between patients with ‘likely neuropathic pain’ and ‘unlikely neuropathic pain’.Sixty-four patients with PsA were recruited from the Rheumatology Outpatient Department. Of the 64 patients recruited, 26.6% had ‘likely neuropathic pain’ and 21.9% had ‘possible neuropathic-like pain’ according to the PainDetect questionnaire. Patients with ‘likely neuropathic pain’ had higher disease activity, health assessment questionnaire, patient global self-assessment score, tender and swollen joint counts, dactylitis, enthesitis, pain severity and interference with day-to-day activities, fatigue severity and impact, fibromyalgia, anxiety and depression than ‘unlikely neuropathic pain’ patients (Neuropathic-like pain as evidence of abnormal pain processing is common in patients with PsA. It is associated with higher disease activity and fibromyalgia. A significant proportion of patients had ‘possible neuropathic-like’ pain with intermediate disease and symptom score suggesting neuropathic-like pain as evidence of abnormal pain processing is a continuum rather than concurrent fibromyalgia. Pain is the most common complaint in patients with musculoskeletal diseases. Patients with inflammatory arthritis (IA) such as rheumatoid arthritis (RA) ranked pain as the most important symptom , which hPain can be categorised into inflammatory, nociceptive and neuropathic . InflammAbnormal pain processing in the central nervous system, central sensitization, has been demonstrated consistently in neuropathic pain . CentralPatients with neuropathic pain typically experience pain that becomes chronic and less responsive to analgesic medication, as well as sleep disturbance, anxiety, depression and reduced quality of life compared with patients with chronic, non-neuropathic pain . In addiThe definition of neuropathic pain does not distinguish it from pain arising from neuroplastic changes associated with central sensitization so will be referred to as neuropathic-like pain. Of the inflammatory arthritides, studies to date of neuropathic-like pain have focused on RA; however, psoriatic arthritis (PsA) is another common form of inflammatory arthritis, but neuropathic-like pain and central sensitization have not been assessed in these patients and may impact on disease assessment similarly to RA. The aim of this study is to determine the prevalence of neuropathic-like pain and central sensitization using pressure pain threshold and mechanonociception testing —and PainDuring an eight-week period in 2017, all patients with PsA being treated at the Rheumatology department based at the Cardiff and the Vale University Health Board Trust were invited to take part in the study, either by post or in person by the study faculty when attending routine appointments at rheumatology clinics. Patients were eligible to be included in the study if they had a clinical diagnosis of PsA, were aged eighteen or over and consented to being included in this study. Patients were only excluded if they had phantom limb syndrome or complex regional pain syndrome or did not consent to taking part in the study.The patients who were enrolled in this study completed a consent form, demographics form  2010 fibromyalgia (FM) questionnaire score, hospital anxiety and depression scale, fatigue severity score and fatigue impact scale.ösdala, Sweden) [Objective assessment of pressure pain threshold and mechanonociception was conducted using an electronic algometer   and von  Sweden) .von Frey filament testing was carried out on the mid-point between the wrist and elbow on the anterior surface of the forearms and on the skin over the medial end of the spine of each scapula to elicit the mechanical nociceptive threshold and the mechanical pressure sensation threshold. Electronic algometer testing was carried out at the mid-point of the anterior surface of the thigh and the medial end of the spine of scapulae, to elicit the pressure pain threshold (PPT). For electronic algometer testing and von Frey Filament testing, an average of three measurements taken were recorded—since multiple measurements are needed to reliably estimate the threshold being assessed , but cont test or independent samples Mann-Whitney U test as appropriate, to analyse for significant differences. Pearson coefficient correlation testing was carried out to analyse how the parameters assessed varied with ‘pain severity’ and ‘the PainDetect score’.The data was analysed using IBM SPSS Statistics for Windows, V23.0. Armonk, NY: IBM Corp. The data was tested for normality using Shapiro-Wilk. The results for all groups at baseline were analysed using ANOVA and post-hoc analysis using Dunnett’s test and then using independent samples The study was approved by the South East Coast - Brighton and Sussex Research Ethics Committee (17/LO/0147).> 18 years old, were recruited; their demographics are described in Table p = 0.161 and 0.077). On average, the NP group was taking significantly more medications than the PNP and UNP groups (p = 0.025). There were 58 different comorbidities found in the patients enrolled, 15 seen in more than one patient, of which the most common were hypertension (31.0%), type 2 diabetes (13.8%), psoriasis (13.8%) and depression (10.3%).Sixty-four patients with a clinical diagnosis of PsA, aged p = 0.057). Across the three groups, disease activity was trending higher over the 3 categories, from unlikely neuropathic pain, to possible neuropathic pain, to likely neuropathic pain [Disease activity as measured by tender and swollen joint counts, pain score, patient global assessment, dactylitis and enthesitis scores were statistically significantly higher in the NP than that in the UNP group Table . There whic pain .Similarly to disease activity, patients with NP and PNP were statistically significantly more likely have greater pain interference and impact, more severe fatigue and higher levels of anxiety and depression than UNP patients Table .Using the American College of Rheumatology 2010 fibromyalgia (ACR2010FM) questionnaire to assess “fibromyalgianess” , accordOverall PainDetect score correlated positively with measures of disease activity and associated symptoms as well as ACR2010FM PDS score and its components, WPI and SSS Table .Table 3PMechanical nociception as assessed by von Frey filaments were similar across 3 groups. PPT evaluated by electronic algometer was lowest in NP patients than that in UNP or PNP patients, but not significantly Table . As PainThe results of this study suggest there is a high prevalence of neuropathic-like pain (27%) and possible neuropathic pain (22%) in PsA patients. These patients experience greater levels of pain, and all measures of disease activity were higher. This is similar to a Danish study by Rifbjerg-Madsen et al.  investigA limitation of this study may be that our sample population included patients with FM—while only one patient stated they had FM in the demographics questionnaire, according to the ACR 2010 FM criteria  there we) . A euralgia . SimilarA study investigating the similarities and differences of diabetic painful neuropathy and FM found that both groups of patients describe their pain as burning/prickling pain with light touch allodynia , which hA key strength of this study was assessing these patients with the ACR2010FM questionnaire. The majority of NP patients  fulfilled the criteria for FM. One may interpret our data as evidence of concurrent unrecognised FM in patients with PsA—the prevalence of FM in patients with PsA  is much higher than that in the general population of 5% . FurtherThe weaknesses of this study include lack of a control group to compare the study groups with, but as a preliminary study, this is acceptable as the researchers were looking to see if a pattern exists which could be tested more robustly in future. The sample size of this study is relatively small so negative results may be due to a lack of statistical power. Lack of follow-up data meant that the stability of neuropathic pain phenotypes cannot be evaluated. It is also unclear whether more active disease predisposes to NP/fibromyalgia or measures of disease activity are erroneously higher in patients with NP/fibromyalgia.There is a high prevalence of neuropathic-like pain in psoriatic arthritis. The causes of this are unknown, and a better understanding of how this develops may help develop better treatments for PsA patients in the future.PsA patients are severely affected by a variety of symptoms beyond pain and disease activity, which have detrimental biopsychosocial effects. This indicates that their care must be tailored to address all of these problems experienced to achieve the most effective management and therefore best possible quality of life.


Intravesically administered lidocaine is used in patients with bladder pain syndrome (BPS) to test the hypothesis that symptoms have a peripheral versus central mechanism.n = 16) or 20 ml of normal saline (n = 8). These solutions were allowed to remain in situ for 20 min and pain score repeated. Urodynamics was repeated.A cross-sectional study of 24 female patients with BPS was performed. The Central Sensitisation Inventory (CSI) and Kings Health Questionnaire (KHQ) were completed. Urodynamic assessment was undertaken. Women were asked to report their pain using a numeric rating scale at cystometric capacity and post void. Participants then received an intravesical instillation of either 20 ml of 2% alkalinised lidocaine (p = 0.005.) In contrast, there was no significant difference in the saline controls: MCC 190–183 ml (p = 0.879.) Individual analysis revealed five of 16 lidocaine participants did not respond to lidocaine. These five reported a significantly worse quality of life (QoL) than lidocaine responders and had a tendency towards central sensitivity syndromes.There was a statistically significant volume increase following lidocaine treatment: maximal cystometric capacity (MCC) 192–261 ml post lidocaine  pathology. This simple and safe test could be used to stratify patients for research or therapeutic trials.The online version of this article (10.1007/s00192-019-03892-2) contains supplementary material, which is available to authorized users. Bladder pain syndrome (BPS), also known as interstitial cystitis (IC), is a heterogeneous chronic pelvic pain condition. It is defined by the International Continence Society (ICS) as “the complaint of suprapubic pain related to bladder filling, accompanied by other symptoms such as frequency or nocturia in the absence of other proven urinary infections or other obvious pathology” . This diThere are multiple aetiologies about the mechanisms of BPS symptoms. However, one question is whether they are peripherally mediated or arise from abnormal processing of sensory information within the central nervous system (CNS) and become independent of peripheral inputs. There are precedents for both of these mechanisms in chronic pain states, but no consensus with BPS. The peripheral mechanism is abnormal activity or responsiveness in sensory neurones, and there is a large evidence base for a variety of mediators, often inflammatory mediators, producing this kind of change in peripheral nociceptors . The cenIt is both of intellectual and practical interest to understand what is affecting patients with BPS. The practical benefit is that it would potentially help in selecting therapies for individual patients. In this study, the hypothesis that the pain of BPS is driven by a combination of both peripheral and central mechanisms is examined. Our aim was to evaluate the effect of intravesically administered local anaesthetics on perceived pain and urodynamic volumes in patients with BPS. Urodynamics, an objective measure of bladder functionality, is used to assess bladder response to lidocaine instillation in BPS. This is the gold standard examination for the assessment of lower urinary tract disorders. Urodynamics is used in this study to reduce participant performance bias and the placebo effect related to lidocaine treatment. In patients in whom the pain is centrally driven and independent of peripheral pathology, it is hypothesised that instillation of local anaesthetics will not have an effect on perceived pain or urodynamic volumes and bladder capacity.This study was approved by the Cork Research Ethics Committee of the University College Cork and performed at the Cork University Maternity Hospital (CUMH) tertiary referral centre, a European Urogynaecological Association subspecialty-accredited centre in conjunction with the University of Cork. Analysis was performed at King’s College London. Written informed consent was obtained from all participants. Patients with a history of bladder pain accompanied by at least one other symptom, such as urinary frequency, urgency or nocturia, present for at least 3 months, as per the International Continence Society (ICS) definition of BPS, were recruited into the study . Women wParticipants completed the validated King’s Health Questionnaire (KHQ) that evaluates the impact of disease on patient quality of life (QoL) Appendix . In addiUrodynamic assessment was performed to rule out detrusor overactivity (DO). Urodynamics evaluates the effect of bladder filling on bladder function and sensory processing. Since the pain of BPS manifests primarily during bladder filling, performing this study during urodynamic examination is the optimal approach for analysing the mechanisms of pain associated with BPS. Urodynamics was performed by the urogynaecology specialist midwife using the standardised ICS recommendations .Two catheters were inserted: one into the bladder via the urethra and the second into the vagina. The bladder was filled at a rate of 80 ml/min using 0.9% normal saline, as per ICS recommendations . During Subsequently, each study participant was randomly assigned to receive either 20 ml of 2% alkalinised lidocaine or 20 ml of 0.9% normal saline into their bladders. The lidocaine was alkalinised by the CUMH pharmacy department as follows: 3 ml of sodium bicarbonate dissolved in 9 ml of 0.9% saline mixed with 8 ml of 2% lidocaine. To assign either alkalinised lidocaine or saline, a pre-prepared note with alkalinised lidocaine or saline was picked from an envelope by the investigator. Participants were blinded to the treatment received. Solutions were instilled into the bladder using the already present urodynamic bladder catheter and allowed to remain in situ for 20 min, at the end of which the numeric pain score was again recorded. Finally, the urodynamic assessment as above was repeated. These urodynamic indices are applicable, consistent and reproducible and are thus used to evaluate response to instillation with either lidocaine or saline.In this study, there was a discrepancy in the number of patients treated with lidocaine vs saline, with a 2:1 difference. This is because the main question evaluated was the difference in response to lidocaine bladder instillation. Urodynamic parameters are prone to accommodation. Hence, participants who received saline were present to demonstrate what no treatment with local anaesthetic should appear like on subsequent urodynamic distension: they therefore represent the control group. Rather than healthy controls, patients with BPS were chosen so comparisons could be made on the effects of saline and lidocaine on urodynamic distention patterns. Consequently, by studying the one disease state, variability in urodynamic test results could be reduced and saline controls used as a reference group.Post urodynamics, all participants were referred for cystoscopy. Though hydrodistension is a therapeutic strategy in BPS management, in this study, cystoscopy was performed for diagnostic purposes, to check for BPS and to exclude any other bladder or urethral pathologies. While under general anaesthesia, the patient’s bladder was filled by placing a bag of saline 80 cm above the bladder and allowing distension under gravity. The European Society for the Study of IC/BPS (ESSIC) criteria for cystoscopic BPS diagnosis and assessment was followed, providing a structured scoring system for cystoscopic findings . These it test. To reach a power of 80%, a sample size of 16 patients in the lidocaine group was calculated, with an alpha level of 0.05 and an effect size of 0.9 derived from previously reported data of lidocaine effect on BPS/IC by Nickel et al. [t test was performed for urodynamic tests volumes. Two-way analysis of variance (ANOVA) was used to compare patient groups and volumes. P value of <0.05 was deemed statistically significant. As pain scores are categorical data, the non-parametric Mann–Whitney U test was used to calculate pain scores on the numeric rating scale. Means with standard deviation (SD) are used to describe pain scores, and a frequency distribution of responses table is presented.Power analysis was conducted using a priori sample size calculator for Student’s l et al. . Analysin = 4) or had no cystoscopic evidence of disease (n = 8). A further ten  were excluded following the first urodynamic examination, as they were unable to tolerate the pain associated with urodynamic distension and requested that they not proceed further with the protocol and be removed from the study. The remaining 24 participants had a history of bladder pain for at least 3 months. There was obvious correlation between patient age, parity, body mass index (BMI) and risk-factor assessment. No participant had concurrent lower urinary tract disorders or any other chronic pain disorders, and all midstream urine specimens were normal. All showed one or more signs suggestive of BPS on urodynamics and were allowed to complete the study; 16 were assigned to receive alkalinised lidocaine and eight normal saline. All participants had evidence of BPS on cystoscopy.Forty-six female patients were screened for inclusion in the study following referral from the Gynaecology Outpatients Department. Thirty-four participants (74%) met inclusion and exclusion criteria. Twelve of the 46 patients (26%) recruited were not ultimately included either because they presented no features suggestive of BPS on urodynamics and excluded following the first urodynamic examination . This was not observed in the five non-responders (p = 0.89)  Fig. a. Unlike89) Fig. b. On cysp = 0.028. In addition, they had a significantly higher mean score on pain bother: 3.0 and 2.31, respectively; p = 0.044  2.609, 95% CI 4.377–1.858. Total concomitant CSS diagnoses were made in 24 lidocaine non-responders versus 16 in the responders , thus rendering peripheral treatment strategies ineffective.n = 4) with no urodynamic features of BPS being excluded. This was done to reduce the risk of studying patients with presumed bladder pain due to extra-urinary disease. Subsequently, these four patients had cystoscopies, which additionally confirmed no evidence of BPS.Though patient reports remain valuable, it is open to subjective bias and inaccuracies due to misunderstanding the protocol or requirements. Patient reports in studies involving use of analgaesics or local anaesthetics are also open to participant performance bias and the placebo effect . For thaIntravesically administrated lidocaine is one way to assess the relative contribution of peripheral versus central pathologies in BPS patients. It is a non-selective voltage-gated sodium channel blocker that blocks all nerve fibres, including motor, sensory and autonomic fibres, consequently reducing neuronal depolarisation , 16. ThuLidocaine is a weak base provided in an acidic aqueous solution. Following tissue injection, the anaesthetic is buffered by the surrounding tissue and converted to the lipid-soluble base form, allowing for tissue penetration . With inCentral sensitisation is the “augmentation of responsiveness of central pain-signalling neurons to inputs from low-threshold mechanoreceptors” . ChronicPhantom pain is a sensation of pain described by the individual as related to a limb or organ that is not physically present. This, too, is hypothesised to be as a result of central sensitisation mechanisms . It occuESSIC criteria for the diagnosis of BPS recommends performing cystoscopy with hydrodistension to confirm BPS and rule out any confusable diseases of the lower urinary tract . All recWe additionally used urodynamics for identification of BPS patients. Bladder compliance can either be normal or low. Low compliance, due to changes in viscoelastic properties of the bladder secondary to chronic inflammation, can be attributed to certain clinically relevant conditions, such as neurogenic bladder, radiation cystitis and BPS. All women with a history of neurological disorders that may predispose to neurogenic bladder, as well as women with radiation cystitis, were excluded at recruitment. Consequently, the finding of low compliance in this cohort, backed up by pain history and reduced bladder volumes, is further suggestive of BPS. Of note, only one participant had an MCC > 300 ml. She, however, had a pain score of 10 at MCC, low compliance and reduced sensations. She also had cystoscopic evidence of BPS and was thus included in the analysis.To identify lidocaine responders versus non-responders, the difference in numeric pain scores pre- and post-lidocaine treatment was computed. Previous studies used a 50% reduction in pain score as a cutoff measure of non-responders , 23. ThiThe results of this study allow for consideration of the pathophysiology of pain associated with BPS. Characterising patients with BPS in this manner can aid in streamlining treatment strategies. Patients with central dominant pain may receive central therapies earlier using a multidisciplinary approach to pain management, while those with peripheral dominant disease may be managed with peripheral bladder therapies. Additionally, when all other treatments have failed, prior to radical management options such as cystectomy or urinary diversion for intractable pain, this simple technique may distinguish those for whom phantom bladder pain may persist postoperatively.Lidocaine use, in this small observational study, allowed for the evaluation of BPS from a pain perspective. The findings of this study have important implications for day-to-day practice, because by using this simple technique to stratify patients into central or peripheral dominant pain mechanisms or a combination of both, treatment strategies can be more focused, bypassing the routine stepwise trial-and-error approach commonly used in BPS management. A study evaluating the central neural response to invoked bladder pain in BPS patients, such as those using functional magnetic resonance imaging, is warranted to confirm the role of central mechanisms in the BPS pathology. The promising early findings from this study introduces a setting in which additional recruitment and further research will provide confirmation.ESM 1(PDF 17 kb)ESM 2(PDF 269 kb)ESM 3(PDF 102 kb)ESM 4(DOCX 39 kb)ESM 5(DOCX 68 kb)