Patients with serious or life-threatening illnesses are typically referred to palliative care to discuss goals of care, advance care planning, and to seek control of their cancer-related pain. Physicians who care for patients near the end of life quite often attribute worsening pain to advancing disease. We present a case of a patient with metastatic gallbladder adenocarcinoma who presented to a palliative care clinic with complaints of worsening chest and back pain, uncontrolled with her established opioid pain regimen. Findings on physical examination prompted the search for other etiologies of this patient’s worsening pain. An initial review of her recent investigations revealed a suspicious positron emission tomography (PET) scan obtained prior to her clinic appointment, which showed a large right-sided pneumothorax with tension physiology. The patient was urgently sent to the emergency room for emergent placement of a chest tube. This case attempts to bring awareness to the potential bias physicians may have regarding the pain experienced by patients with advanced disease and who are near the end of life. The performance of a thorough physical examination can be neglected in a developed, resource-rich country where imaging is easily accessible. Although the adoption of a stepwise ladder in pain management for patients at the end of life is frequently implemented, forgoing a thorough history and physical examination can have detrimental effects. Consideration of other etiologies of acute pain remains imperative when treating patients at the end of life. Physicians encounter a wide array of symptoms in patients with cancer, including but not limited to pain, dyspnea, anxiety, depression, and fatigue . The manA 53-year-old female with multiple hospital admissions related to abdominal pain presented with complaints of severe, sharp right-sided chest and abdominal pain with radiation to her back. Computed tomography (CT) of the abdomen showed an ill-defined heterogeneity and hypodensity in the gallbladder fossa with adjacent edema that was concerning for malignancy. Biopsy of the mass revealed gallbladder mucinous adenocarcinoma. Initial CT of the chest after the diagnosis of gallbladder adenocarcinoma showed no intrathoracic lymphadenopathy or lung metastases. A follow-up PET scan was ordered for staging purposes to be completed on an outpatient basis. Oncology planned to start the patient on a chemotherapy regimen once she was medically optimized to include gemcitabine and cisplatin every three weeks. Palliative care was also consulted for the management of her cancer-related pain. She was initially started on a pain regimen inpatient that included hydromorphone and morphine sulfate extended-release tablets for the treatment of severe cancer-related pain.The patient was followed up in an outpatient palliative care clinic with complaints of severe abdominal and back pain that was unrelieved by her established opioid regimen. Physical examination revealed a cachectic patient in moderate distress. The examination was remarkable for the complete absence of breath sounds on the right-sided lung fields. She was euvolemic on examination, with no evidence of jugular venous distension or pedal edema. The palliative care team started to further investigate the patient’s case with a chart review including prior imaging studies of her chest. Multiple imaging scans of the chest, including chest x-rays (CXR) and CT scans, had no acute abnormalities. However, the patient had a PET scan completed days prior to her current visit that had not yet been read by a radiologist. The most remarkable finding on the PET scan was the incidental finding of a large right-sided pneumothorax Figure .Closer evaluation of the chest portion of the PET scan is shown in Figure The patient was urgently sent to the emergency department for further management. The patient developed acute hypoxic respiratory failure, requiring intubation for mechanical ventilation. She had an aspiration event prior to intubation and developed septic shock shortly thereafter, requiring pressors for vasoactive support. CXR on admission redemonstrated a large right-sided pneumothorax with tension physiology evidenced by leftward deviation of the heart and mediastinal structures Figure . The patThe patient was extubated two days after admission. The chest tube was removed three days after admission. She continues to follow up with oncology and palliative care for ongoing care.Our patient had multiple admissions with complaints of chest pain, abdominal pain, and back pain. After her diagnosis of metastatic gallbladder carcinoma, she was started on a pain regimen that included hydromorphone and morphine sulfate extended-release tablets. Due to multiple presentations secondary to worsening pain presumed secondary to cancer progression, there was consideration for alternative approaches to pain management, such as celiac plexus nerve block. Because the physicians in the palliative clinic prioritized comprehensive patient care in this case, it allowed for prompt recognition of an unexpected diagnosis that has the potential for serious morbidity and mortality if left untreated. This allowed the patient to receive prompt intervention and prevention of possible death.The exact etiology of this patient’s pneumothorax remains unknown. However, the patient had a placement of a right-sided chemotherapy port three weeks prior to the diagnosis of pneumothorax on a PET scan. It is hypothesized that the patient developed a pneumothorax as a complication of chemotherapy port insertion. It is important to note, however, that CXRs completed after insertion of the chemotherapy port did not show evidence of pneumothorax. Pneumothoraces have also been shown to occur in the setting of malignancy. Clinicians should consider the possibility of lung metastases in a patient with the development of pneumothorax with known malignancy. However, our patient had no evidence of metastases to the lungs at the time of this evaluation.The most common symptoms encountered in the palliative care setting include pain, dyspnea, anxiety, depression, and fatigue . The treEmergencies in palliative care can include hemorrhage, convulsions, fractures, spinal cord compression, and acute confusion . Acute sPhysicians who frequently care for patients with cancer and those near the end of life can develop a bias toward labeling all pain experienced by their patients as occurring secondary to the progression of their disease. However, it is important for physicians to remember that palliation should continue to encompass comprehensive medical care for patients and should not only be considered an alternative when traditional medical therapies have failed . ComprehPatients at the end of life often seek palliative care to help alleviate the pain associated with their progressive condition. Physicians who frequently care for patients at the end of life may have premature closure with respect to pain in a known cancer patient. However, it is imperative for physicians who care for patients at the end of life to complete a thorough interview and physical examination to exclude other causes of acute and chronic pain. This case presents a near miss of a pneumothorax first diagnosed on a PET scan in the outpatient setting. The physicians in this palliative care clinic performed a comprehensive interview and physical examination. Physical examination findings raised suspicions about this patient's breakthrough pain; a recent PET scan revealed the incidental finding of a large pneumothorax, explaining this patient’s worsening pain and discomfort. This allowed us to redirect this patient to the emergency room to receive timely intervention and prevention of serious morbidity and mortality. Had the physicians in this clinic chosen to simply escalate this patient’s pain regimen, she could have experienced serious complications or premature death. This case highlights why it is important for physicians who treat patients at the end of life to consider other etiologies of pain to provide the best and most comprehensive care for these patients.


The clinical pharmacist detected a high incidence of polypharmacy, PIMs, DDIs, and inappropriately prescribed RRDs on hospital admission. This study highlights the importance of early detection of pharmacotherapy problems by using the BPMH in order to prevent their circulation during a hospital stay. The positive correlations between polypharmacy, PIMs, DDIs, and inappropriately prescribed RRDs indicate that they are not independent, but rather occur simultaneously.Transfer of care is a sensitive process, especially for the elderly. Polypharmacy, potentially inappropriate medications (PIMs), drug-drug interactions (DDIs), and renal risk drugs (RRDs) are important issues in the elderly. The aim of the study was to expand the use of the Best Possible Medication History (BPMH) and to evaluate polypharmacy, PIMs, DDIs, and inappropriately prescribed RRDs on hospital admission, as well as to determine their mutual relationship and association with patients’ characteristics. An observational prospective study was conducted at the Internal Medicine Clinic of Clinical Hospital Dubrava. The study included 383 elderly patients. Overall, 49.9% of patients used 5–9 prescription medications and 31.8% used 10 or more medications. EU(7)-PIMs occurred in 80.7% (n = 309) of the participants. In total, 90.6% of participants had ≥1 potential DDI. In total, 43.6% of patients were found to have estimated glomerular filtration rate < 60 mL/min/1.73 m Transfer of care is a vulnerable process that increases the risk of drug-related problems, especially in the elderly. The World Health Organisation (WHO) launched the third Global Patient Safety Challenge with aim of improving the medication safety, “Medication Without Harm”, where the key areas of the challenge represent the transfer of care, polypharmacy, and high-risk situations. High-risk situations include hospital treatment, and drug management in elderly patients, as well as those with concomitant renal impairment. The WHO’s goal is to reduce severe avoidable harm related to medications by 50% .More than 20% of the European Union (EU) population are the elderly, and by 2050, this figure will double at the global level . PopulatTreatment of chronic kidney disease (CKD) represents a global health burden with a significant share of health care costs . Older aWith the length of hospital stay the number of medications increases, which complicates pharmacotherapy management and jeopardizes patients’ safety . The detMedication reconciliation is a relevant safety procedure in medication management during the transition of care which has also been proven as a cost-saving measure . MedicatThe aim of the study was to evaluate polypharmacy, PIMs, DDIs, and RRDs by using the BPMH on hospital admission and to determine their mutual relationship and association with patient characteristics.An observational prospective study was conducted at the Internal Medicine Clinic of Clinical Hospital Dubrava. Clinical Hospital Dubrava is a tertiary care, 600-bed teaching institution whose emergency service provides care to a population of approximately 350,000 inhabitants. The Internal Medicine Clinic consists of eight departments: Department for cardiovascular medicine, Department of endocrinology, diabetes, diseases of metabolism and clinical pharmacology, Department of gastroenterology, hepatology and clinical nutrition, Department of Rheumatology and Clinical Immunology, Department of nephrology and dialysis, Department of pulmonology, Department of haematology and Department of intensive care medicine. Patients aged 65 or older were eligible to participate if they had been admitted to the Internal Medicine Clinic in the period from December 2018 to March 2020 and were willing to sign the informed consent . Participants were randomly selected, using a computer-generated random number table. The sample size was based on data availability in this period.The hospital clinical pharmacist created the BPMH for each patient within 24 h of admission. The standardized process of obtaining BPMH was in accordance with the Protocol on Medication Reconciliation and Implementation Guide . By patiPatients’ therapies in BPMH were listed according to the Anatomical Therapeutic Chemical (ATC) Classification System. The use of prescribed medications in BPMH was divided into the following categories: low medication use (<5 medications), polypharmacy (5–9 medications), and excessive polypharmacy (≥10 medications) . The EU screening program was used for pharmacotherapy analysis. Lexicomp classifies potential DDIs according to clinical significance in 5 classes . Classes C, D and X, interpreted as “monitor drug therapy”, “consider therapy modification” and “avoid combination” are clinically significant and are included in the analysis.2), stage G2 (eGFR 60–89 mL/min/1.73 m2), G3a (eGFR 45–59 mL/min/1.73 m2), G3b (eGFR 30–44 mL/min/1.73 m2), G4 (eGFR 15–29 mL/min/1.73 m2), and G5 (eGFR < 15 mL/min/1.73 m2) [Data for renal function was documented upon hospital admission. Kidney Disease: Improving Global Outcomes (KDIGO) classification of renal impairment includes following categories G1–G5 based on the estimated glomerular filtration rate (eGFR) values: stage G1 (eGFR ≥ 90 mL/min/1.73 m1.73 m2) . The eGFp-value, was set at p < 0.05.R Core Team  was used for data management and analyses . Standar2 . Detailed patients characteristics are shown in The research included 383 elderly patients with a median age of 76 (70–80). A total of 43.6% of patients were found to have eGFR < 60 mL/min/1.73 mOverall, 49.9% of patients used 5–9 prescription medications, and 31.8% of patients used 10 or more medications. The median number of medications in the BPMH per patient was 8 (5–11). The number of OTC drugs and dietary supplements reported in patients’ BPMH was 98 and 88, respectively. The patterns of medication use and frequency were presented in PIMs based on EU(7)-PIM criteria occurred in 80.7% (n = 309) of the patients. A total of 689 PIMs were reported in BPMHs with 56 different drugs. The average number of PIMs per patient was 1.8. The most common PIMs were pantoprazole, diazepam, tramadol and moxonidine .Overall, 2629 potentially clinically significant drug interactions were determined; 2270 (86.3%) of them required increased patient monitoring, while 323 (12.3%) interactions required specific therapy modification and 36 (1.4%) should be avoided. In total, 90.6 % of patients had ≥1 potentially clinically significant DDI in their BPMH; 87.5% had at least one C interaction, 46.7% had at least one D interaction and 8.1% of patients had at least one X interaction. The overall rate of clinically significant DDIs was 6.9 per patient. The most common potential clinically significant DDIs are shown in A total of 279 RRDs were reported in BPMH in patients with renal impairment. There were 183 drugs needing dose adjustment and 96 drugs with a contraindication with regard to renal function. For 47% (n = 86) of drugs needing dose adjustment, the dose was adjusted in BPMH with regards to patients’ renal function, while more than half of drugs  did not have an adjusted dose. Of all patients with renal impairment, 64.7% had one or more inappropriately prescribed RRDs in their BPMH (unadjusted dose and contraindicated drugs); 32.3% of patients had one or more contraindicated drugs with regards to their renal function; 47.9% of patients had an unadjusted drug dose and 41.3% of patients had an adjusted drug dose. The most represented RRDs were: perindopril (separately and in fixed combinations), moxonidine, metformin, and ramipril .The relationship between polypharmacy, PIMs, DDIs, and inappropriately prescribed RRDs is described in The association between patients’ characteristics and polypharmacy, PIMs, DDIs, and inappropriately prescribed RRDs is presented in Transfer of care is a sensitive process that increases the risk of ADEs, especially in the elderly. In our study, a clinical pharmacist, using multiple sources of information, obtained and evaluated BPMH for 383 hospitalized older patients admitted to the Internal Medicine Clinic. This research determined a very high incidence of polypharmacy, PIMs, DDIs, and inappropriately prescribed RRDs detected in BPMH. To the best of our knowledge, this is the first study to explore the incidence and types of polypharmacy, PIMs, DDIs, and inappropriately prescribed RRDs by using BPMH, and to determine their mutual relationship and association with patient characteristics.A high level of polypharmacy was identified in in this research. According to a recent review by Khezrian et al., the prevalence of polypharmacy varied between 10% and 90% . PolyphaThe BPMH is a valuable source of information for deprescription. The most important instruments for deprescription are PIM tools. The EU7)-PIM list employed in this study presents the most comprehensive and up-to-date tool for the evaluation of PIM prescribing in Europe. It is specifically designed to cover the European drug market more appropriately than the other existing PIM criteria -PIM list,31, and The most frequently detected EU7)-PIM drugs were proton pump inhibitors (PPIs) 40%), previously detected in numerous studies ,33,37. E-PIM drug%, previoOur research found a high prevalence of potential clinically significant  DDIs upon admission (90.6%). Regression analysis showed that women have a higher risk for D interactions and a lower risk for X interactions as opposed to men which could be explained by the fact that drugs that depress the CNS, most often represented in D interactions, are more commonly used by women . On the 2). Recent research conducted in Croatia that included 1211 patients also found this interaction to be the most common [The most common potential consequence of the identified X interactions was an increased anticholinergic effect, with its side effects particularly high in elderly patients. Additionally, the most commonly identified clinically significant interaction between perindopril and indapamide carried an increased risk of nephrotoxicity. This result is of particular importance considering the fact that more than 40% of patients upon admission had impaired renal function  implying the need to reconsider RRD use in the BPMH already on hospital admission. A lower level of renal function for certain drugs may require therapy adjustment and increase the risk of adverse drug events . Our res2 ,46. This study compared the prescribing of inappropriately prescribed RRDs in patients with impaired renal function according to gender. Regression analysis showed that women were at higher risk of having inappropriately prescribed RRDs, which puts them at higher risk of ADEs. The epidemiology of CKD differs by gender; it reports a higher prevalence of CKD in women compared to men . Faster ACEIs were the most common RRDs in this study. Inappropriate prescription of ACEIs in elderly patients with renal impairment has been noted in other studies ,52. ACEIThis research had certain limitations. The study included one hospital, one clinic, and was observed at only one point of care transition. Further research should also evaluate the scope of polypharmacy, PIMs, DDIs, and RRDs upon hospital discharge. The study did not include surgical patients who are considered as patients requiring more complicated therapeutic management and future research should broaden the research focus.Despite limitations, our study suggests that the BPMH is a useful tool for detecting a wider spectrum of pharmacotherapy problems. High incidence of PIMs, DDIs, and inappropriately prescribed RRDs indicate the need for their early detection. Detection of pharmacotherapy problems upon admission is one of the crucial steps for therapy optimization during a hospital stay. The clinical pharmacist has specific pharmacotherapy knowledge and therefore, can significantly contribute to pharmacotherapy rationalization and patient safety. Although there are different decision support systems for detecting pharmacotherapy problems, they cannot adequately replace medication reconciliation and clinical pharmacists’ professional interpretation of data . DecisioClinical pharmacists’ evaluation of the BPMH showed high exposure to polypharmacy, PIMs, DDIs, and inappropriately prescribed RRDs upon hospital admission in the elderly. This study highlights the need for its detection to prevent the transfer and circulation of pharmacotherapy problems during the hospital stay, further facilitating drug optimization. The positive correlations between polypharmacy, PIMs, DDIs, and inappropriately prescribed RRDs indicate that they are not independent and that there is a greater than random probability they will occur simultaneously.


Background and objectiveIn light of the scarcity of data and research about the management of pain in a low-resource setting, we conducted this study with a view to assessing the effectiveness of intravenous ketamine in comparison to that of intradermal lidocaine in reducing postoperative pain. Postoperative pain can lead to significant morbidity, longer hospital stay, and the development of chronic pain. Our study was formulated to assess the effectiveness of a ketamine bolus in comparison to intradermal lidocaine at the wound site in terms of decreasing pain scores postoperatively.MethodsIn our study, 99 patients were randomly selected to undergo inguinal hernia repair under spinal anesthesia. After obtaining informed consent from the participants and approval from the hospital ethical committee, the patients were randomly classified into the following three groups: the lidocaine group (group A), the ketamine group (group B), and the control group (group C). The patients in the lidocaine group received 0.6 mL/kg of 0.25% lidocaine (1.5 mg/kg) infiltration at the wound site. The ketamine group was given a 50-mg ketamine bolus at the end of the operation, and the control group did not receive either ketamine or intradermal lidocaine at the wound site. Postoperative pain was recorded using the Visual Analog Scale (VAS) scoring and the results were compared. The time of the first request for analgesia was also recorded.ResultsThe pain scores measured via VAS scores were higher in patients who received intradermal lidocaine (group A) at the wound site as compared to group B that received a bolus of 50-mg ketamine (p<0.0001); the control group (group C) had pain scores higher than both groups A and B (p=0.0001).ConclusionBased on our findings, administering ketamine bolus can significantly decrease VAS scores and reduce the incidence of chronic post-surgical pain as compared to lidocaine infiltration. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, provides excellent pain relief and analgesia, which decreases overall pain scores. In an acute postoperative setting, it is essential to provide maximum pain relief to patients to reduce the length of hospital stay and facilitate rapid ambulation. The research on pain management in low-resource settings is minimal. Therefore, we believe that this study, which aims to compare the use of ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, with intradermal wound infiltration with 0.6 mL/kg of 0.25% of lidocaine 1.5 mg/kg) to reduce postoperative pain, is very significant. Surgical procedures to treat inguinal hernias are commonly performed, and they can lead to significant postoperative pain. Acute postoperative pain might result in prolonged bed rest, which can cause other medical issues such as thromboembolism. Inguinal hernias are common in the male population. It causes bulging in the area of the groin, leading to acute pain and a decrease in the quality of life. In some cases, an inguinal hernia may also lead to intestinal obstruction [.5 mg/kg The major complications of inguinal hernia repair are recurrence and acute pain. Using 0.6 mL/kg of 0.25% lidocaine (1.5 mg/kg) solution of anesthesia intradermally at the surgical site can reduce the incidence of acute postoperative pain following the open repair of an inguinal hernia. Using local anesthesia infiltration offers many advantages and its use is recommended in open repair techniques. It is recommended that patients start ambulation as soon as possible after surgery. Studies have revealed an increased incidence of postoperative pain in this patient population. Lidocaine is considered to be the least toxic local anesthetic agent. The low dose of 0.6 mL/kg of 0.25% lidocaine (1.5 mg/kg) is considered safe and effective in producing regional blocks -4.Acute postoperative pain decreases over time but debilitating pain may lead to the aggravation of medical conditions due to prolonged bed rest and increases the length of hospital stay. Poor pain management in an acute setting might lead to the development of persistent pain at the site of surgery. Chronic postoperative inguinal pain is a cause for concern as this affects daily work-life balance and decreases the quality of life. It is defined as pain that lasts for around three months and then decreases over time. It has been suggested that local infiltration of the dermis with lidocaine can decrease the incidence of acute pain as well as the incidence of chronic pain. Intravenous ketamine can also provide pain relief by acting on NMDA receptors. Low-dose ketamine bolus may be useful in reducing opioid consumption and preventing the development of chronic pain -6.Infiltration of a wound with 0.6 mL/kg of 0.25% lidocaine (1.5 mg/kg) has been associated with a decrease in pain at the incision site. Lidocaine applied at the end of surgery involving skin and subcutaneous tissue can decrease postoperative pain. Lidocaine works by blocking voltage-gated sodium channels, leading to a decrease in nerve stimulation and transmission of impulses. Patients are regularly operated on for inguinal hernia repair as it is one of the most common surgeries performed in hospitals .This study was carried out at the Abbasi Shaheed Hospital in Karachi, Pakistan. After obtaining approval from the hospital ethical committee, we designed a randomized and double-blinded study. The sample size for each group was calculated based on the random sampling method, and it was decided that each group would have 33 participants. The inclusion criteria were men aged 55-75 years without any comorbidities. Those with any systemic disease or any history of previous surgery or use of psychiatric drugs were excluded from the study.In this comparative trial, 99 patients were randomly selected; all of them were scheduled to undergo inguinal hernia repair under spinal anesthesia. All patients were aged between 55-75 years and had no prior history of abdominal surgery. They were divided into three groups with 33 participants each according to the principles of a randomized sampling method.Informed consent was obtained from all patients selected for the study. The Visual Analog Scale (VAS) scoring method was clarified to the patients: 0 stands for no pain and 10 represents the worst pain.Patients scheduled for surgery were randomly selected and divided into the following three groups: the lidocaine group (group A), the ketamine group (group B), and the control group (group C). In the lidocaine group, where all patients were scheduled for unilateral inguinal hernia repair under spinal anesthesia, 0.6 mL/kg of 0.25% lidocaine (1.5 mg/kg) was injected at the wound site when the surgeon completed the operation. In the ketamine group, which also included patients undergoing unilateral hernia under spinal anesthesia, they were given ketamine 50 mg bolus after the completion of the surgery. The control group consisted of patients having unilateral hernia repair under spinal anesthesia who did not receive any intervention for pain management. Postoperative pain was recorded using a VAS scoring system with scores ranging from 1 to 10.Postoperative pain was evaluated at the post-anesthesia care unit at 30, 60, and 120 minutes postoperatively. The data were analyzed using SPSS Statistics version 26.0 . All quantitative variables such as age, weight, duration of surgery, baseline heart rate, baseline mean arterial pressure, and VAS scores were assessed for their distribution. Age was presented with mean ±standard deviation (SD) while the median (interquartile range) was used for reporting other non-normally distributed variables. The analysis of variances (ANOVA) test was applied to assess the difference between the three groups regarding age. Other statistical differences were identified using the Kruskal-Wallis test. A p-value of ˂0.05 was considered statistically significant. For significant differences, pair-wise comparisons were done and presented with a subscript  at the wound site. In low-resource settings, it is critical to use the minimum quantity of drugs available to provide maximum pain relief to patients. Pain management strategies are lacking in terms of guiding toward the best modes of pain relief in low-resource settings or places where there is a scarcity of medicine. It is vital to reduce acute postoperative pain as it might lead to problems such as thromboembolism, increased pressure on hospital resources, and decreased patient satisfaction -10.The lidocaine Infiltration of the surgical wound has been used to sensitize the nerve ending, leading to the decreased entry of noxious and paralyzed stimuli. The study also stresses that infiltration reduces the pain scores in the acute postoperative period. Combination with spinal anesthesia can also contribute to reducing VAS scores and decreasing overall opioid requirements. The baseline values of mean arterial pressure, age, etc., are all presented in Table In our study, a decrease in VAS scores was seen in the ketamine group, in which a bolus of 50 mg of ketamine was given at the end of inguinal hernia repair. In comparison, the VAS showed a higher score in the lidocaine and control groups. In the control group, at the end of the surgery, no ketamine or intravenous or surgical infiltration was performed. Patients who requested analgesia were given oral non-steroidal anti-inflammatory drugs (NSAIDs) if they experienced pain -13.Table The benefits of ketamine have been demonstrated in a similar study in which an intravenous ketamine bolus was used. The ketamine given at a low dose was found to be effective in reducing acute postoperative pain, and patients reported better pain control and higher satisfaction. It also highlighted that patients were managed with minimal clinical resources, and no special care was required -15.Ketamine bolus is highly effective in decreasing VAS scores and reducing the incidence of chronic post-surgical pain as compared to lidocaine infiltration. Ketamine, an NMDA receptor antagonist, provides excellent pain relief and analgesia, which decreases overall pain scores. Lidocaine infiltration of surgical wounds did not decrease pain scores in the acute postoperative period. While further research is necessary to quantify the long-term effects of ketamine on pain scores, our study provides valuable insights into the management of pain in low-resource settings.


Symptoms of depression are transdiagnostic heterogenous features frequently assessed in psychiatric disorders, that impact the response to first-line treatment and are associated with higher suicide risk. This study assessed whether severe mental pain could characterize a specific phenotype of severely depressed high-risk psychiatric patients. We also aimed to analyze differences in treatments administered.2,297 adult patients  treated in several Italian psychiatric departments. Patients were assessed for psychiatric diagnoses, mental pain, symptoms of depression, hopelessness, and suicide risk.More than 23% of the patients reported high depression symptomatology and high mental pain (HI DEP/HI PAIN). Compared to patients with lower symptoms of depression, HI DEP/HI PAIN is more frequent among females admitted to an inpatient department and is associated with higher hopelessness and suicide risk. In addition, HI DEP/HI PAIN  were more frequently diagnosed in patients with personality disorders and had different treatments.Patients reporting severe symptoms of depression and high mental pain presented a mixture of particular dangerousness (high trait hopelessness and the presence of suicide ideation with more frequency and less controllability and previous suicide behaviors). The presence of severe mental pain may act synergically in expressing a clinical phenotype that is likewise treated with a more complex therapeutic regime than that administered to those experiencing symptoms of depression without mental pain. Depressive symptomatology is a transdiagnostic feature frequently comorbid in psychiatric disorders, with highly heterogeneous symptoms, typically physical and emotional-cognitive symptoms encompassing feelings of worthlessness, guilt, shame, lowered self-esteem, and hopelessness. Heterogeneity and comorbidity of depression symptoms impact the response to first-line treatment –4, contrScholars have reported that mental pain is higher in suicide attempters than nonattempters and suicide ideators than nonideators –9. FurthAdditionally, the severity of depressive symptoms in major depressive disorder (MDD) was reported to be associated with an increased risk of an MDD-related hospital encounter in the short term . A recenThe present study, therefore, aimed to assess whether severe mental pain could characterize a specific phenotype of severely depressed high-risk psychiatric patients. We hypothesized that regardless of the diagnoses, patients with current self-reported symptoms of severe depression and severe mental pain are at higher suicide risk and are more prone to trait hopelessness when compared with psychiatric patients with severe symptoms of depression but lower mental pain. Since pharmacological treatment represents a major therapeutic intervention for properly managing given diagnoses and treating specific symptoms, including the manifestation of depression, we aimed to analyze treatments administered to severely depressed patients with severe psychological pain to assess whether these differed from depressed patients with lower psychological pain.A multicenter observational study was a joint project with numerous mixed Italian academic and clinical settings (represented by the authors’ affiliations). We reported complete information in a previous article . BrieflyThe study was conducted ethically following the World Medical Association Declaration of Helsinki. Patients participated voluntarily and provided written informed consent following review and approval of each participating center’s research ethics review board, ensuring that data would be reported anonymously and in aggregate form.Participants were 2,297 adult patients  treated in several psychiatric inpatient and outpatient departments.Patients were assessed for psychiatric diagnoses according to the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria, the Structured Clinical Interview 5th Edition (SCID—DSM-5) , via psyA web-based system with codes and anonymous labels was devised for this study. Each center entered all data via a guided digital procedure to minimize data entry errors.All the patients were administered a comprehensive battery of psychological tests and semi-structured interviews, including the Physical and Psychological Pain Scale (PPPS) , the BecA rating scale evaluating suicidal ideation in individuals aged 12 years and older . The C-Snone) to 10 (maximum possible pain) [A self-administered questionnaire that evaluates the intensity of physical and mental pain on a dimensional scale from 0 (le pain) : the curle pain) . CronbacA 21-item self-report instrument evaluating the presence/severity of depressive symptoms during the previous 14 days . A singlA 20-item self-report measure of trait hopelessness about the future , 29. HigPatients were included in three groups according to their self-reported depression and worst psychological pain levels in the past two weeks. Patients with BDI-2 scores ≥20 and psychological pain scores in the upper quartile (≥75th percentile) were included in the high depression symptomatology and high psychological pain (HI DEP/HI PAIN) group. Patients with BDI-2 scores ≥20 and psychological pain scores in the lower quartiles (<75th percentile) were included in the HI DEP/LO PAIN group. Patients with BDI-2 scores <20 were included in the low depression symptomatology (LO DEP) group. Considering the high number of categories, DSM-5 diagnoses were included in two separate variables, a variable for personality disorders  and one other variable for all diagnoses. In the DSM-5 diagnosis variable, all patients included in the category none had a personality disorders or substance abuse.v ≤ 0.2 indicates a small effect, v ≤ 0.6 indicates a medium effect, and v > 0.6 indicates a large effect [A series of ANOVAs and chi-squared tests were used to evaluate bivariate differences among groups. Bonferroni correction was used to correct for multitesting, and measures of effect sizes were reported. Partial eta squared of 0.01 indicates a small effect, ≥ 0.06 medium effect, ≥ 0.14 large effect. Cramer’s e effect .Variables significant in the bivariate analyses after correction for multitesting (except for DSM-5 diagnoses) were included in multinomial regression models with groups as a criterion. Odds ratio (OR) and their 95% confidence intervals (CI) are reported as measures of association. In addition, DSM-5 diagnoses and treatments were included in a separate log-linear model to analyze further the links between these variables and the presence of mental pain.In the past two weeks, 535 patients reported HI DEP/HI PAIN, 550 reported high depression symptomatology (BDI ≥ 20), but low psychological pain (below the 75th percentile) (HI DEP/LO PAIN), and 1,188 reported LO DEP.p < 0.05) with HI DEP/HI PAIN > HI DEP/LO PAIN > LO DEP for the presence of females, PDs, BHS scores, lifetime suicide attempts, BDI-2 suicide risk, recent nonsuicidal self-harm, and antipsychotic and anxiolytic treatments. Patients with HI DEP/HI PAIN had also been prescribed mood stabilizers more frequently and were more often inpatients than the other two groups, while the HI DEP/HI PAIN and HI DEP/LO PAIN patients had more frequently been prescribed antidepressants than the LO DEP group. Finally, HI DEP/HI PAIN and HI DEP/LO PAIN patients differed from LO DEP regarding DSM-5 diagnoses. LO DEP patients (compared to the HI DEP groups) more frequently had diagnoses of schizophrenia and other psychoses  or other specified DSM-5 diagnoses , and less frequently had diagnoses of MDD  and eating disorders .In All variables (excluding DSM-5 diagnoses) were included in a multivariate model with groups as the criterion . When coχ2181 = 137.36, p = 0.99. HI DEP/HI PAIN and HI DEP/LO PAIN did not differ for DSM-5 diagnoses (p between 0.053 for other specified diagnoses and 0.93 for MDD) and the frequency of antidepressant treatments (p = 0.21). HI DEP/HI PAIN (compared to HI DEP/LO PAIN) were more frequently diagnosed with personality disorders , and they were more frequently treated with antipsychotics , mood stabilizers , and anxiolytics .To further differentiate HI DEP/HI PAIN from HI DEP/LO PAIN patients, diagnoses and treatments were included in a log-linear model with groups as the criterion (HI DEP/HI PAIN vs. HI DEP/LO PAIN) (not reported in the tables). The model fitted the data well (Pearson p < 0.05) differed in the presence of suicide ideation and characteristics of the ideation . Post hoc comparisons were significant (p < 0.05) for all the variables. HI DEP/HI PAIN patients differed from the LO DEP group and from HI DEP/LO PAIN patients for the presence of more severe suicide ideation and for the existence of higher frequency, more duration, less controllability, fewer deterrents, and for having higher pain as a reason for suicide ideation than other groups.Groups were compared for last month’s suicide ideation according to the C-SSRS . DEP/PAIχ210 = 568.92, p < 0.001; Nagelkerke R2 = 0.26). All the variables were significantly associated with DEP/PAIN groups (p < 0.05). Compared to the LO DEP patients, HI DEP/LO PAIN patients reported significantly higher frequency , lower controllability , and pain more frequently as a motivation for suicide ideation  but no differences related to duration  and deterrents . Compared to the LO DEP group, HI DEP/HI PAIN patients reported significantly higher frequency , lower controllability , and pain more frequently as a motivation for suicide ideation  but no differences regarding duration  and deterrents .Variables characterizing the previous month’s suicide ideation were included as predictors in a multinomial regression model with DEP/PAIN groups as the criterion (not reported in a table). The model fitted the data well , denoting severe pessimism, poor expectancies for future positive events, and poor future orientation. In our sample, patients with HI DEP/HI PAIN also showed a gender gap, with females more highly represented in this subpopulation of patients (>70%). Such findings may be relevant compared to a study investigating gender inequalities in inpatient suicide rates during psychiatric inpatient treatment and after discharge in 12 countries. The authors reported a similar gender gap in suicide risk, with females having higher suicide rates during and after hospitalization . HoweverTherefore, the subpopulation of HI DEP/HI PAIN patients was a high-risk category. They reported a long-lasting, higher suicide risk than other patients. Current suicide ideation was reported with more frequency and less controllability, and lifetime suicide attempts were more frequent than other patients. According to Zou et al. , the higPsychiatric diagnoses did not help differentiate this group from patients with HI DEP/LO PAIN, except that they more frequently had a personality disorder diagnosis . Nevertheless, mental pain in depressed patients was associated with differences in the treatments administered. The presence of current severe mental pain was related to the more frequent prescribing of antipsychotics, mood stabilizers, and anxiolytics. It is reasonable to acknowledge that depressive symptoms and mental pain may act synergically in expressing a clinical phenotype that is likewise treated with a more complex therapeutic regime than in patients experiencing symptoms of depression without mental pain. We found that patients with HI DEP/HI PAIN (compared to HI DEP/LO PAIN) were more often treated with antipsychotics, mood stabilizers, and anxiolytics. It seems reasonable to assume that mental pain as a form of inner turmoil may require sedative, tranquilizing, and mood-modulation agents to relieve patients’ suffering –48.Such possible implications of psychopharmacology in psychiatric patients experiencing mental pain have been reported as central to implementing patient-reported outcomes; any report comes directly from patients about how they function or feel concerning a health condition or therapy . In addiMental pain features are also crucial for the early detection of suicide risk . In a prAlthough this is one of the most extensive investigations into the role of mental pain and depressive symptoms in explaining suicide risk among psychiatric patients, there are limitations. First, the many centers participating in this research may point to the heterogeneity of assessment and evaluation procedures through psychometric instruments. Second, patients had several psychiatric diagnoses, making it difficult to characterize single groups. Furthermore, some centers did not manage to recruit the number of patients set at the beginning of the study, thus influencing the heterogeneity and representativeness of the final sample. Finally, there are also limitations concerning the instruments used to assess the patients .The results presented in this article demonstrate that the combination of depressive symptoms and mental pain in psychiatric patients is a critical condition that increases suicide risk. Conversely, such risk was lower in patients who reported high rates of depressive symptoms but low rates of mental pain. Therefore, the former construct is a strategic perspective for the clinician for adding a complete understanding of patients’ mental status in their assessment and ultimately in delivering tailored treatments.


In this placebo-controlled trial, we aimed to evaluate the clinical results of using PDE-5 inhibitor, tadalafil 5 mg OD, for management of CP/CPPS.140 patients ≤ 45 years old with moderate/severe CP/CPPS associated with ED (IIEF-5 < 22) were randomly divided and received either tadalafil 5 mg OD  or placebo (control-group) for 6 weeks. Post-treatment CPSI scores were compared to baseline and to placebo. Clinically significant responders (≥ 25% reduction from baseline score) were calculated. Tadalafil-induced changes in IIE-5 were evaluated in correlation to that of CPSI scores.p < 0.5. When compared to placebo, all 6th week CPSI domains scores, except for pain, were significantly better in tadalafil-group (p < 0.05). Post-treatment pain score didn't significantly differ between both groups . Clinically significant responders were 30 patients (50.8%) in tadalafil-group vs. 3 patients (5.4%) in control. Tadalafil-induced changes in IIEF-5 score had weak but significant correlation to Qol domain .By the 6th week, 59 and 56 patients were available in both groups respectively. Compared to baseline, tadalafil-group patients showed significant improvement in total, pain, urinary and Qol domains of CPSI , Tadalafil 5 mg OD can significantly improve all CPSI domains as compared to baseline. Post-treatment CPSI scores, except for pain, were better than placebo. About 50.8% of patients can develop ≥ 25% reduction in their total CPSI scores after treatment. Apart from Qol domain, these changes are not significantly correlated to tadalafil-induced IIEF-5 scores changes. Chronic prostatitis associated chronic pelvic pain syndrome (CP/CPPS) is one of the most common medical conditions in urology with estimated prevalence of 2.2–13.8% in men from different societies . The exaCP/CPPS could be a seen across all adult men regardless their age; however, it's more a diagnosis of young men  with preThe common pathophysiological pathways of sexual dysfunction and prostatic pain/voiding symptoms is not yet clear. Increased Rho-kinase activation and impaired nitric oxidase synthase in pelvic structure (including prostate and penis) may increase intraprostatic pressure and decrease smooth muscle relaxation of penile tissues causing prostatitis symptoms and erectile dysfunction, respectively. Also, autonomic hyperactivity, atherosclerosis and metabolic syndrome may play a main or a co-mechanism for prostate associated sexual dysfunction –12.Based on previous pathways, PDE5-inhibitors could be expected to have a role in treatment of CP/CPPS. It was proven that tadalafil can down-regulate Rho-kinase activity. Rat model of chronic non-bacterial prostatitis had significantly suppressed pelvic pain and prostatic inflammation after tadalafil medications , 14. AlsIn their clinical observation, Grimsley and colleagues found that known CP/CPPS patients prescribed PDE5-inhibitors for associated erectile dysfunction showed improvement in their prostatitis symptoms. They hypothesized that PDE5-inhibitors may mediate relaxation of prostatic duct smooth muscle which may reduce prostatic inflammation .Clinically; few limited studies had investigated the outcome of PDE5-inhibitors in management of CP/CPPS, unfortunately, these studies mostly lacked control arm –22. In tOur study run as double-blind placebo controlled clinical trial at urology department, Tanta University during the period from January 2019 till January 2022. The study was approved by our local review board and an informed written consent was given by each participant.The study included male patients ≤ 45 years old with long history of CP/CPPS (≥ 1 year) who had recurrent/persistent symptoms after previous treatment with 4–6 weeks antibiotics and/or alpha blockers and who claimed complaints of erectile dysfunction. After careful history taking including all medications history, all patients were asked to fill Arabic translated and validated versions of NIH-CPSI and IIEF-5 forms , 24. AllExcluded patients were those with mild symptoms , IIEF-5 ≥ 22, abnormal DRE or PSA values, history of uncontrolled diabetes mellitus, cardiac or nitroglycerine medications, ureteric/urinary bladder stones, urethral stricture or neurogenic disorders affecting lower urinary tract. Also, patients with renal or hepatic dysfunction, active urinary tract infection or bacterial prostatitis were excluded.3-agonists and NSIADs) for 2 weeks before start of treatment.All selected patient were asked to stop any related medications  to randomly distribute patients into two equal groups (70 for each). Tadalafil-group patients were given tadalafil 5 mg once daily at bedtime and placebo group (control-group) were given placebo starch tablet at bedtime for 6 weeks. Both patients and physician were blind regarding treatment given.Our primary endpoint was the evaluation of the 6th week’s CPSI domains score in comparison to baseline as well as to placebo with evaluation of clinically significant responders . Our secondary endpoint was to find if the changes in CPSI domains scores are related to that of IIEF-5 scores.based on data from previous literatures, an expected reduction of 25% or 4–6 points in total CPSI scores at treatment arm or 3 points difference between both groups is expected to be clinically significant . With astcalculated as (∆CPSI = 6th week score-baseline CPSI score) where the negative values refer to symptoms’ improvement. Statistical analysis included two tailed paired/unpaired test to compare domains scores within each group or between both groups. Chi-square test was carried out to compare categorical variables in both groups. Pearson studies applied to define the correlation between ∆IIEF-5 score to ∆CPSI domains (both presented as percentage). For all statistics, p value was considered significant at p < 0.05.All data were presented as mean ± SD. For each patient, the change in CPSI score was By the end of the study, 59 and 56 patients were available in groups I and II, respectively. It was noticeable that 7 patients in tadalafil-group 10%) reported medicine related side effect including muscle ache, headache and flushes during the 1st week and didn’t continue the study protocol . Compared to baseline, tadalafil-group patients showed significant reduction of all CPSI domain scores after treatment (p < 0.05). Regarding post-treatment results in both groups; only urinary, Qol and total CPSI domains were significantly better (p < 0.05) but pain score did not (p = 0.07)  Table .Table 2Bp < 0.05, .Changes in CPSI domains scores (∆CPSI) were greater in tadalafil-group than control-group, 05, Fig. . The clir = − 0.28, p < 0.05). For other CPSI domains changes, that correlation was insignificant   Fig. .Fig. 3ReTraditionally, we used antibiotic, anti-inflammatory, and α-blockers either alone or in combination to treat CP/CPPS. Although widely used, there are weak evidences to guarantee satisfactory outcome .Several studies showed that tadalafil 5 mg once daily can significantly improve LUTS independent of severity or improvement in ED . In addiIn a non-controlled 3 months follow up study, Benelli et al. reported that tadalafil significantly improved all NIH‐CPSI domains scores; this reduction was noticed as soon as one month post treatment and was mainly seen in pain score (reduced from 13.7 ± 3.7 to 5.4 ± 2.2) as well as total, micturition and QOL CPSI sub-scores . Further decline was seen by the 2nd and 3rd months .To standardize the outcome of CP/CPPS clinical treatment trials, many researchers suggest ≥ 25% reduction in post treatment total CPSI score to be clinically significant and perceived by patients as improvement , 29.Although Benelli’s study didn’t report those clinically significant responders, but the very big difference in pre/post treatment median scores suggest that there was a good number of clinically significant responders . The small number of included patients in their study (14 patients) may not give enough study power to guarantee the results. Also, the selection criteria (only 3 months symptoms duration) may explain that great response.Many clinical trials studied tadalafil effect in CP/CPPS associated with BPH. Due to overlapping of CP/CPPS urinary symptoms and those of BPH/LUTS, the reduction in pain subscore may be considered as the valuable parameter to detect improvement. Hiramatsu et al. reported that 3 months of tadalafil treatment can significantly reduce pelvic pain associated with LUTS/BPH. For the subgroup with severe pain (domain score ≥ 4), mean improvement in total CPSI and pain sub‐scores were -10.0 ± 7.8, and − 4.4 ± 4.5. Also, there was a significant reduction in micturition and QOL domains (− 2.5 ± 3.0 and − 3.1 ± 2.7) . In spitIn Pineault et al. study, 25 patients (mean age 44.4 ± 12.9 years) were treated with tadalafil 5 mg daily for a mean duration of 1.3 ± 1.6 years. Although lacked control arm, they concluded that daily use of tadalafil for long time was associated with significant decreases in CPSI total, pain, urinary symptom and quality of life scores  The significant changes in CPSI scores, compared to baseline, in our study are found to be in accordance with the previously mentioned reports but with much limited changes. That limited changes of CPSI may be explained as our study included younger ages with longer duration of moderate/severe complaint or may be attributed to shorter study duration.p > 0.05). The lack of previous controlled studies makes it difficult to explain the cause. The chronicity of symptoms or the short period of study could be possible factors.To our knowledge, this is the first placebo controlled clinical trial comparing tadalafil effect to placebo in young adults with refractory CP/CPPS. Unlike other CPSI domain scores, pain subscore didn't achieve statistically significant improvement when compared to placebo . That relation was not seen between IIEF-5 changes and CPSI total, pain or micturition scores.Due to poor long-term treatment success, CP/CPPS can impact quality of life (Qol) and can contribute to erectile dysfunction , 32. VicLimitations in our study included the short duration. CP/CPPS is considered a chronic inflammatory process and longer treatment protocols are usually advised. However, even with 6 weeks duration, our results are promising for future longer duration studies.Another limitation was our selection criteria; tadalafil is currently not approved for management of CP/CPPS, so we used it only in those with CP/CPPS concomitant ED. The overlapping effect of tadalafil-induced IIEF-5 score changes and Qol subscore was reported to be weak but significant which may affect our conclusion. Further controlled trials in CP/CPPS patients without co-morbid ED may be required.In this placebo-controlled clinical trial, patient with moderate/severe CP/CPPS managed by tadalafil 5 mg once daily for 6 weeks showed significant improvement of all CPSI domains  compared to baseline. When compared to placebo, CPSI pain domain didn’t achieve such significant improvement unlike all other domains which were significantly better. The changes in pain, urinary and total scores were not correlated with the change in IIEF-5 score. The fact that only 50.8% of patients get clinically significant improvement  suggests this medicine may be considered in combination with other treatment protocols in the future studies.


Emerging evidence suggests that access to chiropractic care may reduce the likelihood of initiating an opioid prescription for spinal pain; however, the impact of chiropractic care for patients already prescribed opioids is uncertain. We undertook a sequential explanatory mixed methods study to evaluate the association between initiating chiropractic care and continued opioid use among adult patients attending an Ontario community health centre (CHC) and receiving opioid therapy for chronic non-cancer spinal pain.We conducted a retrospective cohort study of 210 patient records between January 1, 2014 and December 31, 2020. We used generalized estimating equations, adjusted for patient demographics, co-morbidities, visit frequency, and calendar year, to evaluate the association between receipt versus non-receipt of chiropractic services and continued opioid use  up to one year following the index chiropractic visit. We also completed follow-up interviews with 14 patients and nine general practitioners from the CHC and integrated these data with our quantitative findings.Over 12-month follow-up, there were lower rates of opioid fills  and refills  among chiropractic recipients (n = 49) versus non-recipients (n = 161). Although patients who did and did not receive chiropractic care began the study with the same dose of opioids, recipients were less likely to be prescribed higher-dose opioids  compared to non-recipients at three months , six months , nine months , and 12 months . Interviews suggested that patient self-efficacy, limited effectiveness of opioids for chronic pain, stigma regarding use of opioids, and access to chiropractic treatment were important influencing factors.We found that continued prescription opioid use among patients with chronic non-cancer spinal pain who received chiropractic care was lower than in patients who did not receive chiropractic care. Four themes emerged in our qualitative interviews to help provide a richer understanding of this association. Randomized controlled trials are needed to establish the effect of chiropractic care on opioid use for chronic spinal pain.The online version contains supplementary material available at 10.1186/s12913-022-08632-9. Chronic non-cancer pain affecting the spine or other musculoskeletal tissues is a prevalent and global health problem associated with considerable socioeconomic burden. Worldwide, approximately one in five people live with chronic non-cancer pain –4, with Emerging evidence suggests that early access to chiropractic treatment is associated with lower initiation of opioid prescribing among patients with non-cancer spinal pain –21. A 20To help address these knowledge gaps, we conducted a mixed methods study to evaluate the association between initiating chiropractic care and continued opioid use among adult patients with chronic non-cancer spinal pain attending an Ontario community health centre (CHC) , 26. We Our study was approved by the Hamilton Integrated Research Ethics Board at McMaster University (project number 2021–10930). Approval to conduct this study was also obtained from the Chief Executive Officer at the Langs CHC . All metWe used a sequential explanatory mixed methods design . In the The Langs CHC is located in Cambridge, Ontario, Canada , 26, a mWe included records for all adult patients (aged ≥ 18 years) who received one or more prescriptions for opioids dispensed over a minimum period of three consecutive months, and who attended two or more appointments relating to a diagnosis of chronic spine  pain at the Langs CHC between January 1, 2014, and December 31, 2020. The start date for quantitative sampling was January 1, 2014, which was the inaugural date of the Langs CHC’s chiropractic spine pain program . Patienthttps://www.ices.on.ca) with their Ontario health card number. ICES is an independent, non-profit research institute whose legal status under Ontario’s health information privacy law allows for the collection and analysis of healthcare and demographic data, without consent, for health system evaluation and improvement. Patients whose health card number was incorrectly recorded in their EMR were excluded.We linked EMR records of all patients in our study to medical drug claims data at the Institute for Clinical Evaluative Sciences (ICES) , and the prescribed opioid dosage. These outcomes were measured for up to 12 months from the date of first opioid prescription following a patient’s index visit for chronic non-cancer spinal pain. To maintain temporality, the index visit for patients who received chiropractic care was their first chiropractic visit. Other variables that were extracted from the EMR included socio-demographics (age and sex), general health (smoking status and body mass index), co-morbidities , and the total number of healthcare  visits. These variables have been shown to be associated with opioid use , 41–48. Baseline characteristics were compared between the exposed (receipt of chiropractic care) and non-exposed groups using the chi-squared test for categorical variables (or Fisher’s exact test if there was a cell frequency of < 5) and the Mann-Whitney U test for skewed continuous variables. We used generalized estimating equations (GEEs) to explore the association between exposure to chiropractic care and opioid prescribing , 50. To p-values.We used GEEs with a Poisson distribution when the outcomes were counts . We estimated incidence rate ratios (IRRs) for differences between the chiropractic and non-chiropractic groups using Poisson log-linear GEEs and reported the associated 95% CIs and p-values. To calculate the MED for each prescribed opioid, we multiplied the quantity × the milligrams per unit dispensed × drug-specific conversion factors  morphine equivalents daily (MED) or lower (< 50 mg) MED  and compFor each outcome of interest, we built univariable and multivariable models to estimate the crude and adjusted associations, respectively, between patients that did or did not receive chiropractic care  and opioid use. We grouped covariates into blocks  and these were sequentially entered into our models, with time  as an additional covariate and chiropractic/non-chiropractic care as the main exposure variable. To guard against over-fitting of our regression models , we set We assessed model fit using the quasi-likelihood under the independence model criterion (QIC) , 52. CorFor the qualitative phase of our study, we used stratified purposive sampling to select a sub-sample of chiropractic and non-chiropractic patients, whose charts we examined in the quantitative phase, to participate in one-on-one interviews . This waThe lead author (PCE), a health research methodologist with expertise in mixed methods and qualitative research, conducted one-on-one  semi-structured interviews with participants. Interviews were conducted either virtually n = 3) using the Zoom videoconferencing application  or in-person (n = 20), based on participant preference. We promoted confidentiality by conducting the interviews in a private office separate from the medical clinic at the Langs CHC. We obtained informed consent from participants before the start of each interview. Five members of our research team  developed the patient and GP interview guides . The lead author (PCE) also took field notes after each interview to document other observations and emergent themes. To promote trustworthiness in our qualitative data, we employed member-checking  by sendihttp://www.maxqda.com), and the lead author (PCE) transcribed the audio recordings verbatim. After participant identifiers were removed, another member of the research team (JD) reviewed a random sample of 15% of the transcripts for accuracy and found only a few minor typographical errors. All transcripts were then independently coded by two investigators  using an inductive content analytic approach [We transferred all interview audio recordings into the software program, MAXQDA  to compare themes and arrive at a final, agreed-upon set of themes through discussion. We organized these themes into tabular form and selected representative quotations for each theme/sub-theme . We creaWe identified a total of 1,166 patient records, and 210 met eligibility criteria for inclusion in our quantitative analysis  of patients were ≥ 45 years of age, over half (58%) were female, approximately one-third 36%) were smokers, and 18% were obese. Patients presented with high rates of co-morbid conditions including cardiovascular disease (65%), depression (55%), anxiety (42%), diabetes (29%), and fibromyalgia (11%). The median number of healthcare visits per patient over 12 months was 5 , and 23% received chiropractic services. In terms of opioid use, the median number of unique opioid fills over 12-month follow-up was 2 , the median number of 30-day  opioid refills was 4 , and baseline opioid dosage ranged from 2 to 840 mg MED . Chiropractic recipients had similar baseline characteristics to those who did not receive chiropractic services  or refilling an opioid prescription   and were less likely to be receiving higher dose opioids at three months  and six months  , two scheduled interviews but did not attend , one declined for health reasons and one was not interested. Of those who were interviewed, eight were chiropractic recipients and six were non-recipients. Among GPs, four of six medical doctors and five of six nurse practitioners completed interviews. Two medical doctors declined participation because of lack of time, and one nurse practitioner expressed interest but did not respond to further interview requests. In total, 23 interviews were completed . The median durations of interviews were 25 min  for patients and 38 min  for GPs.The majority (79%) of the 14 patients we interviewed were female, most 86%) were either receiving disability benefits or were unemployed, and the majority (71%) had previously received at least one opioid prescription for chronic non-cancer spinal pain. The median dosage for those currently receiving opioid medications was 19 mg MED . Among patients and GPs, there was a large range of ages (33 to 82) and number of years attending the Langs CHC (patients: 2 to 43) or years in practice (GPs: 1 to 26), demonstrating variability among participants ; only one new code emerged from non-recipient interview 4 (with no new codes from interviews 5 and 6); and only one new code emerged from GP interviews 7, 8 and 9. At this point, participant recruitment was concluded.We identified 37 codes across interviews which were categorized into four major themes: (1) patient self-efficacy, 2) accessibility of non-pharmacological services, (3) stigma regarding use of opioids, and (4) impact of treatment. Codes pertaining to patient self-efficacy were stratified into two sub-themes, ‘active versus passive approaches’ and ‘resistance to taking medication.’ This latter sub-theme was common among chiropractic patients. For our second theme, we created the sub-themes ‘lack of access to non-pharmacological treatment options’ and ‘access to chiropractic services at the Langs CHC.’ Lack of access to non-pharmacological services  was identified in nearly all (21 of 23) participant interviews and was reported as a common facilitator of opioid use. Our third theme captured codes related to the opioid crisis such as negative media coverage or lived experiences. Some patients also expressed a sense of judgement from others for using prescription opioids. The remaining codes related to patients’ or GPs’ perspectives on the impact of treatment for chronic non-cancer spinal pain, including sub-themes of pain relief, functionality, recognition of the limited effectiveness of opioids for chronic pain, and anxiety and fear surrounding opioid withdrawal. Descriptions and frequency counts of each of our major themes, sub-themes, and representative participant quotes are provided in Additional file  accessibAmong patients receiving long-term opioid therapy for chronic non-cancer spinal pain, we found that initiating chiropractic care was associated with fewer fills and refills for prescription opioids and, when prescribed, reduced dosage of opioids. Based on our qualitative findings, use of opioids was influenced by patients’ self-efficacy and concerns about opioid-related harms, recognition of the limited effect that opioids may have on chronic pain, increasing stigma regarding use of opioids, and access to non-pharmacological treatment options.Our findings are supported by other uncontrolled observational studies –24. A reThe integration of quantitative and qualitative methods in our study generated several insights into our results. As highlighted in our interviews, patients who were referred for chiropractic services at the Langs CHC may have been more resistant to taking opioid medication than patients not referred for chiropractic services, a sentiment supported by some published evidence . In addiSimilar to previous research , 44, we We found that patients with an index visit date in a more recent calendar year had fewer opioid prescription refills and were less likely to receive higher opioid doses at 3- and 6-month follow-up. Current guidelines , 60 reco“…having access to any kind of additional modalities in a timely and efficient manner … would probably reduce the need for opioids in the first place.” GP 9Several observational studies have reported an association between use of chiropractic services and reduced opioid prescribing –21, 61 oOur findings add to a growing body of observational evidence that suggests integration of chiropractic services into primary care centres , 34–39 aOur qualitative findings suggest that lower opioid use is also related to factors such as self-efficacy and concern about opioid-related harms, access to non-pharmacological care, stigma, and knowledge of opioid effectiveness on chronic pain. Future research should investigate these factors further to inform their association with opioid use.a priori to provide greater confidence in our findings. Third, we used GEEs to account for hierarchical clustering and to control for differences in confounding factors between our exposed (receipt of chiropractic care) and unexposed groups. To account for policy changes in opioid prescribing, we controlled for calendar year in our analyses. This helped to more clearly delineate between a reduction in opioid use associated with access to chiropractic services versus confounding by policy change. Additional strengths included limited missing data (< 1%), direct data export from the EMR to avoid extraction errors [Our study has several strengths. First, we used patient health card numbers to link EMR data with medical drug claims data from the Narcotics Monitoring System database at ICES to verify patient opioid prescriptions and dosages. Second, we specified the anticipated direction of association for each independent variable in our regression models n errors , and valOur study also has several limitations. Due to the retrospective design in our quantitative phase, certain variables that may be associated with opioid use were unavailable. For example, due to the constraints of data recorded in the Langs EMR, we were unable to extract information on co-interventions that patients may have received outside of the CHC, as well as baseline severity/chronicity of patients’ spine-related pain, and additional potential confounders such as employment status or other mental health and pain conditions. However, Langs CHC patients are unlikely to access private healthcare services elsewhere due to socioeconomic disadvantages , 34–40. We found that patients with chronic non-cancer spinal pain who received chiropractic care obtained fewer and lower dose opioid prescriptions than patients who did not receive chiropractic care. Follow-up interviews suggested this relationship was influenced by patient self-efficacy and concerns about opioid-related harms, limited effectiveness of opioids for chronic pain, stigma regarding use of opioids, and access to non-pharmacological treatment options. Although overall results are promising, large rigorously-conducted randomized controlled trials are needed to establish the role of chiropractic care in reducing opioid use for chronic spinal pain.Below is the link to the electronic supplementary material.Additional file 1. Good Reporting of A Mixed Methods Study (GRAMMS) checklist. Additional file 2. Morphine equivalents daily conversion factors. Additional file 3. Interview guide (patients). Additional file 4. Interview guide . Additional file 5. Investigator reflexivity. Additional file 6. Comparison of recipients versus non-recipients of chiropractic services. Additional file 7 (a-g). Univariable and multivariable regression models for each outcome of interest. Additional file 8. Characteristics of interview participants. Additional file 9. Qualitative themes generated from semi-structured interviews.


P = 0.806). There was also no significant difference in the frequency of analgesic rescue medication use (P = 0.213) or NRS scores  between the two groups. The Gel, which continuously delivers a local anesthetic to operative sites, can thus be considered an effective device for analgesia and pain relief for midline incisions in laparoscopic colorectal surgery.Continuous wound infusion with local anesthesia is an effective method for reducing postoperative pain after laparoscopic colorectal surgery. However, most subcutaneous local anesthesia is delivered through continuous injection, which can be inconvenient for patients. This study compared the effectiveness of postoperative pain relief from the application of a local poloxamer 407-based ropivacaine hydrogel (Gel) to the incision site with continuous infusion-type ropivacaine administration (On-Q) in patients undergoing laparoscopic colorectal surgery. This prospective, randomized, non-inferiority study included 61 patients who underwent laparoscopic colorectal surgery with an incision length of 3–6 cm. All 61 patients were randomly assigned to the Gel group  or the On-Q group . Postoperative analgesia was induced in all patients with intravenous patient-controlled analgesia (IV-PCA). The outcome measures, which were assessed for 72 h after surgery, included the total amount of fentanyl consumed via IV-PCA (primary endpoint), and the amount of rescue analgesia (pethidine) and postoperative pain intensity assessed using a numeric rating scale (NRS) [secondary endpoints]. The Gel was administered to 31 patients and On-Q was used for 30 patients. There was no significant difference in the total usage of fentanyl between the two groups (Gel group, 1623.98 mcg; On-Q group, 1595.12 mcg;  Currently, multimodal analgesic methods such as preperitoneal infusion, epidural analgesia, and intravenous pain relief are widely used to manage pain related to surgery. Regional anesthetic techniques are often the most effective methods for managing immediate postoperative incisional pain4. Of these regional anesthesia techniques, continuous wound infusion (CWI) is often used during surgery as an opioid-sparing method for reducing acute postoperative incisional pain and was shown to have many advantages in several studies4. A systematic review of randomized, controlled trials demonstrated that postoperative wound infusion with local anesthesia could reduce postoperative pain and associated opioid use5. These findings were supported by a recent Cochrane database review of the use of CWI as a local anesthetic for postoperative pain after midline laparotomy for colorectal resections in adults6.Postoperative pain is common after most surgical procedures, including laparoscopic colorectal surgery3. Although there are benefits, CWI is associated with certain complications as the process involves the initial insertion of a catheter between the peritoneum and the fascia, followed by removal of the catheter several days after surgery, which can lead to drug leaking out of the catheter and malfunctioning of the On-Q pump10. Therefore, there is a need for pain control products that are easier to apply as the use of such products could reduce the discomfort and inconvenience of patients after surgery.One method of administering local anesthetic  via CWI is the On-Q system (On-Q). In patients undergoing laparoscopic colorectal surgery, On-Q has been shown to control acute postoperative pain and reduce the associated usage of opioid analgesicsThis study assessed the efficacy of a local poloxamer 407 (P407)-based ropivacaine hydrogel (hereafter referred to as Gel). After mixing the hydrogel and ropivacaine to maintain a stable local anesthetic. The product, which transforms from a liquid form at room temperature to a gel at body temperature, can be easily applied to wounds (without the need for catheter injection) between the peritoneum and the fascia. The objective of this confirmatory clinical study was to compare the effectiveness of the Gel and On-Q for postoperative pain relief at the incision site in patients undergoing minimally invasive colorectal surgery.P = 0.036), the two treatment groups were well-balanced.Figure P = 0.806)  scores were also measured to assess the degree of pain in patients at the same times as the above-mentioned PCA fentanyl usage and pethidine administration frequency were evaluated. A comparison of NRS scores between the two patient groups at each time did not reveal any significant differences. The specific values are shown in Fig. P = 0.841). There were no statistically significant differences in other variables such as the location of the primary tumor, operation time, anesthesia time, or estimated blood loss between the two groups. Compared to patients in the Gel group, patients in the On-Q group had a significantly longer mean hospital stay . One patient in the On-Q group underwent surgery due to chronic constipation with a prolonged hospitalization of 18 days due to postoperative ileus. One patient in the Gel group had a wound seroma, which was treated with a simple dressing in the ward. Any association with the Gel was unclear.The surgical and postoperative outcomes of the patients in the two groups are reported in Table To our knowledge, this was the first study to compare the efficacy of Gel  and On-Q in patients undergoing laparoscopic colorectal surgery. In this study, Gel showed no significant difference in the primary (amount of IV-PCA fentanyl usage up to 72 h postoperatively) and secondary (rescue medication [pethidine] and pain scores) outcomes compared to On-Q. These findings are meaningful from clinical and practical perspectives because the use of On-Q requires the insertion of a catheter, the patient needs to continue to receive the product for some period  after surgery, and catheter removal needs to be performed while the patient is still hospitalized. In contrast, the Gel can be applied easily after surgery without the need to mount or remove the product after recovery.11. Abdominal surgery is particularly known to be associated with postoperative pain due to abdominal incisions13. Therefore, many analgesic and anesthetic medications have been studied to reduce postoperative pain from abdominal incisions. The continuous infusion of anesthetics is a method that has been applied widely16, and multiple studies showed that the continuous injection of ropivacaine could reduce postoperative pain18. However, the pain control devices developed in the past have been difficult to apply to patients, which has the disadvantage of prolonging operation times. For example, infusion pumps such as On-Q require training in both assembly and application. Therefore, they generally need to be used by skilled medical personnel.Despite the many advancements in the field of analgesia, postoperative pain remains a considerable concern for patientsTo overcome these disadvantages and help patients achieve postoperative pain relief, we developed a gel-type infusion kit that could be applied simply and directly to surgical incisions by mixing with local anesthetics. As shown in the results of this study, patients recovering from laparoscopic colorectal surgery using the Gel showed no significant postoperative differences in total PCA fentanyl usage, the amount of rescue medication (pethidine), or the degree of pain compared to patients using the On-Q system. Moreover, the total dose of ropivacaine used in the Gel group was 22.5 mg, which was notably less than the 192 mg dose used in the On-Q group. Thus, we obtained meaningful results in that, compared to On-Q, the Gel could be applied to patients more easily, and it could achieve a similar analgesic effect while using less ropivacaine without inconvenience to the patient due to catheter removal or the discharge of ropivacaine.The study had several strengths and limitations. First, the nature of the surgical intervention precluded patients and investigators from being blinded to the treatment allocations, which could introduce an element of bias to the study. However, selection bias was minimized through the randomization process. Nevertheless, the median age of the patients in the Gel group was significantly lower than that in the On-Q group, possibly reflecting inadequate randomization. Moreover, the study focused on short-term outcomes associated with acute postoperative pain ; other outcome measures—including time to first bowel movement, ambulation, and quality of sleep and recovery—determined over a longer time would provide a broader picture of the effectiveness of the Gel beyond the immediate 72-h postoperative period. The design of future larger confirmatory studies will incorporate these considerations.This confirmatory, randomized clinical trial showed that the Gel was at least as effective as On-Q in controlling acute postoperative pain after laparoscopic colorectal surgery while using considerably less ropivacaine. Both products were considered to be safe and well-tolerated. However, as it is convenient to use, the Gel overcomes some of the disadvantages associated with On-Q while reducing patient discomfort after surgery. Therefore, the Gel can be considered to be an effective method for analgesia and pain relief for midline incisions in patients undergoing laparoscopic colorectal surgery.Patients who underwent minimally invasive colorectal surgery from March 2018 to December 2018 at Samsung Medical Center, Seoul, Korea, were selected as the subjects of this study. Minimally invasive surgery included conventional laparoscopy, single-incision laparoscopic surgery, and robotic surgery. The inclusion criteria were as follows: patients aged > 19 years, with no clinically significant abnormal findings on preoperative examination, who underwent minimally invasive surgery expected to produce an incision length of 3–6 cm, and who could use a patient-controlled analgesia (PCA) device. Patients with hypersensitivity to (or a history of hypersensitivity to) ropivacaine or other local amide anesthetic agents, those who had local emergency surgery or a septic condition, those who had a mental illness, those who had been on drugs and pain-related medications within one month prior to surgery, and those with severe co-morbidities such as liver cirrhosis, renal failure, or myocardiopathy, were excluded. This study was approved by the Institutional Review Board (IRB) of Samsung Medical Center (IRB No.2018-01-109), and written informed consent was obtained from all subjects participating in the trial. This study was carried out in accordance with all relevant guidelines and regulations. The trial was registered with the Clinical Research Information Service (CRIS) . This study did not receive research funding from the Ministry of Health and Welfare, so there was no obligation to register with the CRIS before the study. Following the recommendations, we enrolled the clinical study in the CRIS after the start of the study.19. The application of Gel and On-Q was performed during surgery, in the process of completing intra-abdominal surgery and suturing the wound. The Gel package consisted of one syringe prefilled with gel, one syringe connector, and one empty syringe for ropivacaine  Fig. .Figure 7Immediately after surgery, both groups received concomitant intravenous PCA , which was delivered via a manual infusion pump . The total volume of PCA was 100 mL, the flow rate was 1.0 mL/hour, the bolus volume was 1.0 mL, and the lockout time was set at 15 min. In cases where the patient complained of pain (NRS score ≤ 4), rescue medication (pethidine 25 or 50 mg) was allowed up to 72 h postoperatively.Patients were assigned to either the experimental group (Gel) or the active comparator group (On-Q) according to a randomization table. Randomization (in a 1:1 ratio) was performed to reduce bias that might arise in the allocation of patients and to increase the comparability of the two groups. Block randomization was performed by generating random numbers with four decimal places per person using the Random Function (RAND) in Microsoft Excel (Microsoft Excel 2019 MSO 16.0.10389.20033). Each assignment envelope was sealed and delivered to the investigator. The subject numbers were assigned by the clinical laboratory, and the envelope was opened by the clinical trial coordinator in charge of the study. Patients and investigators were not blinded to the treatment allocations.The amount of PCA fentanyl used, the amount of rescue analgesic (pethidine) used, and the pain score  were assessed at 6, 24, 48, and 72 h postoperatively. Blood pressure, pulse rate, body temperature, complete blood count, prothrombin time, activated partial thromboplastin time, and serum laboratory data  were measured at 48 h, 72 h, and 8 days ± 4 days after surgery to capture the occurrence of any adverse reactions.The primary endpoint was the mean total consumption of fentanyl used in IV-PCA up to 72 h after surgery in both treatment groups. The secondary endpoints were the amount of rescue analgesia (pethidine) used as well as pain scores (NRS) 6, 24, 48, and 72 h postoperatively. The occurrence of adverse events was monitored during the admission period. Data on vital signs and laboratory tests were collected and assessed for safety outcomes.During the admission period, careful monitoring for adverse events was performed. Data on the vital signs and laboratory test results described above were collected and analyzed to evaluate safety.20. According to previous studies21, the maximum mean difference in PCA fentanyl usage for 72 h between the Gel and On-Q treatment groups was 409.96 mcg and the mean difference in the total amount of fentanyl used up to 72 h postoperatively between the two groups was 394.80 mcg. The noninferiority margin (197.4 mcg) was conservatively set as one-half of 394.80 mcg. Based on this value, it was calculated that 62 patients were needed, including a dropout rate of 10%, with a type 1 error of 2.5% and a power of 80%.The study was designed to determine non-inferiority for the primary outcome based on the non-inferiority hypothesisp-value was less than 0.05.This study used SPSS for Windows version 27.0  for all analyses. The chi-squared test, Fisher’s exact test, independent two-sample t-test, or Mann–Whitney U test  were used to analyze differences between the two treatment groups. For multiple comparisons, analysis was performed by repeated-measures analysis of variance (ANOVA), and a post-test was confirmed for point-to-point comparison. The two-group effect test was not statistically significant, so the independent two-sample t-test was additionally performed to compare the two groups at each point in time, and the significance level was corrected using the Bonferroni correction method. Results were considered to be statistically significant when the This study was approved by the Institutional Review Board (IRB) of Samsung Medical Center (IRB No.2018-01-109), and written informed consent was obtained from all subjects participating in the trial. The trial was registered prior to patient enrollment .This study was approved by the Institutional Review Board (IRB) of Samsung Medical Center (IRB No.2018-01-109), and written informed consent was obtained from all subjects participating in the trial.