Cancer is a major burden of disease in low- and middle-income countries (LMICs) yet financial barriers limit access to life-saving oncology drugs. Medical donation and other drug access programs can help improve patient access to essential medicines, such as quality assured oncology drugs in LMICs. However, there are no published examples of the conduct of pharmacovigilance with donated medical products intended for use in LMICs where pharmacovigilance is weak. We describe a partnership between a pharmaceutical company and a non-governmental organization as a case example that addresses the challenges in performing pharmacovigilance with donated medicines in LMICs. The Max Foundation’s direct to patient model is designed to improve global access to quality assured oncology drugs through access programs such as the Glivec® (generic name: imatinib) International Patient Assistance Program (GIPAP).Between 2013 and 2016, in the course of managing the GIPAP program, The Max Foundation was made aware of 13,039 instances of adverse events (AEs). These AEs were reported to The Max Foundation by physicians, patients, and caregivers. The Max Foundation reported these AEs to Novartis through the AE reporting tool within its Patient Assistance Tracking System (PATS). Physicians were the reporters for 58% of the AEs while the remainder of the AEs were reported directly by patients or caregivers. The overall rate of reported AEs remained relatively steady for the years 2013 through 2016 at 92, 95, 86, and 97 AEs reported per 1000 persons who received Glivec® per year, respectively. The vast majority of adverse events (85%) were reported from countries where The Max Foundation has a MaxStation, i.e., where The Max Foundation staff interact directly with physicians and patients at clinics or over the phone. AE reporting rates were consistently higher in all years studied from countries where The Max Foundation has a MaxStation. While India accounted for the largest number of reported adverse events in 2016 (1990), Bolivia had the highest rate of reported adverse events at 484 AEs per 1000 patients.International patient assistance programs that provide access to medicines can have an important role in assisting pharmaceutical companies in fulfilling their pharmacovigilance obligations. Adverse event information collected through PATS can potentially contribute to the overall body of knowledge on the safety of medicinal products. Medical product donation programs and other treatment access programs can address multiple needs that arise in a variety of situations, including health system strengthening in low- and middle-income countries (LMICs). Pharmaceutical companies alone donate drugs valued at an estimated 3.8 billion USD annually . While mIt is essential for medical product donation and other access programs to include provisions to ensure patient safety. To help ensure patient safety with medical products, medicine regulatory agencies, such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), routinely receive and analyze information on adverse events (AEs) to drugs, vaccines, and medical devices during the post-approval period. An AE is “any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which does not necessarily have a causal relationship with this treatment,” whereas an adverse drug reaction is “a response to a drug which is noxious and unintended and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of disease or for modification of physiological function.” As pharmaceutical companies and others make oncology medicines available to patients in LMICs, they are responsible for including provisions that monitor and evaluate patient safety on a continuous basis. Market authorization holders (MAH), i.e., pharmaceutical companies, are legally required to collect, investigate, and submit reports of adverse events concerning their products, regardless of country of occurrence. For example, the EMA stipulates that marketing authorization holders in the European Union (EU) are required to report all suspected adverse reactions occurring in the EU and in other markets . And in Despite such requirements and recommendations, we could find no published examples whereby pharmacovigilance was systematically performed by pharmaceutical companies or by non-governmental organizations with donated medical products used in LMICs where pharmacovigilance systems are weak. Assessments of pharmacovigilance systems in LMICs have identified gaps indicating many LMICs have minimally functional pharmacovigilance systems, including low rates of reporting of AEs –10. MoreThe largest international oncology patient access program, the Glivec® International Patient Assistance Program (GIPAP), was developed by Novartis to ensure patients with cancer receive treatment, e.g., chronic myeloid leukemia (CML) and metastatic malignant gastrointestinal stromal tumors (GIST) . GIPAP wThe Max Foundation developed the Patient Assistance Tracking System (PATS), a proprietary, in-house, web-based, customer relationship management tool, to support and coordinate all of the organization’s activities in GIPAP, including the recording and reporting of all AEs that they become aware of from physicians, patients, or caregivers within GIPAP . All teaAs a proxy of Novartis, The Max Foundation reports all adverse events to Novartis that they become aware of occurring within GIPAP. Following each AE report submitted by The Max Foundation, the Novartis Safety team works with each treating physician to complete any additional information that may be required and submits AE reports to health authorities as per their specific regulatory reporting requirements. The GIPAP agreement between The Max Foundation and approved institutions/physicians specifies that the qualified institution/physician should report adverse events as required by their national legislation. Further, the agreement states that The Max Foundation: “will report to Novartis all AEs that they learn of through the participation of a patient in the GIPAP program regardless of the seriousness or suspectedness of the event. This reporting is separate from the local reporting obligation that physicians must adhere to based on their local reporting requirements. Novartis will direct all follow-up questions to the GIPAP physician (including for reports received from patients and/or caregivers) and will submit AE reports to Health Authorities as required.”The Max Foundation’s pharmacovigilance activities are supported by the organization’s standard operating procedures along with PATS. The Max Foundation staff undergoes training on AE reporting and performs quality control of reported AEs in accordance with established policies and procedures. Initial and annual training is performed by a Novartis drug safety representative for all staff at The Max Foundation involved in GIPAP. The AE reporting training modules include information on the importance of reporting, what should be reported to Novartis, AE definitions, timelines for reporting, and monitoring activities to ensure AEs are reported completely and accurately. In addition to annual training performed by Novartis, The Max Foundation undergoes mid-year training for all team members involved in GIPAP to ensure that there is clarity on the process and requirements for reporting. This includes training team members to provide narrative and contextual information and word-for-word reports, as relevant, by the reporter. In some cases, reports are also submitted in the same language as the reporter.The PATS system is designed to extract all pertinent fields and narrative information to construct each AE report and send these reports to the Novartis Patient Safety organization. In the case of AEs reported by physicians into the PATS system, the system automatically submits all physician-reported AEs immediately and in real time to the Novartis Safety Desk. AE reports received verbally or in writing, from any reporter are entered manually by The Max Foundation’s team into PATS within 24 hours of receiving the report. The PATS system forwards them to the Novartis Safety Desk immediately. All reports submitted in PATS are retained indefinitely. A reporting feature within PATS enables the team to reconcile reports submitted by The Max Foundation and received by Novartis as well as perform quality control of reports against the original source documents on an annual basis.Figure Counts of adverse events reported through PATS were obtained for the 4-year period of January 1, 2013 through December 31, 2016. Additionally, the number of patients receiving Glivec® annually through GIPAP was obtained for this time period. Data were analyzed by year, country, reporter (physician or patient/caregiver), and whether or not the country had a MaxStation, i.e., where The Max Foundation staff interact with physicians and patients at clinics, including where MaxStation staff call patients for follow-up. Descriptive statistics are expressed as counts, percentages, or rates per 1000 patients who received Glivec® through GIPAP. The Chi square test was performed to determine if there was an association between AE reporting by physicians and whether or not the country had MaxStation.n = 6679 AEs) whereas physicians were reporters for 83% of the AEs (n = 1605) among countries without a MaxStation. In contrast, 40% of the AEs (n = 4421) were reported directly by patients or caregivers among countries with a MaxStation while only 17% (n = 334) of AEs were reported directly by patients or caregivers among countries without a MaxStation, Chi square = 364, p < 0.0001. The overall rate of reported AEs remained relatively steady for the years 2013 through 2016 at 92, 95, 86, and 97 AEs reported per 1000 persons who received Glivec® through GIPAP per year, respectively. While India accounted for the largest number of reported adverse events in 2016 (1990), Bolivia had the highest rate of reported adverse events at 484 AEs per 1000 patients (Table Between 2013 and 2016, a total of 13,039 AEs were reported through The Max Foundation’s Patient Assistance Tracking System Tables . Among cThe Max Foundation experience indicates that the training, procedures, and systems established by the organization led to establishing a pharmacovigilance system that recorded and reported AEs from physicians and patients/caregivers to the market authorization holder. Initial and ongoing staff training emphasizes AE reporting importance, the type of information to report, and timelines for reporting. The Max Foundation procedures delineate roles and responsibilities on AE recording and reporting for this NGO, participating institutions/physicians and the MAH. Moreover, the AE reporting tool within PATS ensured timely reporting, as well as tracking and retention of AE reports.The highest number of reported adverse events was from those countries with a MaxStation, most likely due to a combination of factors, including higher use of Glivec® through GIPAP in those countries as well as regular interactions among The Max Foundation staff, patients, and physicians. Others have cited the importance of ongoing interactions with focal persons in promoting reporting of adverse events , 15. EffIndia had the highest volume of AE reports. The volume of reports in India is due, in part, to the high volume of patients enrolled in the program. Over the reporting period, patients receiving Glivec® in India accounted for approximately 50% of all patients enrolled globally each year among all countries with a MaxStation. As a result of high enrollment, The Max Foundation’s team in India also account for more than half of all staff, enabling patients to have more touch points with a member of the team. Such touch points are critical for patients who have questions about doctor’s appointments, how to take the medication, what to do in the case of side effects, and attending patient meetings to connect with other patients and learn more about their disease.Pharmacovigilance of oncology medicines poses certain challenges that many LMICs may be ill-equipped to properly address. The potentially high toxicity and narrow therapeutic window of many oncology drugs makes pharmacovigilance essential in oncology. Moreover, frequent use of multiple treatment regimens makes it difficult to disentangle the side effects of individual as well as combinations of medicines. Evaluation is complicated further due to many patients likely having significant disease-related morbidity. Finally, lifelong treatment with certain oncology medications, such as Glivec®, makes it likely that patients may experience AEs during their extended course of treatment. Based on findings presented here, training, procedures, and technology provided by The Max Foundation can improve drug safety reporting in LMICs.This analysis has limitations. Our analysis does not characterize the types of AEs reported through PATS as this was beyond the scope of our study and beyond the scope and expertise of most NGOs. Rather, our aim was to demonstrate that AE reporting for medical donation programs is feasible through well-planned and coordinated efforts between the NGO and the MAH involving training, procedures, agreements, and systems. We also do not know the extent to which AEs from this program led to specific risk management or risk communication actions either on the part of the company or any of the national pharmacovigilance programs. There is anecdotal information of concerns raised by a few of the donation recipient countries’ health authorities, due to the high volume of AE reports in the access programs managed by The Max Foundation, while it is evident that other access programs under-report AEs. This creates an artificial bias towards potential safety concerns being highlighted for Glivec®. Nevertheless, reporting of AEs is recognized as a cornerstone of pharmacovigilance by efficiently generating safety signals and better characterizing at-risk groups, risk factors, and clinical characteristics of AEs. Spontaneous reported AEs can be evaluated and may be acted on for risk management and communication even for medicines, such as Glivec®, that have been marketed for use for many years and whose common adverse events are known.. Finally, we do not know whether or not AE reporting rates for Glivec® in these LMICs begin to achieve the level AE reporting rates for this drug in high-income countries. However, it is likely that the AE reporting rates achieved through GIPAP are higher than those that are found for this or most other medicines in LMICs. For example, AE reporting rates to NMRAs have been reported to be low by Aagaard et al., and by Ampadu et al. , 18 BothIn 2017 The Max Foundation and Novartis renewed their commitment to patients by launching CMLPath to Care™ a collaboration aimed at providing humanitarian access to treatment for CML and other rare cancers for those patients for whom no other form of national treatment access exists today . CMLPathPatient assistance programs that provide access to medicines can have an important role in global pharmacovigilance by collecting AE reports and submitting them to market authorization holders. Such real world data has the potential for informing the ongoing evaluation of the safety profile of donated marketed drugs. Future studies should examine the contribution of AE reporting performed by drug donation programs to strengthening the pharmacovigilance systems of LMICs.


There is no defined gold standard for pain management after video-assisted thoracic surgery (VATS) for pneumothorax. In addition to systemic analgesia, various loco-regional analgesic techniques have been proposed but remain poorly evaluated in this context. We aimed to assess the analgesic efficacy of several of these techniques for the management of postoperative pain.n = 59). Patients received systemic analgesia (i) alone (n = 15); (ii) combined with a continuous paravertebral block (n = 9); (iii) combined with a continuous serratus plane block (n = 19); or (iv) single-shot serratus plane block (n = 16) as decided by the attending physician. Pain scores and analgesic-related side effects were prospectively collected by an independent observer during the first postoperative 72 h. The primary endpoint criterion was the cumulative oral morphine consumption at the end of the third postoperative day. Statistical analysis used univariate and multivariate step-by-step forward logistic regression models to determine risk factors associated with the main criteria.We conducted a monocentric prospective observational cohort study from February 2017 to April 2018 in patients suffering from spontaneous pneumothorax and scheduled for VATS (p = 0.03).Mean pain scores and morphine consumption were not significantly different between the 4 groups. In the multivariate analysis, the use of a continuous serratus plane block through a catheter was the only technique associated with a reduced incidence of high-dose oral morphine consumption (OR 0.09–95%CI [0.01–0.79], This study suggests that serratus plane block combined with continuous infusion through a catheter may have some benefits, although further studies are needed to confirm these results and determine the true place of the serratus plane block in pain management after VATS for pneumothorax. Spontaneous pneumothorax (SP) has an overall incidence of 24/100,000 in caucasian males , it remaEvery year, more than one hundred patients are referred to the on-call emergency unit for pneumothorax management in our institution, among whom 60% require surgical treatment. Postoperative analgesia is commonly ensured by a loco-regional analgesic technique, but the choice of technique remains at the discretion of the attending anesthesiologist. Consequently, we evaluated the efficacy and the side effects of several techniques in a cohort of patients scheduled for VATS to treat SP..This study followed the STROBE statements .This study is a monocentric prospective observational cohort study conducted at Tenon Hospital, Paris, France. Consecutive patients over 18 years old and suffering from pneumothorax requiring VATS treatment between February 2017 and April 2018 were included in the study. The exclusion criteria were: secondary pneumothorax, pregnancy, chronic preoperative analgesic treatment and opioid addiction, associated hemothorax, supra-segmental parenchymal resection and the lack of social health insurance coverage. Intraoperative conversions of VATS into thoracotomy and revision surgery within the first postoperative 72 h were also excluded from the study.Except for the choice of the postoperative loco-regional analgesic technique, the anesthetic management of patients undergoing VATS for pneumothorax is standardized in our institution. All the patients were anesthetized using a targeted concentration infusion of propofol  and sufentanil , while the depth of anesthesia was monitored with a bispectral index coupled with standard anesthetic monitoring. Atracurium  was used for muscle relaxation. Dexamethasone 8 mg IV (Mylan) was systematically used to reduce postoperative nausea and vomiting. Intraoperative ketamine administration  was considered as a co-analgesic except in cases of high blood pressure in the operating room, or significant active cannabis intoxication. Oral postoperative multimodal analgesia routinely included acetaminophen , nefopam  and tramadol . Intraoperative IV lidocaine  and postoperative ketoprofen (50 mg 4 times a day – Sanofi-Aventis) administrations were left to the discretion of the attending anesthesiologist. All patients were immediately extubated at the end of the surgical procedure.Surgery was conducted under one-lung ventilation after intubation with a double-lumen tube. Single-port VATS was the first choice method; multi-port surgery being reserved for cases when that failed. VATS was standardized as previously described , with a The loco-regional analgesic technique was left to the discretion of the physician in charge of the patient and was performed at the end of the surgical procedure. A paravertebral block was performed by the surgeon through a transparietal approach with insertion of a catheter under direct vision until placement of the tip into the paravertebral space , and theWe collected demographic data , as well as information about active smoking status and chronic drugs consumption  for each patient. The following surgical data were also collected: the number, side and site of surgical incisions and thoracic drains, the duration of surgery, the surgical technique used  and the duration of postoperative drainage. We also recorded the anesthetic and analgesic agents administered to patients during anesthesia, such as ketamine, intravenous lidocaine, dexamethasone, paracetamol, nefopam, tramadol, ketoprofen and/or morphine.The morphine titration cumulative dose and pain intensity score (graded from 0 to 10 on a VAS) at rest and on coughing were collected in the recovery room upon the patient’s arrival and after one hour. Finally, pain VAS values were also collected at rest and on coughing in the wards at 2, 12, 24, 48 and 72 h after surgery. Cumulative oral morphine consumption was collected as well as daily and total doses of other analgesics such as acetaminophen, nefopam, tramadol, IV lidocaine and ketoprofen. The occurrence of nausea, vomiting and urinary retention were noted for each patient. The hospital length-of-stay was recorded.p value ≤0.2 were integrated into the multivariate step by step forward logistic regression model. P < 0.05 was considered significant. Statistical analysis was performed using SPSS version 23 .The primary endpoint was the cumulative oral morphine consumption (expressed in mg) during the first postoperative 72 h. The secondary endpoints were: 1) the intensity of postoperative pain at rest and on coughing, and 2) the incidence of side effects most frequently associated with opioid consumption such as nausea, vomiting and urinary retention. Quantitative data were expressed as median values [25-75th percentiles] and qualitative data were expressed as numbers (percentages). Primary and secondary endpoints for each analgesic technique used were compared using the Kruskall-Wallis test with Dunn’s correction. We defined a priori a morphine consumption > 50 mg within the first postoperative 72 h as a reasonable marker of difficult pain control and high-dose morphine consumption. Factors associated with a high-dose morphine consumption were assessed by univariate logistic regression and chi-square for quantitative and qualitative variables, respectively. All variables with Sixty-seven patients underwent VATS for SP during the study period, out of whom 61 were included in the study  had a serratus plane block with a single injection and 19 (32%) had a serratus plane block with insertion of a catheter for continuous loco-regional analgesic infusion. A paravertebral block with insertion of a catheter was performed in 9 patients (15%). Fifteen (25%) patients received oral multimodal analgesia alone, including rapid-release morphine. Values of pain intensity score corresponding to the analgesic technique used are reported in Table 7% had a p > 0.05 - Table p value ≤0.2 when comparing patients with low-dose and high-dose morphine consumption were the use of a continuous serratus plane block (p = 0.06), the use of systemic analgesia alone (p = 0.02), a single-port incision (p = 0.16) and the postoperative use of tramadol as a co-analgesic (p = 0.19) (Table p = 0.03) (Table p = 0.057) and a single-port surgical procedure (p = 0.052)  Table . In the 3) Table . Non-sig2) Table .Fig. 2DaThis prospective cohort study shows relatively high pain intensity and morphine consumption after VATS for pneumothorax. In this context, the serratus plane block with insertion of a catheter for continuous local anesthetic infusion, in addition to multimodal systemic analgesia, provided satisfactory pain control during the first postoperative 72 h and decreased high-dose morphine consumption.Pain treatment after thoracic surgery is challenging, thoracotomy being considered as one of the most painful surgical procedures. The gold standard for pain treatment after thoracotomy is epidural analgesia . HoweverVATS is considered less painful than thoracotomy , explainThis study has several limitations. First of all, the number of patients included in the study is limited making it only a preliminary assesment of the effect of a serratus plane block. Indeed, although the serratus plane block with continuous infusion through a catheter is associated with reduced high-dose morphine consumption, we did not observe any significant difference in the global morphine consumption between the different groups. Although a serratus plane block is theoretically advantageous in the context of pleurodesis, we did not report any superiority of the serratus plane block over the paravertebral block regarding pain score or global morphine consumption. However, it could be hypothesized that our study lacks power to demonstrate such a superiority, in particular as a trend towards a lower morphine consumption in the continuous serratus plane block group existed. Further larger studies are required to confirm these preliminary results.Secondly, since it is not a double-blind randomized study, several biases may have been introduced. However, pain scores and morphine administration were not evaluated by the physicians who performed the block in the operating theatre, providing an acceptable assessment of postoperative pain and morphine consumption. However, it can not be ruled out that certain differences in intra-operative features  may have impacted the pain scores and postoperative morphine consumptions, which could only have been avoided with a randomized design. It could also be hypothesized that, in the absence of randomization, surgical features may have impacted both postoperative pain scores and locoregional analgesia efficacy. However, 92% of patients had single-port VATS, which is a standardized procedure in our structure , thus liThirdly, the definition of the morphine consumption threshold used in our study could be challenged. We chose a threshold of 50 mg of cumulative oral morphine administration over the first postoperative 72 h to define high-dose consumption and assess the efficacy of the loco-regional analgesic techniques. As there is no agreed definition of what constitutes high-dose morphine consumption after VATS for pneumothorax, we chose the mean value from our institution. It should be noted that the validity of this threshold is reinforced by other recent studies reporting close postoperative morphine consumptions in patients scheduled for VATS , 12. TheThis study suggests that serratus plane block combined with continuous infusion through placement of a catheter may have some benefits, although further studies are needed to confirm these results and determine the true place of the serratus plane block in pain management after VATS for pneumothorax.


This descriptive record-based study included 75 patients who had engaged in domestic property damaging (DPD) and needed assessment by an urban emergency psychiatric service team in The Netherlands. The DPD patients were compared to 1145 other patients referred because of aggression, suicidality or other reasons. DPD patients were more often diagnosed with a psychotic disorder or a manic episode, had more often a migration background, were less often diagnosed with depression, and had lower GAF scores. There were no differences with respect to personality disorders or substance use. DPD patients were two to six times more likely to be (mostly involuntarily) admitted to a psychiatric department (64%), than the other patient groups . The findings indicate that DPD patients represent an exclusive group who possibly have more intercultural and communication disadvantages due to less cultural acceptance or lack of knowledge about mental healthcare in the Netherlands. The connection between violence and mental illness is often a topic of debate Friedman . FrequenThe literature describes different characteristics of patients who engage in violence. Several risk factors have been identified that play a role in aggressive behaviour  the prevalence of referrals to the EPS of patients engaging in DPD, (b) the association with different factors possibly playing a role in violent behaviour including possible problems in communication , and (c) which management options are mostly decided to with respect to DPD patients. The study was conducted at the EPS in Utrecht, the Netherlands, operating in the city of Utrecht and its surrounding suburban municipalities.The current study is a descriptive medical record study which took place at the EPS of Altrecht Mental Health Care, research section ‘Schroeder van der Kolk’. The EPS of Altrecht operates in the city of Utrecht, with approximately 340,000 inhabitants, and about 200,000 inhabitants in the surrounding suburban region. The study was approved by the Scientific Committee of Altrecht Mental Health Care (2010-14/oz1007).The patients were included in six separate assessment periods between 2009 and 2016 which were (1) 25-03-2009 up to including 24-04-2009; (2) 18-10-2010 up to including 22-11-2010; (3) 10-09-2012 up to including 21-10-2012; (4) 24-04-2014 up to including 07-06-2014; (5) 10-01-2015 up to including 15-02-2015; (6) 19-09-2016 up to including 25-10-2016. In these assessments periods the records of DPD patients and of EPS comparison patients were collected consecutively. A part of the subsample of the DPD patients was collected outside the assessment periods and was collected in a consecutive series from 22-10-2006 up to 12-12-2010 in the daily reports at the EPS of Utrecht. Thus, the DPD patients are partly identified by the above assessment periods and partly aside from the assessment periods.The DPD subsample consists of patients who were referred to the EPS with the reason of DPD (A). The comparison patients were divided into three groups based on reason of referral: patients with aggression not restricted to DPD (B) patients with suicidal behaviour not restricted to DPD (C) and patients with the remaining referral reasons not restricted to DPD (D). Aggression as reason of referral has been chosen as a comparison group to verify whether DPD patients represent a type of aggression that needs a different understanding and perhaps a different clinical approach. Suicidality as a reason of referral and the remaining reasons of referral are chosen to determine the difference between DPD patients and the main EPS population. A total of 1220 patients was included in the study in which 75 of the cases engaged in DPD (A), 156 patients were included in the aggression group (B), 543 patients were included in the suicidal group (C), and 446 patients were included in the group with remaining reasons of referral (D). Patients who engage in other types of violent behaviour are referred to with the term ‘aggression’. The ‘remaining referrals’ groups (D) included intoxicated states , cognitive problems, and depression and anxiety states .within 1 or 2 days), new appointment with the EPS (within 1 or 2 days), back-referral to the general practitioner’. In The Netherlands, with short geographical distances to care facilities, there is an increasing reliance on high frequent, acute out-patient care . The form included the following characteristics: age, gender, the place of residence, referring agency, referral reason, location of administration, current legal status, psychiatric medical history, substance use, cultural background, working diagnosis of the acute mental state, any known previous diagnosis of a personality disorder, GAF score, and the management after the intake. Not all characteristics of the form were included in the study. With respect to the current legal status patients were divided into those who were under Dutch Mental Health Act and patients who were not , testing for significant differences using T-tests. For all other associations, multivariate logistic regression models were employed, including demographic, diagnostic and care variables, computing Odds ratios and 95% confidence intervals. The main types of management as applied at the EPS were compared within these groups by using Odds ratios. There are no known conflicts of interest for any of the authors. All authors certify their responsibility for the manuscript.Among all presentations to the EPS, the 30-days incidence of presentations with DPD amounted to 1.2%. On average 151 patients were referred to the EPS in 30 days. This is tantamount to about 1 to 2 DPD patients being referred to the EPS every 30 days in the care region with about 540,000 inhabitants. With respect to how the DPD manifested itself the records provided some additional information on the type of DPD. Table Table The GAF scores  were significantly lower in the DPD group (37.6) compared with the other groups combined , the aggression group  and the suicidality group . There was no significant difference with the ‘other referrals group’ .Table The aim of the current exploratory study was to examine characteristics of patients who damage their own household property and who were assessed by the EPS in Utrecht, The Netherlands. We compared the DPD patients to several other groups by reason of referral. Compared to patients referred because of suicidality, DPD patients were more often male, migrant, suffering from psychosis or mania and less frequently depressed. In comparison with patients referred because of aggression, the DPD patients were more frequently diagnosed with mania. With respect to age, substance use and personality disorder, no significant differences were observed. The DPD group had significantly lower scores on the GAF scale and had a higher chance of being hospitalised involuntarily and voluntarily (up to 64%) as compared to the other groups.Many studies have illustrated the association between violence and various factors, such as substance use, personality disorder and environmental stressors  substance use disorders. This paper provides some preliminary evidence that, at least in the Netherlands, DPD represents a distinguishable subgroup among patients with externalizing aggression. These patients may have special needs to attend to during the care process e.g. they may have more intercultural and communication disadvantages due to less knowledge about care facilities, cultural habits and lack of understanding and prejudice amongst the public resulting in violent escalations such as DPD.Clinical consequences of the current study pertain to more recognition for this crisis phenomenon as well as to future research. For future research, we suggest focussing on how DPD patients perceive their need of care as well as their obstacles to communicate about their needs with relevant others. DPD patients might be interviewed and invited to reflect on their actions and on their intentions at the time of the DPD. Deepening our understanding of this behaviour will be a next step in our future research. Furthermore, it would be relevant to know whether DPD patients show other types of aggressive behaviour over time, e.g. in previous episodes. The ideas of DPD patients about the origins (lack of access to care) and consequences  of their behaviour could be further assessed. An example of prevention may include formulating a crisis plan with relatives and mental healthcare professionals generating a better or earlier access to mental health care in future crisis situations. Besides these suggestions, further research should also prevent any xenophobic motivations towards non-natives and the possible risk for the society suggested in these results. As suggested in this study migrants might not be able to follow the usual pathway in the mental healthcare. This is a responsibility of healthcare authorities to make this pathway more accessible and prevent escalated situations like DPD.


Chronic pain is among the most burdensome conditions. Its prevalence ranges between 12% and 30% in Europe, with an estimated 21% among Austrian adults. The economic impact of chronic pain from a societal perspective, however, has not been sufficiently researched. This study aims to provide an estimate of the societal costs for working-age adults with chronic pain in Austria. It explores the impact of sex, number of pain sites, self-reported pain severity, health literacy and private health insurance on costs associated with chronic pain.A bottom-up cost-of-illness study was conducted based on data collected from 54 adult patients with chronic pain at three Viennese hospital outpatient departments. Information on healthcare costs including out-of-pocket expenses and productivity losses due to absenteeism and informal care were collected over 12 months. Resource use estimates were combined with unit costs and mean costs per patient were calculated in € for year 2016.Mean annual societal costs were estimated at EUR 10191. Direct medical costs were EUR 5725 including EUR 1799 out-of-pocket expenses (mainly pain relieving activities and private therapy). Productivity losses including informal care amounted to EUR 4466. Total costs for women and patients with three or more pain sites were significantly higher. No association with health literacy was found but there was a tendency towards higher out-of-pocket expenses for patients with complementary private health insurance.This study is the first to provide a comprehensive assessment of the individual and societal burden of chronic pain in Austria. It highlights that chronic pain is associated with substantial direct medical costs and productivity losses. Patient costs may show systematic differences by health insurance status, implying a need for future research in this area. Chronic pain is considered as one of the most burdensome diseases in industrialized countries . AccordiIn the same study, prevalence of chronic pain was estimated at 21% for Austria, amounting to 1.83 million people in 2003 . AccordiTo assess the societal and economic impact of chronic pain, several cost-of-illness studies have been conducted across Europe e.g. –17). Dif. Dif17])Regarding drivers for differences in the costs of chronic pain, several studies have investigated associations between demographic factors, socioeconomic characteristics and disease severity with cost levels e.g. , 23–25) –25 23–25The aim of this cost-of-illness study was to estimate the economic burden of chronic pain in working-age individuals from the health care, patient and societal perspectives. The impact of sex, number of pain sites, self-reported pain severity, health literacy and complementary private health insurance status on costs associated with chronic pain were also explored. Such a cost-of-illness analysis allows assessing the overall economic impact of chronic pain and its main cost components, aids the priority setting for health care policies and may inform future resource allocation , 28.Patient recruitment took place between December 2012 and February 2014 as part of the study ‘Chronic pain and its development depending on social environment, health literacy, and previous treatment and associated costs’. Participants were recruited from three hospital outpatient departments  located at two  ViennesFollowing a medical check, participants were informed about the study. After signing the informed consent form, participants completed the baseline questionnaire with the help of a research assistant. The baseline questionnaire captured socio-demographic details including sex, age, relationship status, employment status, highest educational attainment, monthly household income (after taxes), complementary private health insurance and exemption from prescription fees. The location and derived number of pain sites was assessed based on a pictorial representation. The number of pain sites was categorized into ‘1 or 2 pain sites’ and ‘3 or more pain sites’ and served as a proxy for the widespread nature of the pain. A visual analogue scale (VAS) ranging from 0  to 100 (‘the worst possible pain’) captured the subjective pain intensity and was categorized into high self-reported pain severity (VAS>36) and low pain severity (VAS≤36) based on the observed mean . PolyphaA cost diary was used to capture disease-attributable resource use within the past three months. It was informed by previous research  and piloTotal costs were calculated from a societal perspective following a bottom-up approach . Direct Resource use data were multiplied with unit cost estimates to calculate costs. Unit costs were retrieved from a number of sources  based onBased on the information provided in the four cost diaries, costs were calculated for 12 months. In the case of missing cost diaries, we assumed that costs described in 3, 6 or 9 months were representative for the missing months and reported them for a 12-month period. All costs were calculated in Euro for year 2016 to reflect the latest available unit cost information at the time of manuscript submission. Cost data from previous years were inflated based on the national medical component of the consumer price index .The database was initially set-up in Microsoft Excel (2013) and double-checked by two authors . Most cost diaries were fully completed. Missing items only accounted for 0.5% of all data entries and were replaced with mean values from all patients with relevant resource use. As some patients dropped out during the study, the cost data of these participants were extrapolated proportionately based on their available cost diaries. A sensitivity analysis restricted to patients with full cost information over the 12 months follow-up period was also conducted.All statistical analyses were performed using Stata 14 . DescripThe study was approved by the Ethics Committee of the Medical University of Vienna  for the General Hospital of Vienna and the municipality of Vienna  for the Orthopedic Hospital Speising. While advance information of potential study participants was started in December 2012, no primary data were collected prior to receiving formal ethical approval.Out of a total of 121 participants initially enrolled in the chronic pain study, 54 participants had at least 3 months of cost data  and were included in the cost-of-illness analysis . Thirty-three patients had full 12 months cost data and were included in the sensitivity analysis. With one exception, no differences in demographic, socio-economic and clinical characteristics  were found between all initially enrolled patients (n = 121), the responders (n = 54) and the patients with 12 months cost data (n = 33). A higher percentage of the initially enrolled patients  reported living in a partnership compared to the 54 patients  included in the main analysis (p = 0.03). In total, 78% of the study sample were female (n = 42) . Men andOn average, patients were aged 50 (SD: 8.0) years, 69% (n = 37) worked and 63% (n = 34) lived in a partnership . Fifty-sDetails of the mean annual resource use are provided in Out of the 54 patients, 33 (61%) reported having taken at least one prescription medication over the last 12 months  and 15% From the viewpoint of the patient, pain reducing lifestyle activities that prevent or alleviate chronic pain (e.g. sports like swimming and yoga) , private therapist costs  and household help  were the dominant contributors to out-of-pocket expenses . A totalOverall, productivity losses  contributed to almost half of the total costs , Fig 1. Mean total annual cost per chronic pain patient were estimated at EUR 10191  . In the Total costs for men and women differed significantly  and were estimated at EUR 3095 (SD: 2709) and EUR 12219 (SD: 13422), respectively . Mean toThis cost-of-illness study aimed to comprehensively assess the economic burden of chronic pain in the working-age population in Austria. Based on a sample of patients recruited from three hospital outpatient departments, annual societal costs were estimated at EUR 10191 per patient for the year 2016. The findings emphasize the high economic impact of chronic pain on both the individuals and the society. The highest direct medical costs were associated with out-of-pocket expenses (18%), inpatient costs (14%) and outpatient costs (8%). Highest productivity losses were associated with early retirement/work reductions (16%) and sick leave (14%). In terms of potential drivers for differences in chronic pain costs, women and patients with three or more pain sites had significantly higher total costs than men and patients with one or two pain sites. No association between costs and health literacy or self-reported pain severity was found. There was a tendency towards higher out-of-pocket expenses for chronic pain patients with a complementary private health insurance.In comparison with another Austrian study measuring the direct costs of chronic low back pain in 2008 (EUR 1837 in 2008) , total dOn the other hand, the patterns in costs components found in our cost-of-illness analysis are consistent with other national and international studies. Out-of-pocket expenses were similar to the out-of-pocket expenses of Dutch chronic pain patients USD 1350 in 1999) . The ten0 in 1999In terms of differences in chronic pain costs by subgroups, female sex was found to be a major determinant of cost differences. While this result is in line with some previous work , 23, it The identified tendency for higher out-of-pocket expenses for people with complementary private health insurance  needs to be interpreted in the light of the Austrian two-tier health system. While private health insurance status is likely to be also related to higher socioeconomic status , it is aTo our knowledge, this is the first study to estimate the societal burden of chronic pain in Austria. In addition, this is one of the few studies internationally that measures related societal costs comprehensively. Besides investigating commonly researched associations between costs and demographic and clinical characteristics, this study also adds to the literature through the analyses of the impact of health literacy and complementary health insurance on the costs of chronic pain.The findings of this cost-of-illness analysis need to be interpreted in the health care system context and considering potential limitations. The small study sample and recruitment from three outpatient clinics in the capital might impair the generalizability of the results to the national level. Firstly, with an average of 17 years, the duration of chronic pain was longer than the (more conservative) general Austrian estimate of 6 years from 2003 . AnotherThe costs of chronic pain including patients’ out-of-pocket costs were found to be substantial in Austria and the trend towards systematic differences by health insurance status calls for future research in this area. The comparatively low proportion of patients contributing to the high productivity losses illustrates the need to emphasize and strengthen early diagnosis, prevention and better management of chronic pain as a priority from a public health policy perspective. More effective and efficient treatment programs–even if these treatment costs are high–could potentially reduce early retirement and sick days and lead to a good value policy option with overall lower cost-of-illness in Austria.S1 Text(DOCX)Click here for additional data file.S2 Text(DOCX)Click here for additional data file.S3 Text(DOCX)Click here for additional data file.S1 File(XLSX)Click here for additional data file.


Widely-prescribed prodrug opioids  require conversion by liver enzyme CYP-2D6 to exert their analgesic effects. The most commonly prescribed antidepressant, selective serotonin reuptake inhibitors (SSRIs), inhibits CYP-2D6 activity and therefore may reduce the effectiveness of prodrug opioids. We used a machine learning approach to identify patients prescribed a combination of SSRIs and prodrug opioids postoperatively and to examine the effect of this combination on postoperative pain control. Using EHR data from an academic medical center, we identified patients receiving surgery over a 9-year period. We developed and validated natural language processing (NLP) algorithms to extract depression-related information  from structured and unstructured data elements. The primary outcome was the difference between preoperative pain score and postoperative pain at discharge, 3-week and 8-week time points. We developed computational models to predict the increase or decrease in the postoperative pain across the 3 time points by using the patient’s EHR data  captured before surgery. We evaluate the generalizability of the model using 10-fold cross-validation method where the holdout test method is repeated 10 times and mean area-under-the-curve (AUC) is considered as evaluation metrics for the prediction performance. We identified 4,306 surgical patients with symptoms of depression. A total of 14.1% were prescribed both an SSRI and a prodrug opioid, 29.4% were prescribed an SSRI and a non-prodrug opioid, 18.6% were prescribed a prodrug opioid but were not on SSRIs, and 37.5% were prescribed a non-prodrug opioid but were not on SSRIs. Our NLP algorithm identified depression with a F1 score of 0.95 against manual annotation of 300 randomly sampled clinical notes. On average, patients receiving prodrug opioids had lower average pain scores (p<0.05), with the exception of the SSRI+ group at 3-weeks postoperative follow-up. However, SSRI+/Prodrug+ had significantly worse pain control at discharge, 3 and 8-week follow-up (p < .01) compared to SSRI+/Prodrug- patients, whereas there was no difference in pain control among the SSRI- patients by prodrug opioid (p>0.05). The machine learning algorithm accurately predicted the increase or decrease of the discharge, 3-week and 8-week follow-up pain scores when compared to the pre-operative pain score using 10-fold cross validation . Preoperative pain, surgery type, and opioid tolerance were the strongest predictors of postoperative pain control. We provide the first direct clinical evidence that the known ability of SSRIs to inhibit prodrug opioid effectiveness is associated with worse pain control among depressed patients. Current prescribing patterns indicate that prescribers may not account for this interaction when choosing an opioid. The study results imply that prescribers might instead choose direct acting opioids (e.g. oxycodone or morphine) in depressed patients on SSRIs. Opioids are currently a first-line treatment of postoperative pain and surgery may be a gateway to opioid misuse ,2. Most Opioids are thought to exert their analgesic effects by binding to the Mu opioid receptor in the brain and spinal cord. Some opioids directly bind to the mu-opioid receptor in their native form including oxycodone, morphine, hydromorphone, fentanyl, and methadone . Other oOur study’s objective was to quantify the effect of the combined administration of prodrug opioids and SSRI antidepressant medication on postoperative pain among depressed patients undergoing surgical procedures. We hypothesized that patients taking SSRI who are prescribed a prodrug opioid will have worse postoperative pain. We further hypothesized that we could utilize a machine learning approach to predict the increase or decrease in the discharge, 3-week and 8-week postoperative pain scores stratified by prescription of a prodrug opioid.Using electronic health records (EHRs) from a tertiary care academic medical center, we identified patients undergoing a major operating room procedure from 2009 to 2016 based on ICD-9 codes. We built a predictive model for postoperative pain evaluation using ElasticNet regularized regression and internally cross-validated the model using 10-fold cross validation ,14.This study and a waiver of written consent was approved by Stanford University’s Internal Review Board, approval #34551. This study used routinely collected medical data captured in electronic health records. Patients were identified from the EHR from Stanford University Hospitals and Clinical, an academic hospital that has maintained the EHR system  since 2008. We identified patients undergoing common surgical procedures using ICD-9/10 and CPT codes, including orthopedics, vascular, and general surgeries.  PatientsPatient variables included Gender, Race/ethnicity , age at surgery, marital status, insurance type , Charlson Comorbidity Index , and body mass index (BMI). Patient vital information included deviation of the systolic and diastolic blood pressure from the normal range of 80 mm/Hg and 120 mm/Hg respectively. The heart rate was represented as a categorical variable with values normal, abnormal, or unknown. Body temperature deviation from the normal value was also included. Preoperative pain was included as the latest reported mean pain score up to 30 days before date of surgery. Medications were represented as binary indicator for the presence or absence of a particular therapeutic class of medications within 30 days prior to the surgery. Opioid tolerant (non-naïve) patients were defined as any patient with an outpatient opioid prescription within 12-months prior to the admission for the surgical procedure.The drug formulary and vocabularies were mapped to a 2016 version of RxNorm. Prescription orders were distilled to the ingredient level. The algorithm used for data extraction accounted for any combination medications and trade names. The average daily oral morphine consumption for the inpatient stay was calculated using oral morphine equivalent conversion factors .Patients were included in the cohort if they had a diagnosis, medication, or symptom for depression within 1 year of the surgery date using a combination of structured and unstructured EHR data. The NLP algorithm (described below) identified clinical concepts from the unstructured clinical notes and medications and diagnosis codes were extracted from structured variables . SimilarOpioids were classified as a prodrug based on previous literature review . ProdrugWe assessed pain outcome measurements according to the numerical rating pain score . Pain scWe constructed and evaluated all prediction models with repeated 10-fold cross validation, which partitions the original sample into ten subsets, and uses nine of those subsets in the training process and then makes predictions on the remaining subset. We averaged model performance metrics across test folds.Affirmed or Negated using the NegEx algorithm, which identifies the negatives pertinent to the diagnosis in each sentence, see examples in Affirmed label was given the priority in case of a tie. The performance of the NLP algorithm was evaluated using randomly sampled 100 manually annotated clinical notes using standard metrics: precision, recall and the F1 score.The NLP algorithm works with unstructured clinical notes to identify depressed patients. A pre-processing step was performed that involved converting the numeric values to string, converting the text to the standard encoding format of UTF-8, normalizing case, and to remove any extraneous spaces, lines, or characters. Each cleaned note is tokenized, which means it was split into identifiable elements–in this case, words and punctuation, sentence boundary detection, identification all the stop words, and removal of ≤ 2 letter words using Natural Language Toolkit (NLTK) . We incoIn order to predict the increase or decrease of three discrete postoperative follow up pain scores, we built three isolated classification models using an integrated feature vector which was constructed using a subset of EHR record data captured before surgery. Particularly, the feature vector was built upon six EHR components: patient demographics, clinical characteristics, diagnoses information, medications, vital statistics, and a categorical variable to indicate the patient group: SSRI+/- and Prodrug+/-. The final feature vector consisted of 65 variables.(Δt = PostOpPaint—PreOpPain) at three discrete time points (t): (1) at discharge, (2) 3 weeks, and (3) 8 weeks after surgery. We used an ElasticNet regularized regression, which combines L1 penalties of Lasso and L2 penalties of Ridge where the objective function is defined as:X is the 65 dimensional feature matrix, β is the computed coefficients, λ controls the overall strength of the penalty, αϵ. ElasticNet performed shrinkage of the quantitative feature matrix while maintaining the pairwise correlation between features which allows to select more than one correlated variable. Given the possibility of high correlation between the EHR variables, selection of grouped features rather than sparse selection is an important aspect of the prediction. Due to the limited number of training samples, instead of multi-level regression, we formulated the prediction problem as binary where we predicted the improvement/worsen of the absolute pain score at discharge, 3 weeks and 8 weeks compared to the preoperative baseline pain score of each individual.We used the 65 predictive features to train three individual machine-learning models to predict change in postoperative pain Our regularized regression models are designed to predict change in postoperative pain outcomes among depressed patients who were either taking an SSRI or receiving an opioid prodrug. We use 10-fold cross validation where the original training sample at each time-point is randomly partitioned into 10 equal size subsamples. Of the 10 subsample sets, a single set is retained as the validation data for testing the model, and the remaining 9 subsamples are used as training data. The cross-validation process is then repeated 9 times (the folds), with each of the 10 subsamples used exactly once as the validation data. The main advantage of this method is that all patients included in our cohort are used for both training and validation, and each observation is used for validation exactly once. The hyper parameter tuning was performed using a 5-fold nested cross validation on the train set for each fold. The hyper parameters corresponding to the best model were chosen empirically to be alpha = 0.3, lambda = 0.05.In order to test generalizability of the proposed model, we presented the receiver-operating curve (ROC) for each test fold and computed the mean ROC by combining the results of each fold. We consider the mean of the area under the receiver-operating curve (AUCROC) as the final validation metrics. All analyses and validation were implemented in python using scikit-learn library. All python-code we developed for statistical modelling is available upon request.Among total of 41,713 patients, 4306 patients are identified with depression using clinical notes and structured variables. There were 1164 males and 3142 females in the study with a mean age of 58.34 years. The cohort consisted of 69.5% patients to be White, followed by Hispanic, Asian, Black and other races. There was no statistical difference in the receipt of a discharge prodrug opioid by SSRI prescription (p = 0.4196). The developed NLP algorithm achieved precision of 0.92, recall of 0.987 and an F1 score of 0.95 when being compared against gold standard of 100 manually annotated clinical notes. A total of 3663 patients were identified as depressed using clinical notes while 4066 patients were identified to be depressed from the ICD-9 diagnosis codes. 1751 patients were identified as depressed in both methods. The NLP algorithm helped to identify an additional 1912 depressed patients who were not recorded for depression using ICD-9 codes at the academic hospital but their notes indicated that they were depressed patients. Similarly, an additional 700 patients were identified to be on SSRIs apart from those patients that were obtained from the structured medication data. Pain control, as measured by the mean difference between the postoperative and preoperative pain scores, are shown in discharge), the ElasticNet model with a 65-dimensional feature vector achieved a mean AUC of 0.87 with +/- 0.02 standard deviation, while the model achieved mean AUC of 0.81 +/- 0.05 and 0.69 +/- 0.02 for 3 weeks (Δ3week) and 8 weeks(Δ8week) respectively. The ROC indicating the model’s performance at each fold are shown.  computed by the 10-fold cross validated ElasticNet  where the ranking of the features is derived by analyzing the coefficient of the features  when prescribing to this population. Indiscriminate opioid prescriptions have contributed to the current opioid epidemic . IdentifThis study of real-world evidence revealed that depressed patients taking the combined SSRI and Prodrug opioid combination had worse postoperative pain control compared to patients in the SSRI non-Prodrug opioid group, while depressed patients not taking an SSRI had no difference in pain control by Prodrug opioid use. These differences were statistically significant and approach the threshold of minimal clinically significant difference (MCSD) in pain scores . ProdrugThe success of machine learning models in medicine depends not only on accuracy of prediction but also their ability to generalize. In this study, the algorithms had high accuracy, which shows a good prediction ability of the model as well as little deviation in AUCs between folds in 10-fold cross validation for both discharge pain and 3-week postoperative pain, which shows less overfitting during training thus good ability to generalize. Moderate prediction performance at 8 weeks mainly shows complexity of the task, in which the prediction of 8 weeks follow up pain change is done by only looking at the preoperative data. Crucially, this study offers a pipeline to identify useful predictors for poor pain management and to validate clinical trials or research hypotheses using real world evidence.If replicated, our results have multiple clinical implications. First, clinicians prescribing prodrug opioids should routinely screen for SSRI use and consider it in their decision making. To ensure consistent, predictable effect of prescribed opioids, it may be advisable where possible to prescribe opioids whose effect does not depend in liver metabolism . In cases where this is not possible, patients should be warned that any change in their SSRI use could have implications for their pain level and opioid-related risk. For example, a patient on high-dose hydrocodone who stops taking SSRIs may begin experiencing an effectively higher opioid dose, raising their risk of adverse side-effects . For their part, clinicians initiating patients onto SSRIs should inquire about any prodrug opioids the patient is taking, as they may wane in effectiveness when the psychiatric medication is taken. This is worrisome both because it could increase pain but also because it could lead patients to ramp up their opioid dose on their own, exposing themselves to risk.underestimate the true analgesic difference between direct acting opioid and prodrug opioids in the SSRI consuming patient. However, because of their common use we include these complicated analgesics in the most conservative way guided by existing evidence of their effects. Additionally, our findings are based on retrospective EHRs, which include inherent bias. However, substantial efforts were made to check accuracy of selection and extractions of variables based on completeness, clinical meaningfulness and distributions. Finally, these results are predictive and do not suggest causality.There are limitations to this study. First, we use data from a single academic medical institute. While these results might have limited generalizability to other populations, because we use all patients seeking treatment at this tertiary care academic center and include a wide variety of surgical procedures, the results are likely reproducible in other population cohorts. Second, we capture only medication that was prescribed or documented in notes, as we do not have information in medications ingested outside of the inpatient setting. However, this included notes from visits 6 months prior to surgery, the inpatient stay, and postoperative/follow-up visits through 90 days’ discharge. Furthermore, at 8 weeks’ follow-up we have a significant number of patients lost to follow-up, a common limitation at tertiary academic centers. Third, two drugs examined have a complex relationship between their metabolism and activity. Oxycodone is active and potent at the mu-opioid receptor in its native form, but is to some extent metabolized to yet a more potent form . SimilarIn conclusion, our results suggest that prodrug opioids for postoperative pain control after discharge are less effective than active form opioids in patients on SSRIs. The inhibition of metabolic conversion of the prodrug opioids by the SSRI had been theorized to impair pain control, however ours is the first study to demonstrate this interaction in a clinical population of depressed patients using SSRI’s therapeutically. Our predictive model may help future researchers better personalize pain management regimes. If confirmed, prescribers should consider alternatives to prodrug opiates in pain management for patients taking SSRIs.S1 Table(PDF)Click here for additional data file.S2 Table(PDF)Click here for additional data file.S3 Table(PDF)Click here for additional data file.


This study compared the efficacy of ketorolac alone versus its combination with tramadol/acetaminophen for pain control after mandibular third molar surgery.A randomized, triple-blind clinical trial was carried out with 52 patients divided into 2 groups: Group K+T+A (1 tablet of Ketorolac 10 mg plus and 1 capsule of Tramadol 37.5 mg/acetaminophen 325 mg) and Group K (1 tablet of Ketorolac 10 mg plus and 1 placebo capsule). The treatments were given 1 h before the surgery and was repeated 4 times per day, for 48 h. The difference in postoperative pain was assessed by 4 primary end-points: pain intensity , rescue medication, overall assessment and adverse effects.p<0.05). The comparison of groups in each time showed significant differences only of 9 h, with lower level of pain intensity for group K+T+A (p = 0.005). The need of analgesics was higher in Group K (p<0.001), the need of antiemetic were greater in Group K+T+A (p<0.0001). No significant difference between groups were observed in overall assessment. The adverse effects was higher in Group K+T+A.Significant differences in pain intensity were observed in the different times (The current study showed that both ketorolac and the combination of ketorolac plus tramadol/acetaminophen showed good control of pain after the extraction of the lower third molars. Although the combination group showed lower pain at 9 h, the difference is small and not clinically relevant. Key words:Ketorolac, molar, third, surgery, oral, Tramadol, Acetaminophen. Third molar surgery is often accompanied by postoperative complications such as pain, buccal swelling and trismus . Among tSeveral biochemical mediators are involved in the pain process, particularly histamine, bradykinin and prostaglandins . The intNumerous studies have investigated alternatives for the management of pain and discomfort generated by third molar surgery . SeveralAmong the nonsteroidal anti-inflammatory drugs investigated, ketorolac is one of the pharmacological options available, it is reported to have a potent analgesic effect similar to opioids  as well Despite these promising findings, rescue medication for pain relief was still necessary, even with the administration of ketorolac, which suggests that preoperative administration is not enough to eliminate postoperative pain ,10.Combining analgesics may provide greater analgesia than the individual agents through the synergistic action of the individual drugs , and allPerhaps combining a nonsteroidal anti-inflammatory drug (NSAID) such as ketorolac with opioid analgesics such as tramadol/acetaminophen may lead to lower postoperative pain. Clinical studies have reported that the combination of tramadol/acetaminophen 37.5 mg/325 mg was effective and well tolerated in patients with dental pain .Third molar surgery pain is an excellent clinical model for acute pain . Pain ofThis randomized controlled clinical trial was approved by the ethics committee of State University of Ponta Grossa, Ponta Grossa, Paraná, Brazil (≠ 1.449.613), registered in the Brazilian Registry of Clinical Trials (≠ RBR-3phy2q) and prepared using the protocol established by the Consolidated Standards of Reporting Trials Statement .All participants included in this study signed a free and informed consent form and underwent surgery during sessions that were part of the Clinic of Oral and Maxillofacial Surgery in the Department of Oral and Maxillofacial Surgery and Dental Specialty Center of the State University of Ponta Grossa, Brazil. This study was performed from March 8th, 2016, to December 14th, 2016, in the city of Ponta Grossa .Participants with classification of surgical risk ASA 1 (American Society of Anesthesiologists) were selected, with indication of treatment for bilateral third-molar removal, in similar inclusion pattern. Orthopantomograms were taken to ensure similarity of the tooth inclinations. Tooth inclinations were determined using the classifications provided by Winter, using only the vertical and mesioangular positions. We included position “B” and class “II” relationship, which was based on the Pell and Gregory classification; with an extraction degree of difficulty from mild to moderate and at least 1/3 of the root formed, according to the radiographic evaluation, ensuring a lower variability in surgical trauma during the extraction on both sides (right and left) in each patient selected.Patients with a history of hypersensitivity to medications used in the study; pregnant women, asthmatics, diabetics, infants, hypertensives, patients with gastrointestinal disorders (ulcer and bleeding), myasthenia gravis, glaucoma, patients who were immunosuppressed, dependent on narcotic drugs, who had neurological and/or behavioral changes, users of anti-inflammatories or antihypertensive drugs were not included in the study.The study followed a crossover design, i.e., a single patient was submitted to two different pharmacological protocols for postoperative pain control.The participants in Group K+T+A – received 1 tablet of Ketorolac 10 mg  plus 1 capsule of Tramadol 37.5 mg/acetaminophen 325 mg  under oral route 1 h before surgery and every 6 h for 48 h. In Group K – received 1 tablet of Ketorolac 10 mg (Toragesic®) plus 1 placebo capsule , under oral route 1 h before surgery and every 6 h for 48 h.Sample size calculation was done by the website www.sealedenvelope.com, using the primary outcome pain intensity of postoperative pain. To determine if oral ketorolac is as effective as its association with tramadol/acetaminophen ; 90% power and type I error of 5%), this equivalence clinical trial required a minimum sample size of 46 participants, but 52 healthy individuals were selected for this clinical trial.The randomization of the groups was performed through the generation of a list that determined the group of the first surgery. This random order of surgeries was kept in opaque and sealed envelopes, which were numbered sequentially. Immediately before the start of the first surgery, the side to be operated was determined by the coin toss. The envelope was opened to reveal the group, so the other side to be operated would receive treatment from the other group, one month after, respecting the washout period between treatments. To keep the operator, evaluator and patient blind, all medicines, were placed in identical capsules, and encoded by an independent investigator, not involved in the surgical and assessment steps. The surgeon and participant were not aware, at any time, of which drug was administered to the chosen side. Antibiotic prophylaxis with pre-administration of amoxicillin 1 g  or clindamycin 600 mg , in those participants allergic to amoxicillin, was given orally 1 h prior to surgery.The surgical procedure was performed according to the principles of third molar removal surgery, from asepsis to synthesis, using routine materials and instruments required for this surgical practice. The same surgical technique was performed on both sides. Anesthesia was performed through the regional block of the inferior alveolar, lingual and buccal nerve using the same anesthesia .Two types of rescue medication were prescribed to be used if needed.1) tablets of acetaminophen 500 mg , with instructions to take 1 tablet of the drug in case of pain every 6 h; and 2) tablets of ondansetron 4 mg , with instructions to take 1 tablet of the drug in case of nausea. The participants were also asked to take notes (day and time) whenever consuming these drugs in an appropriate questionnaire form given by the surgeon after each surgery.-Pain assessmentsAnalgesic efficacy was assessed based on four key endpoints, which the patients were required to record on a pain diary:Pain intensity Participants were instructed to record their postoperative pain intensity  on a VAS 0 to 100 mm scale, where 0 = no pain and 100 = unbearable pain.Total number of rescue medication consumption Participants were also instructed to record the total amount of analgesics (acetaminophen 500 mg tablets) or antiemetic (ondansetron 4 mg) consumed during the evaluation period (48 h) in their form.Global assessmentParticipants were asked to provide an overall evaluation of the efficacy of the surgery regarding pain on a five-point categorical scale at the end of the trial. The categories of scale were 1 = poor, 2 = fair, 3 = good, 4 = very good and 5 = excellent, in which excellent means minimum pain and poor means severe pain .Assessment of adverse effects Participants were asked to include the occurrence of some common side effects such as dizziness, nausea, vomiting, stomachaches or other gastrointestinal discomforts, migraines or effects. The participants were also instructed to note any rarer occurrences such as prolonged bleeding after surgery, renal problems and/or other gastrointestinal disorders .-Statistical analysisThe need for rescue medication (paracetamol and ondansetron) was analyzed by the McNemar’s test. The intensity of pain in each time period, the consumption of rescue medication and the evaluation of the overall effect for the two groups were performed with the Wilcoxon Signed-Rank test. Within each group, pain intensity at different periods was compared with the Friedman and Student Neuman’s tests. All tests were at a significance level of 0.05 with the software Sigma Plot Software program .Three out of the 52 patients did not perform the second surgery due to postoperative complications in the first surgery. The patients were immediately treated, and the complications were controlled, but they did not want to do the second surgery. Two complications were related to the surgical procedure: paresthesia (Group K) and infection (Group K+T+A). The other complication (Group K+T+A) occurred due to gastrointestinal symptoms . All patients recovered well from these adverse effects.Baseline characteristicsp < 0.05; A total of 52 patients were selected Fig. . The oveThe mean difference of pain intensity in the different assessment periods varied from approximately 4 to 7 units in a 0 to 100 VAS scale .p < 0.001). However, the need for antiemetics in Group K+T+A was greater than for Group K (p < 0.0001). No differences in the median number of pills for both rescue medicines  were observed between groups (p > 0.06)  .The patient’s overall assessment of the surgery in relation to pain is shown in p = 0.002), nausea (p = 0.0001) and vomiting (p = 0.0009) were statistically more common in Group K+T+A than in Group K , was used in theory to establish effective blood levels for maximum analgesic effect at the time pain is most severe.Postoperative pain intensity after third molar surgery is moderate to severe, usually starts within the first 3 h and reaches peaks after approximately 6 to 8 h. The highest pain levels are recorded within the first 12 h ,18. FromThe worst scenario of pain was detected at the 3-h period in the present investigation, with an average pain intensity of 15 units in the VAS scale in group K. The higher intensity at 3 h compared to the other time assessments may be due to the fact that we used a medium-duration anesthetic with a 2.5-h duration of analgesia . TherefoThe purpose of using a combination of analgesics with different mechanisms of action is to achieve a synergistic potentiation , yieldinThe major mechanism by which ketorolac exerts its pharmacological effects is predominantly through the peripheral inhibition of prostaglandin synthesis through cyclooxygenase-1 and -2 inhibition . KetorolTramadol hydrochloride, which has a weak opioid activity, produces analgesia through an opioid effect that binds (μ)-opioid receptors and modifies the transmission of pain signals through the inhibition of serotonin and norepinephrine reuptake within pain pathways of the central nervous system .Acetaminophen, on the other hand, produces analgesia by elevating the pain threshold through inhibition of N-methyl D-aspartate or substance P-mediated nitric oxide synthesis and/or inhibition of prostaglandin E2 release in the central nervous system .The mechanisms responsible for the synergism in the analgesic activity of acetaminophen/NSAIDs combinations are not clear. But it seems to involve several mechanisms that are probably implicated in the antinociceptive activities, many of them at central levels producing a supra-additive or synergic analgesic effect . In animAlthough lower pain at 9 h was observed for group K+T+A, this synergism should be viewed with caution because, from a clinical perspective, this difference (or effect size) was of a small magnitude and its benefits did not overcome the greater number of side effects in the combination drug group.Adverse effects of oral ketorolac were mild in intensity and well tolerated, as well as reported by other authors ,28. StomAn antiemetic drug (Ondansetron 4 mg) was also used as a rescue medication for the control of nausea in patients. In group K+T+A, 30.8% of the patients took the antiemetic, in contrast with only 0% from group K. The higher percentage in the association group may be justified by the fact that tramadol induces nausea and vomiting by stimulation of the chemoreceptor trigger zone (CTZ) richly endowed with serotonin receptors. Serotonin stimulates the vomiting center and transmits signals through the stomach, small intestine, diaphragm and abdominal musculature, thus increasing the intragastric pressure that provokes nausea and vomiting.The need of rescue medication for analgesia (acetaminophen) in the ketorolac group (19%) was significantly greater than that observed in the association group (9.6%). The associated group required less rescue medication, probably because of more analgesic potency from the basic medication.Various factors such as: the preemptive dose, the multiple-dose regimens, the same expert surgeon and surgical technique for all procedures, the same surgical difficulty in terms of the magnitude of surgical trauma on both sides of the mandible and the similar amount of anesthetic volume used in anesthesia techniques might in part explain the low amount of analgesics used postoperatively, compared to single dose regimes ,15.The groups presented similar results regarding the overall assessment, which can be explained by the overall low intensity of pain in both groups. In the worst pain situation, where the pain peak occurs, pain intensity ranged from approximately 4-10% of the maximum VAS pain.We cannot rule out the fact that the use of rescue medication adds an additional variable to the research design and may lead to overestimation of the beneficial effect of the group that took more rescue medication. However, with the growing rigor of research ethics committees, it is not currently possible to carry out any research that may submit the participants to painful or other types of suffering that could be avoided. This also explains why previous clinical trials on this issue also employed rescue medication . Thus, rBoth ketorolac alone and ketorolac plus tramadol/acetaminophen showed good control of pain after extraction of the lower third molars. Although the VAS score in the association group was statistically lower at 9 h, the pain difference is small and not clinically relevant, and the association is more expensive and caused more side effects.


Treatment of back pain due to facet joint syndrome has been a challenge for physicians since its recognition ∼80 years ago. Intra-articular injections of steroids, local anesthetics, and phenol have been widely adopted despite their known shortcomings. Recently, intra-articular injection of amniotic membrane-umbilical cord (AMUC) has been utilized in various orthopedic indications, including those involving synovial joints, due to its reported anti-inflammatory properties. Herein, use of AMUC for facet joint syndrome was evaluated.A single-center case series was conducted on patients presenting with pain caused by facet joint syndrome, confirmed by single blocking anesthetic injection and treated using a single intra-articular injection of 50 mg particulate AMUC (CLARIX FLO) suspended in preservative-free saline. Patient reported back pain severity  and opioid use were compared between baseline and 6 months following treatment.P <.05). All patients had ceased use of prescription pain medications, including opioids. No adverse events, repeat procedures, or complications were reported.A total of 9 patients , average age 52.1 ± 15.9 years, were included. Five patients with cervical pain had a history of trauma, 1 patient had suffered lumbar facet injury and 3 had degenerative lumbar facet osteoarthritis. All patients had severe pain prior to injection (8.2 ± 0.8) and 4 (44%) were taking opioids . Six-month post-treatment, average pain had decreased to 0.4 ± 0.7 (Intra-articular injection of AMUC appears to be promising for managing facet pain and mitigating opioid use. Further investigation with larger sample size is warranted. Just like joints of the knee, facet joints consist of a synovial capsule, synovial membrane, hyaline cartilage, and subchondral bone allowing for tension/compression resistance and facilitation of mobility.,3 Stressed facet joints, degenerative arthritic changes, and muscle imbalances are all factors that contribute to a phenomenon known as facet joint syndrome.,4Chronic back pain is the main presenting complaint among patients seen by neurosurgeons and orthopedic surgeons with a prevalence ranging from 60% to 90%.,5 Unfortunately, pain is highly sensitive and intensified in this area due to its dense innervation. Diagnosis is typically made clinically as well as through exclusion of other origins of back pain. The main symptom experienced with facet joint syndrome involves pain that increases with stress, exercise, extension of the spine, and rotational motions. Current conservative treatments for facet joint syndrome involve intra-articular injections of steroids, local anesthetics, and/or phenol, with steroids being the most popular agent used.,2,6 Between 1994 and 2001, facet joint injections increased by 231% among Medicare patients.,8 Widespread use of steroids continues despite variable clinical effectiveness and associated complications such as weight gain, hypertension, osteoporosis, insomnia, and psychosis.–11 Thus, there remains unmet clinical need for a safer and more effective treatment for facet joint syndrome.Facet joint syndrome often results from trauma, arthritis, chondromalacia, segmental instability, and degenerative changes which induce inflammatory mediators.Amniotic membrane (AM) and umbilical cord (UC) tissues are placental tissues that can be processed using cryopreservation so as to retain key biological and structural components of the innate tissue.(1)These tissues have been demonstrated to have both anti-inflammatory and anti-scarring properties in vitro and in vivo which has led to their use in many clinical orthopedic procedures.(2),13For example, intra-articular injection of particulate AMUC has been shown to improve pain in symptomatic knee osteoarthritis (OA), and to prevent cartilage destruction in a rodent model of induced OA.To assess the benefits of intra-articular AMUC in a pain management practice, a retrospective chart review was undertaken to evaluate symptomatic pain relief in patients suffering facet joint syndrome.2The objective of the case series was to evaluate the safety and effectiveness of injection of particulate AMUC for the treatment of facet pain. This case series was approved by the Institutional Review Board and conducted in accordance with the Helsinki Declaration as revised in 2000. Patient's charts were reviewed if they underwent intra-articular AMUC injections for facet syndrome by the author between January and October 2017 inclusive. The inclusion criteria were age 18 to 85 years, and at least 6 months of follow up data.,14 Forty-eight hours following confirmation, each patient underwent injection in each joint (per level) of 50 mg AMUC  suspended in 0.5 mL of preservative-free saline. This dose was recently shown to attenuate pain in knee OA. A total of 0.4 mL was injected into the zygapophysial intra-articular space while 0.1 mL was injected around the inferior capsule area. Patients were allowed to return immediately to normal activities.Diagnosis of facet joint syndrome was routinely performed as follows: flexion–extension radiographs were evaluated first to rule out dynamic instability or listhesis. Next, patterns of referred pain were noted, and range of motion was assessed through flexion, extension, lateral bending, and rotation. When the facet joint was identified as the primary pain source, intra-articular anesthetic injections were performed under fluoroscopy using either 0.5% lidocaine or 0.5% bupivacaine. Facet joints in the lumbar region were injected with a volume of 1.0 mL, while those in the cervical region were injected with a volume of 0.5 to 0.9 mL depending on the level. The patient was then asked to perform normal daily activities to trigger the pain and fill out a pain diary to determine when the pain occurred. This was then compared to the time period the local anesthetic is known to wear off. Concordance of the return of pain with the known duration of effect confirmed the diagnosis.Medical records were reviewed for demographic variables ), diagnosis, opioid use, and patient subjective reported pain, which was obtained prior to and after diagnostic injections, 8 weeks after treatment and at 6 months post-treatment Pain is routinely evaluated using an 11-point numerical pain rating scale (0–10), where 10 represents the most severe pain and 0 represents no pain. Outcome measures were collected pre-injection and 6 months following intra-articular injection. The occurrence of complications, adverse events, or repeated interventions was also assessed for safety. Standard motor, sensory and reflex neurological evaluations were routinely performed.2.1P value of less than .05 was considered statistically significant.All data were recorded using an Excel spreadsheet . Descriptive statistics  are provided for patient demographics and pain scores. Change from baseline in pain score was evaluated using Wilcoxon Signed Rank Test. A 3Among 30 patients treated during the designated timeframe, 9  met the criteria of age and length of follow-up Tables  and 2. CP = .004). Furthermore, no repeated interventions were required and all patients had ceased use of prescription pain medications. No adverse events or complications occurred over the 6-month follow up period.Before AMUC, all patients were clinically diagnosed with facet joint syndrome and had reported severe pain for an average duration of 25 ± 12 months excluding the aforementioned patient who had suffered lumbar pain for 30 years. All patients complained of pain despite oral administration of NSAIDS and acetaminophen. Four of the 9 patients (44%) were taking opioid medication  at the time of the AMUC injection. After receiving AMUC injection, the patient's reported an average 94.6% decrease in pain (4 Intra-articular injection with steroids is a widely utilized approach intended to mitigate this issue, however, there is much controversy on its widespread use.,2,6 For instance, in a double-blind, randomized, placebo-controlled trial, Carette et al found no short- or long-term improvement from intra-articular steroids. Other studies have found the same lack of benefit when compared with placebo injections. Systematic reviews of the literature find no compelling evidence of long term benefit, concluding that these injections are not clearly effective.–11,17–19 In the present case series, intra-articular facet injection of AMUC led to significant pain relief for at least 6 months. The overall decrease in pain was 94.6%, which is comparatively better than what has been reported with corticosteroid use or radiofrequency nerve ablation.–11,17–19 Recent studies have shown radiofrequency ablation to provide a ∼70% relief for more than 6 months with a mean duration for relief of 10.5 months. It will be of interest to examine pain reduction at 1 year following the AMUC therapy.Treatment for chronic back pain resulting from facet joint syndrome is one of the main challenges faced by physicians today. There is no truly effective “gold standard” interventional therapy, leaving patients with significant disability, as well as extraordinary health care and societal costs.,5 Hence, AMUC's anti-inflammatory actions may attenuate the inflammatory mediators and relieve pain. More specifically, AMUC tissues have been shown to downregulate expression of pro-inflammatory cytokines such as TNF-α and IL-6, induce apoptosis of pro-inflammatory cells such as activated neutrophils and M1 macrophages and promote polarization of anti-inflammatory cells such as M2 macrophage. Although AMUC contains a myriad of growth factors, cytokines, and extracellular matrix components, the aforementioned therapeutic effects have primarily been shown to come from a molecular complex known as HC-HA/PTX3. Pre-clinical and clinical studies have confirmed these therapeutic benefits in diseased joints where particulate AMUC attenuated progressive cartilage degeneration and provided pain relief of symptomatic knee OA.,13 Considering that the knee and facet share similar anatomical features and osteoarthritic changes have been a universal finding in facet degeneration, it is not surprising the current case series show similar therapeutic effects as previously seen in those studies.The therapeutic effect of AMUC in facet joint syndrome may be due to the tissue's anti-inflammatory properties. In previous studies, inflammation has been shown to be associated with facet joint syndrome as inflammatory cytokines in the facet joint is found at high levels that may contribute to pain.,23 Consequently, in October 2017, the opioid crisis was declared as a national public health emergency. As such, there remains an unmet clinical need for a novel, non-opioid alternative which provides a more effective treatment to prevent opioid abuse, dependence, and addiction in pain management. Further controlled studies evaluating different dosages are necessary to determine if AMUC injection might be a safer non-opioid alternative to treat pain derived from the facet joint syndrome.A novel finding was that patients relying on opioids for pain relief were able to entirely discontinue their use after AMUC injection. While opioids can provide short-term relief, they are also known to have a high abuse potential and produce several undesirable effects such as nausea, vomiting, constipation, somnolence, and respiratory depression. Each day, about 115 Americans are said to die from unintended opioid overdose, with 40% of those deaths originating due to prescribed opioid use.Conceptualization: Daniel S. Bennett.Data curation: Daniel S. Bennett.Formal analysis: Daniel S. Bennett.Investigation: Daniel S. Bennett.Methodology: Daniel S. Bennett.Project administration: Daniel S. Bennett.Resources: Daniel S. Bennett.Supervision: Daniel S. Bennett.Validation: Daniel S. Bennett.Writing – original draft: Daniel S. Bennett.Writing – review & editing: Daniel S. Bennett.