We perform this protocol for randomized controlled trial to compare the efficacy of intrathecal morphine and local infiltration anesthesia (LIA) in the treatment of the postoperative pain after total knee replacement (TKR).This is a randomized controlled, single center trial which was performed from March 2019 to March 2020. This trial is conducted according to the SPIRIT Checklist of randomized researches. It is authorized via the Ethics Committee of Beijing Friendship Hospital (2019-P2-050-01). Eighty participants who undergo TKR were randomized into 2 groups. Intrathecal morphine group: 0.1 mg of the morphine was intrathecally injected, and the spinal anesthetic was injected at the same time in the group LIA; In the LIA group: the knee joint was infiltrated with epinephrine, ketorologic acid and ropivacaine in the process of operation, and the identical mixture was injected 2 bolus through the intraarticular catheter after operation. The main outcome variables were the visual analog scale and the consumption amount of opioid every 6-hour interval within 2 days postoperatively. The secondary outcome variables were the side effects associated with opioid, the length of hospital stay, motion range, and the loss of blood collected by the closed suction drainage. All the required analyses were carried out via applying the SPSS for Windows Version 19.0.The clinical outcome variables between groups were shown in Table This protocol will provide the evidence on which technique can achieve better analgesia after TKR. Although TKR is popular, approximately 20% of the patients are not satisfied. Published studies indicated that an estimated 40% to 60% of patients report severe pain following TKR, which is the common reasons for dissatisfaction.,5 The aggravation of pain is associated with the proinflammatory states, pain regulation system damage and the tissue damage. Inadequate perioperative analgesia may be related to the increased costs, prolonged hospital stay and adverse clinical outcomes.,7 Many methods have been applied to reduce pain following TKR, including local infiltration analgesia (LIA), oral analgesics, peripheral nerve block, and intrathecal morphine.–11 However, the analgesic efficacy of these techniques and their effect on postoperative opioid consumption remains unclear.Total knee replacement (TKR) is a successful surgical approach for the treatment of end-stage knee osteoarthritis in terms of functional recovery and pain relief.,13 Therefore, multimodal analgesia has been extensively used in perioperative period of TKR. Currently, perioperative analgesia after intrathecal morphine or LIA for TKR still controversial. We perform this protocol for randomized controlled trial to compare the efficacy of intrathecal morphine and LIA in the treatment of the postoperative pain after TKR.LIA via an infusion catheter has been shown to be more effective than single bolus administration, is easy to perform and delivers analgesia directly to the source of pain. Wound infection is a major concern, which is disastrous for arthroplasties. Intrathecal morphine may be delivered at the same time as spinal anesthesia and therefore the additional time required is negligible. One disadvantage, however, is the potential risk of opiate toxicity. In addition, opioid can lead to many side effects, for instance, respiratory depression, gastrointestinal reactions, constipation and urine retention.22.1This is a randomized controlled, single center trial which was implemented from March 2019 to March 2020. This trial is conducted according to the SPIRIT Checklist of randomized researches. It was authorized via the Ethics Committee of Beijing Friendship Hospital (2019-P2-050-01), and it has been registered in the research registry (researchregistry5942).2.2Eighty participants who undergo TKR were analyzed. In the random envelope, all patients were assigned a random number via using the random number Table 1.elective primary unilateral TKR;2.people between the ages of 50 and 70;3.2;BMI less than 40 kg/m4.the acceptance of patients to participate in this work.The exclusion criteria contains:1.patients with the history of severe renal and hepatic dysfunction;2.contraindication to spinal anesthesia ;3.Contraindication to nonsteroidal antiinflammatory drugs;4.Patient has an emotional or neurological condition that would prevent their willingness to participate in the study.2.3All the patients were given 10 mg of diazepam orally 1 hour before the planned operation, and all the surgeries were implemented under the spinal anesthesia, and a 27-G pencil-point spinal needle was utilized in the intervertebral space of L3/L4, with patient in sitting position. In the morphine group, 0.1 mg of the morphine (0.25 ml) was intrathecally injected, and the same volume of 0.9% normal saline and 17.5 mg of bupivacaine without glucose were injected into the LIA group. All the patients were given propofol intravenously or continued intraoperative infusion as required. If the patient experienced pain in the process of operation, the dosage of fentanyl intravenous injection is 25 to 50 μg, up to 300 μg.In the group of LIA, epinephrine (0.5 mg), 30 mg of ketorolac acid and ropivacaine (300 mg) were infiltrated into the periarticular soft tissues via surgeons in the operation process. After cutting the bone and before prosthesis implantation, all the tissues injured during the operation were systematically injected by injecting 40 to 50 mL into the collateral ligament and posterior capsule. After implantation of the prosthesis, an injection of 50 to 70 mL through a capsule incision was performed. Ultimately, 50 mL of the ropivacaine (100 mg) without ketorolac or epinephrine infiltrated subcutaneous tissue before the skin is closed.2.4 every 6 hours until 24 hours. Visual analog scores for the pain is between 0 mm (representing no pain) and 100 mm (representing extreme pain). The secondary outcome variables were the side effects associated with opioid, the length of hospital stay, motion range, and the loss of blood collected by the closed suction drainage. The side effects of morphine included nausea and vomiting, retention of urinary, itching and the respiratory depression.The main outcome variables were the consumption amount of opioids in the patient-controlled analgesia administered every 6-hour within 24 hours after the operation, and the degree of pain assessed postoperatively via the visual analog scores2.5U test or the independent samples t test. And the comparison of categorical variables between the groups was implemented via the Chi-square test. A value of P < .05 was considered as the significant in statistics.All the required analyses were carried out via applying the SPSS for Windows Version 19.0. All data were expressed with appropriate characteristics, for instance, mean, median, standard deviation as well as percentage. The comparison between the 2 groups was conducted through using Mann-Whitney 3The clinical outcome variables between groups were shown in Table 4 Despite the superb results achieved by TKR, offering an adequate postoperative pain control and rehabilitation is a challenge for the providers, as good management of pain can improve patient outcomes. The lack of a definitive “gold standard” and various programs of pain management after operation indicate that there is much room for improving the standards of care. LIA is effective in the knee surgery. It is on the basis of the systematic infiltration of a epinephrine, nonsteroidal antiinflammatory drugs and long-acting local anesthetics mixture into the tissues around surgical area in order to obtain satisfactory control of pain with slight physiological interference, but the outcomes are not generally optimistic. Epidural analgesia has become a commonly used treatment option, which offers excellent pain relief, but there are also some risks, for instance, epidural hematoma, bradycardia, hypotension, and prolonged lower extremity motor block time and other side effects. Based on the above discussion, we perform this protocol to compare the effectiveness of LIA and intrathecal morphine in the treatment of the postoperative pain after TKR.Many end-stage knee osteoarthritis patients have improved the mobility, life quality, and improved the pain after TKR.5This protocol will provide the evidence on which technique can achieve better analgesia after TKR.Lifeng Ma and Ai Guo plan the study design. Bo Yang reviewed the protocol. Jingxin Zhang will collect data. Zhengrong Qi and Zhiyao Li write the manuscript. All authors approve the submission.Conceptualization: Lifeng Ma.Formal analysis: Ai Guo.Funding acquisition: Zhiyao Li.Methodology: Bo Yang, Jingxin Zhang.Software: Bo Yang.Writing – original draft: Zhengrong Qi.


Radiotherapy is commonly used to treat cancer patients. Besides the curable effect, radiotherapy also could relieve the pain of cancer patients. However, cancer pain is gradually alleviated about two weeks after radiotherapy. In addition, cancer patients who receive radiotherapy may also suffer from pain flare or radiotherapy-induced side effects such as radiation esophagitis, enteritis, and mucositis. Pain control is reported to be inadequate during the whole course of radiotherapy , and quality of life is seriously affected. Hence, radiotherapy is suggested to be combined with analgesic drugs in clinical guidelines. Previous studies have shown that radiotherapy combined with oxycodone hydrochloride can effectively alleviate cancer pain. In this review, we firstly presented the necessity of analgesia during the whole course of radiotherapy. We also sketched the role of oxycodone hydrochloride in radiotherapy of bone metastases and radiotherapy-induced oral mucositis. Finally, we concluded that oxycodone hydrochloride shows good efficacy and tolerance and could be used for pain management before, during, and after radiotherapy. Radiotherapy is used as a curative or coadjuvant treatment for malignant tumors and plays an important role in the treatment of cancer. 60%∼70% of patients with cancer require radiotherapy in the clinic. Palliative radiotherapy is commonly used to treat patients with bone metastases to relieve pain-related symptoms. Previous studies showed that radiotherapy alone or combined with other treatment provides beneficial effect in cancer treatment for curative and palliative purposes . RadiothHowever, radiotherapy slowly alleviates pain, and cancer pain is gradually alleviated about two weeks after radiotherapy. In addition, cancer patients who receive radiotherapy also suffer from radiotherapy-induced side effects such as radiation esophagitis, enteritis, and mucositis. It is reported that pain control is inadequate during the whole course of radiotherapy, and quality of life is seriously affected. Hence, it is stated in certain clinical guidelines that radiotherapy should be combined with analgesic drugs. Oxycodone hydrochloride is a semisynthetic opioid interacting with mu- and kappa-opioid receptors, with additional clinical benefit of oxycodone compared with morphine regarding visceral pain due to its characteristics on kappa-opioid receptors, and is primarily used to relieve moderate-to-severe pain. Previous studies have shown that radiotherapy combined with oxycodone hydrochloride can effectively alleviate cancer pain to improve treatment compliance and quality of life for cancer patients. This paper analyzed the status of pain control during radiotherapy and attempted to evaluate the role of oxycodone hydrochloride in the management of the pain during the whole course of radiotherapy.Along with cancer pain, cancer patients receiving radiotherapy also have to experience radiotherapy-induced pain. Despite the types of effective analgesic methods available, the pain management for these patients remains poor. According to the latest research, the pain management was inadequate for almost 50% of cancer patients , among wFor cancer patients who require radiotherapy, almost a week is needed to initiate a series of preparations before radiotherapy, and when combined with the first 3 weeks after radiotherapy begins, approximately 3-4 weeks have passed before the patients experience pain relief. During this time, patients may suffer from more pain caused by tumor compression and invasion to an adjacent organ, nerve, or blood vessel, and the pain is often ignored by clinicians and thus is not well controlled. Poor pain control or even no management of pain will cause physical and mental suffering; meanwhile, it affects postural changes in radiotherapy, thus decreasing the compliance to radiotherapy in cancer patients. Therefore, analgesic treatment before radiotherapy can effectively alleviate the pain of patients during the waiting period and consequently improve compliance and the life quality of patients. Most of the nonsteroidal analgesics are fast-release tablets with a short half-life, which are suitable for treating mild pain; however, for treating moderate-to-severe cancer pain, opioid analgesics, such as oxycodone hydrochloride prolonged-release tablets, should be used.Advanced cancer with bone metastases can cause pain, dysfunction, and pathological fractures, disturbing the daily lives of patients. Intense pain is the main symptom of bone metastases, which seriously affects the life quality and may interrupt the next step of antitumor therapy. Palliative radiotherapy can inhibit or kill tumor cells in bone tissue, reducing tumor volume, minimizing the pressure on the periosteum, and finally relieving pain . StudiesDuring the radiotherapy, sustained adequate analgesia is critical to prevent pain arising from clinical operation. During radiotherapy, postural changes or posture maintenance will further aggravate pain, leading to interruption or even withdrawal of treatment. Consequently, the rational use of analgesics in radiotherapy is necessary to avoid these situations and ensure the smooth performance of radiotherapy , 18.Pain flare presents as a brief increase in systemic bone pain after palliative radiotherapy for bone metastases, especially following a single high dose , which iAfter radiotherapy, the patients almost also need the analgesics to help them to control the pain. For patients who suffer from cancer pain in the first 2 weeks after radiotherapy or who are not relieved completely by palliative radiotherapy, analgesics will help them to relieve pain effectively, increase compliance, and finally improve the life quality of patients and their families.In addition, radiotherapy usually results in acute or chronic pain due to complications, such as radiation esophagitis, enteritis, and mucositis which all require analgesic treatment. Radiation esophagitis is a very common radiotherapy-associated complication in thoracic malignancies and is manifested clinically as dysphagia, odynophagia, and substernal discomfort or pain and usually occurs within 2-3 weeks after radiotherapy initiation, with healing within 3 weeks after completion of treatment . RadiatiDue to the destruction of salivary glands during radiotherapy, reduced salivary secretion and altered salivary composition effectively eliminate the abilitiy of oral self-cleaning, which makes patients susceptible to bacterial and viral infections. In addition, radiation can directly damage the normal epithelial cells of the oral mucosa, and finally ulcers appear. Due to immune system damage after radiotherapy, cancer patients are more vulnerable to bacterial and viral invasion, which aggravates the injury of mucosal epithelium. Previous clinical treatments mainly consisted of oral cleaning, nutritional supplements, local mucosal recovery, and anti-infection treatment, while pain management was ignored. Consequently, eating is affected and leads to a weak immunity, and the treatment of radiotherapy and chemotherapy may be interrupted. Therefore, the use of analgesics is very important to treat radiation-induced oral mucositis in patients with nasopharyngeal carcinoma.µ-opioid receptor agonist. Some animal studies have also shown that the antinociceptive effect of oxycodone is associated with activation of κ-opioid receptors [µ-opioid receptor antagonists, such as β-funaltrexamine (β-FNA), but not by selective κ-opioid receptor antagonists [Oxycodone, extracted from the alkaloid paramorphine, belongs to a potent pure opioid receptor agonist. Oxycodone is a relatively selective eceptors , 28. Howagonists , 30.Oxycodone has intravenous, subcutaneous, intramuscular, and oral formulations, and oral formulations includes immediate-release (IR) tablets (for 4-hourly dosing) and sustained (controlled-release (CR)) release tablets (for 12-hourly dosing) . The IR Oxycodone hydrochloride has a strong affinity for opioid receptors in the brain and spinal cord, which can achieve an effective analgesic effect on bone metastases. Many clinicians have combined radiotherapy with oxycodone hydrochloride to treat moderate-to-severe pain caused by bone metastases of malignant tumors, achieving a combination of short-term and long-term analgesic effects. Hu et al. studied 47 cases of bone metastases with moderate-to-severe pain and found that in the first week when oxycodone hydrochloride was used alone, the overall pain relief rate was 95.7%. Since conventional radiotherapy had been performed in the second week, the pain remission rate was above 91.5% until the fourth week ended, and the pain remission rate reached 97.9% when the fifth week ended . The locP < 0.05). The proportion of patients with an improved life quality in the combined group was significantly higher when compared to the oxycodone hydrochloride alone group . No significant difference was found in adverse reaction rate between the two groups (23.8% vs. 28.5%).In a study by Yi et al. of 42 cancer patients with bone metastases, efficacy of oxycodone hydrochloride treatment alone was compared with that of the combined treatment with radiotherapy . RadiothP < 0.01) [According to previous reports, strong opioid drugs such as oxycodone hydrochloride prolonged-release tablets administered during radiotherapy can effectively reduce the pain caused by radiation-induced oral mucositis for head and neck cancer patients. On the contrary, for patients without opioid drug treatment, the visual analog scale (VAS) pain score increased from 4 points to 7–9 points in the 3rd week of radiotherapy –43. Comp < 0.01) . In addi < 0.01) . In the n = 34) with that of fentanyl transdermal treatment (n = 32) in nasopharyngeal carcinoma patients affected by radiation-induced oral mucositis. It was shown that the pain was relieved in both groups, while the analgesic effect of the oxycodone group was significantly better than that of the fentanyl transdermal group in the 7th week of radiotherapy . The incidence of adverse reactions  was not statistically significant between the two groups, and neither respiratory depression nor addiction occurred.A randomized controlled trial by Yi Yu et al.  was perfAnother study found that the use of oxycodone hydrochloride in the early stage of radiation-induced oral mucositis achieved a better curative effect when compared with the use in the middle or late stage. Recently, a study by Hisamitsu et al.  investigPain often existed in the whole course of radiotherapy. However, studies have shown that pain management is still inadequate for patients undergoing radiotherapy. The reason may arise from cancer pain in the waiting periods but overlooked easily, the slow effect of radiotherapy on improving pain relief, and the radiotherapy-related complications. Hence, clinicians should pay more attention to pain management. Timely, comprehensive, dynamic pain assessment and treatment should be performed before, during, and after radiotherapy. Combining radiotherapy with pain medication is crucial to achieve the full analgesic effect and further improve the life quality of patients and their families , 43. OpiIn summary, radiotherapists should pay more attention to pain management in clinical practice and not only provide information of side effect of radiotherapy and pain management plan to patients and their family but also take appropriate treatment to relieve patients' pain and improve their QoL. As shown in this review, oxycodone hydrochloride shows good efficacy and tolerance profile and could be used for pain management before, during, and after radiotherapy.


Is obesity associated with prescription opioids for pain diagnoses among patients seeking primary care in the United States?In this cross-sectional study of electronic health records of 565 930 patients, osteoarthritis, other joint disorders, and other back disorders were the most important pain diagnoses associated with the increased prescribing of opioids to patients with obesity.The findings suggest that population-level efforts to prevent and treat obesity may reduce the prevalence and severity of joint and back disorders and the associated use of prescription opioids. Prior studies have identified an association between obesity and prescription opioid use in the US. However, the pain conditions that are factors in this association remain unestablished.To investigate the association between obesity and pain diagnoses recorded by primary care clinicians as reasons for prescription of opioids.A cross-sectional study including 565 930 patients aged 35 to 64 years with a body mass index (BMI) measurement recorded in 2016 was conducted. Electronic health records of patients seen by primary care clinicians in the US in the multipayer athenahealth network from January 1, 2015, to December 31, 2017, were reviewed, and data were analyzed from March 1 to September 15, 2019.International Classification of Diseases, Ninth Revision, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, claims within 7 days before each opioid prescription were captured and classified using a pain diagnosis typologic system. Weight was categorized as underweight , normal weight , overweight , obese I , obese II , obese III , and obese IV .Any prescription of opioids in the 365 days before or after the first BMI measurement in 2016 were identified. All Among 565 930 patients, 329 083 (58.1%) were women. A total of 125 093 patients (22.1%) were aged 35 to 44 years, 199 384 patients (35.2%) were 45 to 54 years, and 241 453 patients (42.7%) were 55 to 64 years. A total of 177 631 patients (31.4%) were overweight and 273 135 patients (48.2%) were obese at baseline. Over 2 years, 93 954 patients (16.6%) were prescribed opioids. The risk of receiving prescription opioids increased progressively with BMI . The percentage of patients with opioid prescriptions attributable to an overweight or obese BMI was 16.2% . Prescription opioids for management of osteoarthritis  and other joint disorders  both had stronger associations with obesity than the mean for any pain diagnosis . Osteoarthritis, other joint disorders, and other back disorders comprised a combined 53.4% of the absolute difference in prescription of opioids by obesity.Joint and back disorders appear to be the most important diagnoses in explaining the increased receipt of opioid prescriptions among patients with obesity. Addressing the opioid crisis will require attention to underlying sources of demand for prescription opioids, including obesity, through its associations with pain. This cross-sectional study investigates the association of obesity with prescription opioids for pain diagnoses among US adults seeking primary care. Obesity has a strong positive association with chronic pain through a physiologic mechanism of increasing the risk and severity of painful conditions, such as arthritis and low back pain.22 However, the specific pain diagnoses underlying this association were not well established. Identifying the pain conditions associated with the obesity–prescription opioid association is an important step toward developing targeted interventions to reach patients who are most likely to receive opioids and inform the prioritization of pain management efforts nationwide.A recent analysis of the National Health and Nutrition Examination Survey found evidence of a cross-sectional association between obesity and prescription opioid use.In this study, we used multipayer electronic health record data from the athenahealth network to investigate the association between obesity and prescription opioids. We then examined the association of obesity with prescription of opioids for specific pain diagnoses. Next, we evaluated the diagnoses most associated with the overall difference in prescription of opioids by obesity. In addition, we explored variations in these associations and the prevalence of specific pain diagnoses by sociodemographic traits.23 The national network includes more than 60 million patients seeking care annually from more than 120 000 health professionals in the US.24Athenahealth Inc is a commercial vendor and developer of cloud-based practice management and electronic health record software for a network of outpatient primary care practices.STROBE) reporting guideline.Our analysis relied on deidentified electronic health record data from the athenahealth network. The Boston University Medical Campus Institutional Review Board determined that this analysis of deidentified data qualified as exempt human participants research. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology   reading taken during a visit with a primary care clinician, such as a physician with a specialty in internal medicine, family medicine, or general practice; a nurse practitioner; or a physician assistant, in 2016. We limited the sample to patients aged 35 to 64 years as of January 1, 2016. To ensure that we only included patients with sufficient data on their history and who remained in the network for the study’s duration, we limited the sample to patients who had at least 1 primary care visit more than 2 years before their first BMI reading in 2016 and at least 1 primary care visit more than 1 year after. Patients with a cancer or pregnancy diagnosis within 1 year of their first BMI reading, recorded an extreme BMI less than 18.5 or greater than 80, or had missing values for race/ethnicity or urbanicity were also excluded. These exclusions are detailed in eFigure 1 in the In this cross-sectional study, a patient’s first BMI reading by their primary care clinician in 2016 served as the index value. Prescriptions written by a primary care clinician during the 365 days before or after the index date were captured to determine whether the patient received any opioid prescriptions. Depending on the patient’s index date, the earliest opioid prescription could have occurred on January 1, 2015, and the latest could have occurred December 31, 2017. We captured all diagnosis claims within 7 days before each opioid prescription.25 Other covariates included age , sex , race/ethnicity , census region , urbanicity , and health insurance .Body mass index was measured by the patient’s primary care clinician and was categorized as underweight , normal weight , overweight , obese I , obese II , obese III , and obese IV .eTable 3 in the 26 to generate a list of International Classification of Diseases, Ninth Revision, codes for conditions that commonly cause pain severe enough to require opioid prescriptions. The list was reviewed by a rheumatologist (T.N.) and internal medicine physician (N.E.M.), who categorized the codes into 25 distinct pain diagnoses. eTable 4 and eTable 5 in the International Classification of Diseases, Ninth Revision, and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, codes used to classify the diagnoses.We used a typologic system developed by Sherry et alWe documented whether patients received prescription opioids for management of each of the 25 diagnoses. Patients could have more than 1 diagnosis if they had multiple claims in the 7 days before an opioid prescription or if they had multiple prescriptions. Some patients had no pain diagnosis claim. In these instances, we classified diagnoses as none or other. One possible explanation for this phenomenon is that some patients were diagnosed with a painful condition before the study but renewed their prescriptions by telephone without an associated visit. Claims could have also been generated at a hospital or specialty clinic, but the prescription was written by the primary care clinician. In addition, the claim could have been recorded outside the 7-day window.27We used negative binomial regression with robust SEs to examine the association of BMI category with prescription of opioids, adjusting for age, sex, race/ethnicity, region, urbanicity, and health insurance status. To examine the sensitivity of the results to the exclusion of missing data, we used multiple imputation by chained equations to account for missing data on race/ethnicity and urbanicity and repeated the regression. We then estimated the fraction of patients whose prescription opioids could have been avoided under the hypothetical scenario in which patients who were overweight or obese were of normal weight. We determined the population-attributable fraction for each BMI category by calculating the observed number of cases in each category and the expected number of cases under exposure to the normal BMI category via marginal prediction.Next, we assessed the association of obesity with prescription of opioids for management of each pain diagnosis separately. Based on these models, we estimated the marginal percentages of patients receiving prescription opioids overall and for each diagnosis among patients with obesity and patients with normal weight. Using these estimates, we determined the absolute difference in the percentage of patients with prescription opioids, comparing patients with obesity with those of normal weight. We repeated this calculation to find the absolute difference in prescription opioids for each specific pain diagnosis. In addition, by dividing the absolute difference for each diagnosis by the absolute difference for prescription opioids overall, we determined the percentage contribution of each diagnosis to the overall difference in patients with prescription opioids by obesity.To assess whether patients reported pain diagnoses alone or in combinations, we examined a subsample of patients with obesity who received prescription opioids and had 1 or more pain diagnoses. We tabulated the unadjusted percentage of patients who recorded each of the 15 most common diagnoses alone and in combination with each of the other 14 most common diagnoses.P values less than .05 calculated with an unpaired t test were considered statistically significant. We conducted all analyses using Stata, version 15 (StataCorp), from March 1 to September 15, 2019.In addition, we stratified the sample by each covariate, using negative binomial regression models to calculate the strata-specific association of obesity and any prescription opioids, adjusting for all other covariates. We then estimated the marginal prevalence of each diagnosis among patients with obesity in the strata and ranked the prevalence on a scale from 1 to 25 to explore relative differences between strata. Two-tailed The sample included 565 930 patients aged 35 to 64 years . Of these, 329 083 patients (58.1%) were women and 455 923 patients (80.6%) were non-Hispanic white. At baseline, 177 631 patients (31.4%) were overweight and 273 135 patients (48.2%) were obese. Over 2 years, 93 954 patients (16.6%) were prescribed opioids . Among tThe risk of receiving prescription opioids increased progressively with BMI . The complete regression results are presented in eTable 1 in the The absolute difference in prevalence of prescription opioids between patients with obesity and patients with normal weight was 4.6% . Several pain diagnoses emerged as factors in this difference. Other joint disorders (26.6%), osteoarthritis (16.9%), and other back disorders  (9.9%) were responsible for a combined 53.4% of the elevated prevalence of any prescription opioids in patients with obesity. Radiculitis (4.6%), backache (4.0%), and pain in limb (3.9%) emerged as lesser but still positive factors. Headache syndromes (−1.5%) and cervicalgia (−2.6%) were both less common in patients with obesity and thus were negatively associated with the difference in prescription opioids by obesity .The association of BMI with prescription opioids was stronger among women  compared with men ; in the Northeast  compared with the Midwest , South , and West ; and in metropolitan areas  compared with metro-adjacent  and rural  areas. (eFigure 3 in the In this cross-sectional study of a national sample of electronic health records, we found a significant association between obesity and prescription opioids that increased with progressively higher BMI. Patients in the obese III category had a 48% increased risk of receiving prescription opioids and patients in the obese IV category had a 71% increased risk. At the population level, we estimated that overweight and obese BMI accounted for 16.2% of patients receiving opioid prescriptions.The obesity–prescription opioid association was largely explained by 3 pain diagnoses—osteoarthritis, other joint disorders, and other back disorders—that comprised 53.4% of the absolute difference in risk of prescription opioids by obesity. These 3 diagnoses were also the most prevalent diagnoses overall, and osteoarthritis and other joint disorders were the 2 reasons for prescription opioids most closely associated with obesity. Prescription opioids for other back disorders were less strongly associated with obesity but remained a significant factor because of their high prevalence.28 The pathogenesis of osteoarthritis is related to obesity through excessive joint loading, altered biomechanics, inflammation related to adipose tissue, and potential hormonal dysregulation.30 Thus, osteoarthritis may cause pain in weight-bearing and non–weight-bearing joints.32 Obesity duration may also increase the risk of osteoarthritis.34 Our results suggest that osteoarthritis was a particularly important factor in the risk of receiving prescription opioids among patients with obesity older than 45 years. Many of the conditions captured in the other joint pain diagnoses could also reflect undiagnosed arthritis.35Obesity is an established risk factor for osteoarthritis, which most commonly affects the lower limbs.36 Receiving prescription opioids for management of intervertebral disc degeneration was not as strongly associated with obesity as prescription opioids for other back disorders. One possible explanation for this finding is that, depending on the location of the affected intervertebral discs, degenerative disc disease could manifest as back pain or as neck pain, and the latter is not as strongly affected by excessive loading caused by weight gain.36Obesity is further associated with several back disorders through a similar set of biomechanical and inflammatory pathways.38 These solutions will be particularly important given more restrictive opioid-prescribing guidelines, which may increase the number of patients living with unmanaged chronic pain.40 Tailored physical activity and nutritional counseling interventions, medications for weight loss, and bariatric surgery to reduce obesity could also help reduce pain severity and prevent disability.43 Because environmental factors across the life course may reduce individual capacity to regulate personal diet and physical activity, health policies are also needed to change the obesogenic environment.44 Such efforts may include nutritional labeling, advertising restrictions, targeted taxes or subsidies, public awareness campaigns, regulation of nutritional quality in school cafeterias, and programs to increase the availability and affordability of healthy foods.45Moving forward, our findings suggest a need for greater attention to the prevention and management of painful conditions that underlie the demand for prescription opioids, in particular, joint and back disorders. Reducing prescription opioid use will require expanding access to integrated pain treatments, including nonopioid medications, and nonpharmacologic approaches, such as physical therapy, cognitive behavioral therapy, and acupuncture.47 Thus, future investments in primary and secondary obesity prevention could be framed as efforts to reduce the burden of chronic pain, prescription opioid use, and ultimately future societal costs of the opioid epidemic, including opioid-related overdose and mortality.48Greater awareness is also needed throughout the public health community on how the burden of obesity at the population level includes chronic pain, and in this way, how obesity has factored in to the increased demand for prescription opioids in the US. Specifically, joint and back pain appear to have played a significant role in increasing the demand for pain management among patients, which manufacturers and health care professionals responded to with prescription opioids.This study has several limitations. First, owing to the study’s cross-sectional design, it is not possible to ascertain causality in the associations between obesity, prescription opioids, and pain diagnosis outcomes. We also cannot rule out residual confounding by smoking status, depression, socioeconomic status, and other variables not available in the deidentified data we received from athenahealth. Second, all prescription opioid data in this study refer to prescriptions written, which may not have been filled or, if the prescriptions were filled, the patients also may not have used the medications. Third, patients who seek health care are less likely to be healthy than adults in the general population; thus, associations observed in this study could be weaker than at the population level. Fourth, 15.8% of patients with prescription opioids had no associated pain diagnosis in the electronic health record system during the 7-day window before their opioid prescription. As a result, we may have underestimated our reported prevalence values. Fifth, we were unable to examine obesity duration in this study.In this cross-sectional study of patients seeking primary care in the US from 2015 to 2017, BMI was associated with prescription of opioids. Osteoarthritis, other joint disorders, and other back disorders were the most common pain diagnoses observed in patients with prescription opioids and appeared to be factors most associated with opioid prescriptions in patients with obesity. Future research should address the specific pathways between obesity, chronic pain, the increased demand for prescription opioids, and the epidemic of opioid misuse in the US. As the prevalence of obesity continues to increase, this study provides data for policymakers to consider greater investments in primary and secondary obesity prevention within a comprehensive response to the opioid epidemic.


Fibromyalgia (FM) diagnosis follows the American College of Rheumatology (ACR) criteria, based on clinical evaluation and written questionnaires without any objective diagnostic tool. The lack of specific biomarkers is a tragic aspect for FM and chronic pain diseases in general. Interestingly, the endogenous opioid system is close to the immune one because of the expression of opioid receptors on lymphocytes membrane. Here we analyzed the role of the Mu opioid receptor on B lymphocytes as a specific biomarker for FM and osteoarthritis (OA) patients. We enrolled three groups of females: FM patients, OA patients (chronic pain control group) and healthy subjects (pain-free negative control group). We collected blood samples to apply immunophenotyping analysis. Written tests were administrated for psychological analysis. Data were statistically analyzed. Final results showed that the percentage of Mu-positive B cells were statistically lower in FM and OA patients than in pain-free subjects. A low expression of Mu-positive B cell was not associated with the psychological characteristics investigated. In conclusion, here we propose the percentage of Mu-positive B cells as a biological marker for an objective diagnosis of chronic pain suffering patients, also contributing to the legitimacy of FM as a truly painful disease. Fibromyalgia (FM) is one of the most disabling chronic pain syndromes  affectinThe American College of Rheumatology (ACR) criteria for FM diagnosis have changed over time ,11,12,13Evaluation of cytokines and chemokines levels in stimulated peripheral blood mononuclear cell (PBMC) has shown patterns uniquely present in patients with FM ,25. MetaSince the 1990s, Raffaeli and colleagues have investigated the clinical combined role of opioids and the immune system, in order to personalize pain therapy ,37,38,39Thus, here we propose an observational, cross-sectional, single blind, diagnostic trial in order to investigate whether Mu opioid receptor on lymphocyte membranes could be considered as a FM biomarker or whether it could be a common marker for different chronic pain syndromes. Moreover, given the high prevalence of psychological distress and psychiatric disorders in FM and more in general in chronic pain ,42,43, an = 102), mean age 51 years (n = 59) ranked between moderate (NRS: (4–6); 15.3%) and severe (NRS:(7–10); 84.75%) NRS score. Fifty-nine percent were patients suffering for less than five years, 41% for more than five years. OA patients (n = 19) rated with mild pain (NRS: (0–3); 36.87%), moderate (26.4%) and severe pain (36.87%); 63.1% of OA patients had pain for less than five years and the remaining 36.93% for more than five years  filled them.Following inclusion and exclusion criteria assessment (see 4.2 paragraph), clinical data were collected in a specific Case Report Form (CRF)including: demographics, clinical characteristics and pharmacological history .Pain int51 years . Fifty-eve years . All patWe analyzed the blood samples of all enrolled patients in order to detect the expression of Mu receptors on the membrane of T and B lymphocytes. We used one-way Analysis of Variance (ANOVA) both for group comparisons and for intra-group homogeneity assessment. All data were expressed as mean ±S.E.M. Tukey’s least significant difference multiple comparison was used for post-hoc analysis following one-way ANOVA, to compute the probability values (P) in three-group comparison. A P threshold of 0.05 was considered for statistical significance. p < 0.001), and CTRL and OA ( p< 0.05) (We found that only a very low (mean < 1.3 ± 0.3) percentage of T lymphocytes from FM and OA patients and CTRL expressed Mu opioid receptor B, and wep< 0.05) D.p < 0.001) lower expression of Mu+ B cells  than the control group (mean: 43.80 ± 3.5) ) and severe (NRS (7–10)) pain, did not present any differences in the percentage of Mu-positive (Mu+) B cellsbut both of the subgroups showed a significantly (0 ± 3.5) A. OA pat0 ± 3.5) B.p < 0.001) from the control group (mean: 43.80 ± 3.5) and the mild pain group patients (mean: 52.77 ± 9.2). These last groups did not show any significant differences in the percentage of Mu+ B lymphocytes  and moderate/severe pain OA patients (mean: 18.23 ± 3.7) had almost the same percentage of Mu+ B cells; both the groups were significantly different (phocytes .n = 33) were suffering for more than five years; the remainder were suffering for less than five years . We found a significant difference (p < 0.001) of percentages of Mu+ B cells between the two subgroups  and between the single subgroups and the control pain-free group (mean: 43.80 ± 3.5) (n = 12) were suffering for less than five years, and 37% (n=7) for more than five years. The percentage of Mu+ B cells was not significantly different between the two subgroups . We found a significant difference (p < 0.05) in Mu+ B expression between the control group and OA patients suffering for less than five years  of FM patients (0 ± 3.5) A. Sixty-ve years B.Both fibromyalgic and osteoarthritic patients require pharmacological therapies in order to alleviate their pain. In most cases, medical doctors also decide on a combination of drugs and prescribe formulations for psychological and psychiatric comorbidities, for FM patients. OA patients mostly used NSAIDs for inflammatory pain. Considering the pharmacological therapy at the time of enrolment, we analyzed whether Mu opioid receptor expression on B lymphocytes was influenced by the therapy. We considered the totality of patients and divided the entire number into the following therapy subgroups: antidepressants, benzodiazepines, NSAIDs, nutritional supplement/none, and previous drugs combination. We found that, despite the different pharmacological therapies, the percentage of Mu+ B cells was almost identical across the subgroups (mean: 18.3):antidepressant 17%; benzodiazepines 20%; NSAIDs 22%; nutritional supplements/none 21%; previous drugs combination 20%.n = 53). Mu+ B cell expression had no significant correlations with any psychological aspects investigated.n = 58). Given the similarities in Mu+ B cells percentages between FM and OA patients at the same intensity of pain (NRS (4–6), NRS (7–10)), we conducted the analysis considering together FM and OA patients with moderate and severe pain , where biomarkers play a well-known role. In this context, the objective evaluation of pain intensity is a crucial point, relevant for pharmacological management and especially for the choice of opioid therapy or to determine if or not to use a surgical approach . Thus, the proper diagnosis of pain severity has also an ethical and economical value, in terms of social and national health system costs.The objectivity of pain severity is still described only in terms of pain threshold and patients have to rate their pain considering a numeric rating scale (NRS) of 0 to 10, where zero is a no pain condition and a 10 means the pain is as bad as it could be , even ifThere is no internationally accepted classification of pain severity for FM or chronic diseases and the physician is tasked with careful evaluation in order to determine the most effective treatment . It is oAlthough FM has been included in the ICD-11 as “chronic primary pain” , a greatThe absence of objective diagnostic tools is leading scientists to the identification of chronic pain markers, in order to improve the diagnostic process and reduce the risks of diagnostic delays and misdiagnosis ,54. An oIn this context, in recent years we have focused on the expression of the Mu opioid receptor on lymphocyte membrane, in order to identify this receptor as a hypothetical biomarker of chronic pain conditions. Focusing on the evidence that immune, nervous and opioid endogenous systems share the same opioid receptors, in the 1990sRaffaeli and colleagues studied and reported their crucial role in the pain pathways  and publIn the present study, we certified that FM pain perception is an objective widespread chronic pain status where pain is the primary symptom and FM pathogenesis derives from a characteristic morphological modulation of the endogenous antinociceptive pathway. To demonstrate this, we chose OA as a chronic pain control group, considering our previous research on osteoarthritic pain  and its We found that both FM and OA chronic pain patients present a diverse and significantly lower percentage of Mu+ B cells compared to the negative control group.In our experiments, Mu receptor in T cells was expressed only by a very low frequency population (less than 2%) and there was no difference between the percentage of Mu+ T cells across the three groups, suggesting that the frequency of Mu+ T cells expression could not be a significant biological target in chronic pain patients. However, further investigation will be required to better understand this intriguing data.Thus, we analyzed these data considering the intensity of the pain and found, for the first time, that FM or OA patients with moderate/severe intensity of pain on the NRS presented a lower percentage of B cells expressing Mu opioid receptor than patients in pain-free control group. Of interest is the finding that OA patients with a mild pain sensation showed a higher percentage of Mu+ B lymphocytes, which was not significantly different from the negative control group. The analysis of these data led us to postulate that FM patients effectively show a real pain condition, by having an overlapping opioid marker of the well-established OA patient pain, and their suffering is not merely psychosomatic expression.As a clinical explanation for our results, we suggested that a lower expression of Mu+ B cells in FM and OA patients than in the negative control group seems to be linked to a reduced threshold level of pain response and that a low availability of opioid receptors in FM patients could show altered endogenous opioid analgesic activity. Similar results were presented about Mu opioid receptor accessibility in the central nervous system of FM patients, where a reduction was detected . Thus, aRaffaeli and coworkers here propose that this condition could be classified as the “B-Lymphocytic Reserve MOR Syndrome” theory. Even if further studies are needed in this direction, we postulate that during an endogenous or exogenous pain stimulus, the amount of B lymphocytes presenting MOR could contribute to counteract the algic response. Unlikely, when the intensity of pain appears more severe (high/moderate intensity) we assist to the reduction of Mu+ B cells percentage, and this deficit of B cells presenting MOR could affect pain perception and intensity, leading to an uncontrolled pain condition. Further studies are already ongoing to better identify the possible correlation of the different activation statuses of B lymphocytes with Mu+ Bcells frequency. In this study, we also found two different subpopulations of FM patients considering the duration of pain in years: here we show that FM patients suffering for more than five years have a lower percentage of Mu+ B cells than a subgroup of FM patients suffering for less than five years. In the near future, it could be interesting to analyze the modulation of the percentage of Mu+ B cells expression over the time, by following a specific group of patients from the first clinical evidence of FM.Moreover, we found that the expression of Mu+ B cells is not associated with functional disability, illness representation, depression, anxiety, stress-related symptoms, coping, catastrophizing or pain acceptance. Therefore, these relevant psychological aspects do not seem to correlate with the biological findings, as shown in In conclusion, our results could contribute to the legitimization of FM as a real and serious chronic pain syndrome and could also be helpful in rethinking the description of pain categories: FM and OA are differently categorized in the ICD-11 but our results show similar biological characteristics. Due to this new evidence and to better depict the chronic pain scenario, new trials have already been submitted to the ethical committee in order to clarify whether the “B-Lymphocytic Reserve MOR Syndrome” hence the modulation of B cell presenting MOR is common to more than one chronic pain condition. Further investigation could help clinicians understand if these pathologies share the same pattern of pain.This is an observational, cross-sectional, single blind, diagnostic trial. The current study is approved by the institutional independent ethics committee of Sapienza University of Rome, with the name of “I markers Bio-Psico-Sociali nella syndrome fibromialgica” , on 8 March 2018 (Ref. 4937) and the trial is registered in on ISRCTN registry, ID: ISRCTN24645566, 10 December 2018.All participants were enrolled at the Clinic for the Diagnosis and Therapy of Fibromyalgia, Rheumatology Unit, Sapienza University of Rome (Umberto I Policlinic).Fifty-nine (59) consecutive adult patients affected by FM, according to both 1990 and 2010 ACR criteria [Considering that opioid receptors and lymphocytes activity could be influenced by opioid treatment ,33,34,35A control group of 19OA patients (chronic pain control group) affected by chronic pain due to knee or hip degenerative osteopathy, ongoing active and/or passive therapy, paracetamol and NAISDs for mild/severe pain when needed, was involved.A second control group was composed by 24 healthy people (pain-free negative control group).All eligible and consenting patients signed a specific informed consent form and General Data Protection Regulation (GDPR) obligations, on the day of the first clinical visit. Each allocated patient, after inclusion/exclusion criteria analysis, clinical evaluation and consent form signature were included in a list, with a numeric sequential code, in order to protect confidentiality. Only the medical doctor could access patient names. All information was collected in electronic files. Clinical evaluation and socio-demographic characteristics were assessed by clinicians operating in Sapienza University.Clinical data were collected during patients’ enrolment. Clinicians filled the database following a consequential numbering of the patients.All patients and pain-free people underwent clinical examination. Questions were included about socio-demographic characteristics, duration of pain, comorbidities and current treatments. Clinical pain was reported on a 0–10 Numerical Rating Scale (NRS), with 0 for “no pain” and 10 for “the worst pain imaginable.”A comprehensive battery of self-report tools in their Italian versions was administered to the patients of experimental and positive control groups. The Fibromyalgia Impact Questionnaire  was admThe Illness Perception Questionnaire-Revised  is a 38Blood samples were collected during clinical examination. Blood samples were analyzed within the next 24 h through immunophenotyping analysis. The research biologists were blinded to patients’ personal information and therapy. They received patients’ samples in a sequential numeric code.Peripheral blood was incubated with fluorochrome-conjugated antibodies, specific for different cell population membrane markers, in combination with Mu anti-opioid receptor antibody. In particular, peripheral blood samples were stained with antibodies FITC conjugated anti CD3 (T lymphocytes), APC conjugated anti-Mu and PerCP-Cy5.5 conjugated anti-CD19 (B lymphocytes), all from Becton Dickinson, for 20 min at 4 °C. After staining, samples were incubated for 15 min at room temperature with BD FACS Lysing Solution  and then centrifuged at 1500 RPM for five minutes. The resulting pellets were acquired immediately after adding PBS. Acquisition and analysis were performed on a LSR Fortessa X-20 flow cytometer (Becton Dickinson) using Diva software, in order to detect the percentage of Mu+ cells.Immunophenotyping results were analyzed by one-way ANOVA test for group comparisons and for intra-group homogeneity assessment, with Prism-GraphPad 8.0.2 software . All data were expressed as mean ± S.E.M. Tukey’s least significant difference multiple comparison was used for post-hoc analysis following one-way ANOVA, to compute the probability values (P) in three-group comparison. A P threshold of 0.05 was considered statistically significant.Descriptive statistics were used to describe socio-demographic data, diagnosis, pain intensity and pain duration.Statistical analysis of psychological data was performed with SPSS 23 software. The Pearson’s parametric coefficient was used for the correlation analysis.


Pain is a medical and nursing problem that is common in surgical departments. Inadequate pain management can lead to patient distress, as well as extending the period in which the patient’s quality of life is reduced. The standardized SF-MPQ-2 questionnaire provides nurses with the opportunity to assess pain within a broader context. The aim of this descriptive and exploratory study was to describe the state of pain assessment in surgical patients in the South Bohemian Region and to highlight the benefits of using a standardized tool for proper pain assessment. The research was carried out using a quantitative survey within the South Bohemian Region (Czech Republic). The participants in the study were nurses working in surgical departments in hospitals in the region as well as hospitalized patients. The results show that nurses pay slightly more attention to pain assessments than doctors. We know that, generally, pain decreases with time after surgery. Nonetheless, returning pain, as well as continuous pain, can occur, both of which have an emotional component. The results of this study are directed at nurses and include a call for more effective pain management through improved assessment. Pain is a phenomenon that mankind has had to endure for an immemorial period of time. Surgery is one field of medicine in which health professionals frequently have to deal with patient pain. In most cases, pain is related to injuries and diagnostic procedures, but it is also often associated with surgical procedures. Most patients hospitalized in surgical wards experience some level of pain . If painThis study describes the manifestation of pain and its effects on patients N = 205) hospitalized in surgical departments in the South Bohemian Region (Czech Republic). The most frequently mentioned aspects are physical manifestations, movement restrictions, decreased self-sufficiency, emotional instability, lowered verbal expression, and grimacing due to pain [ hospitalAlthough progress in scientific, pharmacological, and technological areas has improved our ability to dampen pain, we cannot say that the problem of pain management has been completely solved . The firThe essential requirements for any evaluation scale include validity, availability, sensitiveness, the suitability for routine use and the ability of health professionals to work with these tools ,7. FurthOne of the most widely used pain assessment tools worldwide is the McGill Pain Questionnaire, which is available in both long-form and short-form formats. Since the long-form questionnaire contains a total of 78 descriptors, it can be very time consuming, requiring at least 20 min. In contrast, the original short version of the questionnaire only requires about 5 min . The abbThis descriptive and exploratory study focused on describing the state of pain assessment in surgical patients in the South Bohemian Region and examined the potential for using the McGill Pain Questionnaire (short-form) (SF-MPQ) to evaluate pain in a group of surgical patients. Quantitative methods in the form of questionnaire surveys were used to achieve this objective.Study participants were chosen non-randomly based on predetermined selection criteria. These criteria were in line with the objectives of the study, i.e., focused on patients hospitalized in surgical departments and nurses working in surgical departments of medical institutions in the South Bohemian Region. The selection criteria also had a demographic element, i.e., the South Bohemian Region of the Czech Republic, and an age element, i.e., patients had to be aged ≥15 years and hospitalized in a surgical department. The criterion for nurses was that they were working on a surgical ward. The sample size for the study was determined by a statistician and was based on the number of medical facilities in the South Bohemian Region and the number of surgical departments in these facilities.In the South Bohemia region, there are eight medical facilities. The research team found out the number of hospitalized patients in surgical departments per year in the South Bohemia Region from the available statistics data. Additionally, we found the number of nurses in this region, but the number of nurses working in the surgery departments in each of these medical facilities is not available. These details have not been made open access. Therefore, the sample size of nurses working in surgical department was determined by a statistician based on available data. This means that we started from the number of surgery departments and statutory minimum number of staff in health services, which is given by Decree of Ministry of health Czech Republic 99/2012 Sb.A total of 320 questionnaires were distributed to the nurses working in surgical departments of medical facilities in the South Bohemian Region (Czech Republic); of these, 253 (79.06%) completed questionnaires were returned. Additionally, 320 questionnaires were distributed to patients hospitalized in the surgical departments of medical institutions in the South Bohemian Region; of these, 218 (68.13%) questionnaires were returned. Of the 218 questionnaires returned, 13 questionnaires had to be excluded due to incompleteness. The resulting research group consisted of 253 nurses working in the surgical department of a medical facility in the South Bohemian Region  and female = 247 (97.6%)). The resulting set of hospitalized patients included 205 respondents  and female = 114 (55.6%)).The quantitative research survey took place from 1 March 2019 until the end of April 2019 in the surgical departments of medical institutions in the South Bohemian Region (Czech Republic). It was carried out using two sets of questionnaires. The first questionnaire was given to patients hospitalized in surgical departments of medical institutions in the South Bohemian Region and contained a standardized part and a non-standardized part . The questionnaire was distributed by members of the research team (nurses). Patients were acquainted with the questionnaire. If they had any questions about the questionnaire, they were able to ask nurses who were members of the research team. The questionnaire was constructed as a self-evaluation questionnaire. In cases where a patient had a problem with reading , a member of the research team asked the questions face-to-face.The second questionnaire was given to nurses working in surgical departments of medical institutions in the South Bohemian Region. The questionnaire was distributed by members of the research team. If the nurses had any questions about the questionnaire, they were able to ask nurses who were members of the research team. This questionnaire only contained our in-house questions.This questionnaire contained 43 numbered questions. It was made up of a standardized part (questionnaire SF-MPQ-2) and a non-standardized part . The non-standardized section contained closed and semi-closed (with the ability to write in custom answers) filtering, and scale-based questions.The non-standardized questions  were created based on the relevant literature and the experience of the research team. The first three questions were to do with categorization. The next 13 questions were focused on ascertaining felt pain. We used closed, semi-closed, and scale-based questions . We used figures for pain drawing too. The use of these questions gave us the opportunity to describe felt pain, the difference between pain at the time before hospitalization and during the period of hospitalization, the difference between pain before the operation and after the operation, the length of time that the patient felt pain at this intensity, and the impacts of pain. The remaining 27 questions were focused on evaluating pain based on the viewpoint of patients. These questions gave us the opportunity to determine who evaluates patients’ pain, determine the scales used for pain assessment, and determine the levels of patients’ satisfaction with pain assessment in the surgery department and cooperation with physician and nurses. Subsequently, the intelligibility of the questions was verified within the framework of a pilot study carried out using 5 patients hospitalized in the surgical department of a medical facility in the South Bohemian Region. Based on their replies, the questionnaire was modified in cooperation with a statistician. The questionnaire was finalized after the consideration of all recommendations and comments.The standardized part was made up of the short-form of the McGill Pain Questionnaire (SF-MPQ-2). This questionnaire was translated into Czech and pre-standardized in 1990 by Šolcová et al. . In 2009This questionnaire contained only in-house questions of our own design. These questions were created based on theoretical knowledge, studied literature, and the experience of the research team. The intelligibility of the questionnaire addressed to nurses was verified in a pilot study carried out with 4 nurses working in surgical departments in the South Bohemian Region. According to their comments and suggestions, the questionnaire was subsequently modified and finalized in cooperation with a statistician. The resulting questionnaire contained 31 questions. The questionnaire contained closed, semi-closed (with the possibility of entering custom answers), filtering, and scale-based questions. The first four questions involved categorization. The next 27 were focused on pain evaluation from the viewpoint of nurses working in the surgery department. These questions gave us the opportunity to determine who evaluates patients’ pain, how patient pain is evaluated, what scales are used for pain assessment, if nurses are content with the scales being used and what they would like to add into these scales, how objective symptoms of pain are identified in patients, and the level of satisfaction with cooperation between patients and physicians on pain management.This study did not include any ethically contentious issues. The implementation of the study respected Regulation 2016/679 of the European Parliament and the Council of the EU, formed on 27 April 2016 for the protection of individuals during the processing of personal data and the free movement of such data, repealing Directive 95/46ES . All activities related to the inclusion of human subjects in research were carried out in accordance with the 1975 Helsinki Declaration and its latest revision in 2013 and were in accordance with national ethics standards and regulations.Respondents were familiarized with the questionnaires and goals of the study, and the study was conducted anonymously. Participation was voluntary. Respondents agreed to participate by completing the questionnaire. The introduction section of the questionnaires explained the purpose of the study and provided information regarding the potential advantages and disadvantages associated with completing the questionnaire. Both questionnaires were examined and approved by the Ethics Committee of the University of South Bohemia. For the implementation of the study, approval and consent from the relevant surgical departments and medical institutions were also obtained, as was the consent of the nurse supervisors at these medical institutions.After visual inspection, data obtained (from the questionnaire addressed for patients and questionnaire addressed for nurses) were evaluated using SASD version 1.4.10  and SPSS version 24 . Frequency tables were created for each indicator, as well as absolute and relative frequencies, modes, medians, averages, variances, and standard deviations (first degree data sorting).For each variable, a variance estimate, standard deviation estimate, range, interval mean estimate of 0.05, and an interval variance estimate of 0.05 were also calculated. Pivot tables with absolute and relative frequencies and a sign scheme were constructed as part of second degree data sorting. As part of the analysis of relationships, tests were applied according to the nature of the distribution of variables and the frequency of observations.Data analysis of the standardized questionnaire SF-MPQ-2 was carried out using procedure established for this standardized tool in SPSS. To evaluate the overall SF-MPQ-2 score and its individual domains in terms of the strength of relationships with specific variables, it was necessary to first test the distribution of variables using the Kolmogorov–Smirnov and Shapiro–Wilk normality tests. Based on the results that showed that the variables did not have a normal distribution, non-parametric tests  were used to test statistically significant links.A total of 253 nurses working in the surgical departments of medical institutions in the South Bohemian Region and 205 hospitalized patients participated in the survey. Among nurses, significantly more were women (247 (97.6%)), and age categories were similarly represented. Regarding the highest education level attained and the length of health care experience, the distributions were uneven.As with nurses, there were more female patient respondents (114 (55.6%)). Most reported that they had only been hospitalized once over the past year, and most were on post-surgical days 1 or 2. There were 43 pre-surgical patients .For the present state of pain assessment, it was important to define who was responsible for evaluating pain in the surgical department. Therefore, we asked nurses who evaluated pain in their department. The analysis of the nurses’ responses (N = 253) indicated that the assessment of pain in surgical departments is carried out by nurses (253). At the same time, 77.9% of nurses said that doctors carried out the assessment of pain in their surgical department (197). However, in the analysis of responses received from patients, 185 patients (90%) indicated that they had been assessed by a physician, 195 (95%) had been assessed by a nurse, and 17% (34) of patients also mentioned a physiotherapist.2: 40,727; df: 15; p < 0.001). Nurses with higher levels of education, namely a university bachelor’s degree, evaluated the visual analog scale as being rather sufficient or moderately sufficient significantly more often. Therefore, we also evaluated the relationship between the education of nurses and their requirements for the assessment of pain supplementation. A statistically significant association was identified . Nurses with the lowest level of education (secondary school) stated that it is not necessary to supplement anything in the assessment of pain significantly more often. Nurses with a university (bachelor’s) degree recommended the use of a more accurate verbal description significantly more often.Pain assessment is one of the nurse’s competencies, as is the choice of an adequate assessment tool. The visual analog scale was shown to be one of the most widely used scales for pain assessment. One hundred and twenty-nine nurses stated that they use this scale for the pain evaluation of surgical patients (N = 253). In statistically testing of the relationship between the education of nurses and their evaluation of the adequacy of a visual analog scale. It was found that the nurses with the lowest level of education (secondary school) were significantly more likely to state that they did not know whether the evaluation of pain using a visual analog scale was sufficient  with the option of writing in an adjective of their own choice. Patients could choose one or more options. The most frequency options were “sharp” (101), “tiring” (46) and “persistent, blunt” (41).To express their current state of pain, respondents ranked their pain using a numerical scale of 0 (no pain) to 10 (the greatest pain they had ever experienced). The numerical scale was evaluated as follows: numbers 0–3 mean no current pain, weak pain; numbers 4–6 mean moderate pain and numbers 7–10 mean severe pain, highest possible level of pain. We can state that “no current pain or weak pain” was felt by 51 patients (25%), “moderate pain” was felt by 128 patients (64.2%) and “severe pain, highest possible level of pain” was felt by 26 patients (12.6%).To determine the extent of relationship between current state of pain and the SF-MPQ-2 assessment, the Spearman’s Rho non-parametric test was used. Statistically significant associations were found between intermittent pain and the overall SF-MPQ-2 score. When describing current pain, patients (N = 205) assessed it mainly as intermittent pain, which was reflected in the total pain SF-MPQ-2 score .Pain is a phenomenon with both psychological and physical components. As part of second level sorting, relationships between individual variables were monitored, namely, between duration and pain intensity and between pain and its impact on a patient’s mental and physical conditions. Patients were offered a five-point scale to assessment the impact: maximum—high—medium—low—none . In the In the case of the subjective perceived impact of pain , patients were asked to subjectively describe their symptoms. Patients were offered answers with the possibility of adding others. For mental impact, the options were aggressiveness, emotional lability, verbal expressions, apathy, I cannot judge, and others (with the possibility of adding other symptoms). For physical impact, the options were limited movement, limited self-sufficiency, facial expressions (or grimacing), I cannot judge, and others (with the possibility of adding other symptoms). Patients could choose one answer or more answers. Other symptoms, which were stated, were then categorized based on the context.The most common manifestations of the current pain state were emotional lability , verbal expression , apathy , and aggression . In terms of maintaining self-sufficiency, patients reported that their current pain state caused a decrease in mobility  and limited their degree of self-sufficiency .The relationship between the patient’s mental and physical conditions and their pain was also evaluated using the standardized SF-MPQ-2  questionSpearman’s Rho non-parametric test was used to determine the extent of the association between a patient’s age and pain assessed using the SF-MPQ-2. At the same time, the effect of pain  was also calculated. On this basis, statistically significant associations were found between intermittent pain, neuropathic pain, and the overall SF-MPQ-2 score; negative correlations were found in all cases. However, for neuropathic pain and the overall score, the correlation was very weak, and the effect was minimal. The strongest correlation was for intermittent pain. It appears that age was only marginally related to SF-MPQ-2 scores. The greatest effect was observed in association with intermittent pain, which occurred with an inverse relationship to age, i.e., the greater the age, the lower the level of this type of pain .To some extent, an unsatisfactory state of pain assessment and management is still present in medical institutions in the Czech Republic. While research has been carried out and there have been publications dealing with this issue, many of the recommendations are yet to be translated into practice ,18,19. TNevertheless, pain remains a significant medical and nursing problem, especially during the postoperative period . DahlberOur results show that, in the surgical departments of the medical institutions in the South Bohemian Region (Czech Republic), patients are evaluated to a slightly higher degree by nurses compared with doctors. Responses also indicate that pain decreases over time after surgery. Intermittent pain remains problematic, and this affected the results obtained with the SF-MPQ-2. Pain characterized as continuous has a strong emotional component as well as a significant negative impact. We also found that pain-related issues tend to decrease with age.A study by Jang et al. showed  that theThe assessment of patients’ pain is a fundamental skill for nurses working in surgical departments. To some extent, this ability is influenced by clinical experience  as well The use of standardized tools provides a way to evaluate pain objectively. Our results showed that the SF MPQ-2 can assess the physical and emotional components of pain, both of which are important for overall pain management. On the basis of our results, we suggest that a record sheet that also contains the SF MPQ-2 is used for the assessment of surgical patients’ pain. This sheet was offered to medical institutions where research was done. Now the question is, how do we implement these results into practice to improve the quality of care provided to patients?Study participants were selected exclusively from the South Bohemian Region of the Czech Republic. In the case of nurses working in South Bohemian Region, we could not find the number of nurses in each surgical department from the available data. We had to determine the sample size using a statistician based on available data . Given the diversity of the Czech population and the differences in healthcare and health facilities, the results may not be entirely generalizable to other areas, countries, or populations. Additionally, we realize that current state of pain can influenced by physical and psychical condition, type of operation or underlying disease as so as pain management. In the present study, a nonparametric bivariate correlation study  has been conducted. We recognize the risk of bias associated with this type of analysis as we have not controlled for potential confounders.Nonetheless, the importance of using standardized pain assessment tools in surgical patients and their benefits for the patient are evident.


ObjectiveTo evaluate the post-operative outcomes of patients with obstructive sleep apnea (OSA) given intraoperative ketamine.Design: case-control studyA total of 574 patients (287 received ketamine and 287 were matched controls) diagnosed with OSA and body mass index (BMI) > 30 who received general anesthesia were included in this study. Patients given intraoperative ketamine were matched (1:1) with those who did not receive ketamine for age, gender, BMI, ethnicity, anesthesia time, intraoperative fentanyl dose, ketamine dose, and surgery type. A sub-analysis was performed based on the dose of ketamine administered and also on the surgery type. Measured outcomes include post-operative pain scores, post-operative opioid requirements, respiratory status, oxygen use, and duration post-operatively.ResultsIntraoperative ketamine use did not decrease pain scores or post-operative opioid use when compared with the control (no intraoperative ketamine) group. Patients who received high-dose ketamine had significantly higher post-operative pain scores (p=0.048) while in the post-anesthesia care unit (PACU) and required supplemental oxygen for a longer period of time (p = 0.030), pain scores were not significant for patients who underwent orthopedic/spine procedures (p = 0.074), and high-dose ketamine group patients who underwent orthopedic/spine surgery required significantly more opioids in the PACU (p = 0.031). Among patients who received low-dose ketamine, those who underwent head, ear, nose, and throat surgery required significantly more opioids in PACU (p = 0.022).ConclusionsLow-dose intraoperative ketamine did not decrease pain scores or post-operative opioid use significantly and did not improve standard respiratory recovery parameters for OSA patients after surgery. Neither low- nor high-dose ketamine demonstrated the anticipated benefits of low pain scores and reduced post-operative opioid use. These outcomes will differ depending on the surgery type and dose of ketamine used. Obstructive sleep apnea (OSA) affects up to 25% of elective surgical patients , many ofIntravenous (IV) opioids are the most commonly used drugs for pain control in the post-anesthesia care unit (PACU). These analgesics work by binding to mu opioid receptors, which are expressed in both the central nervous system and the peripheral nervous system. Binding inhibits nociceptive signaling, leading to decreased pain sensation. However, these receptors also inhibit autonomic circuits, which help regulate respiratory and cardiac function, leading to the respiratory depression and hypotension often seen following opioid administration . Given tKetamine is a dissociative anesthetic that works by binding to and antagonizing NMDA receptors. In a study by Eikermann et al., ketamine has been shown to activate respiratory muscles despite loss of consciousness during general anesthesia . AdditioSingle-institute patients undergoing general anesthesia with a current diagnosis of OSA who received general anesthesia between January 1, 2016, and January 6, 2018, were 18-100 years of age, had an American Society of Anesthesiologists Score (ASA) 1-4, and had a body mass index (BMI) of >30 were included in this study. Obstetric patients and patients who underwent a cardioversion and sleep endoscopy procedures were excluded. For patients who had multiple procedures during the study period, only the first procedure was included. All study activities were approved by the University of Alabama at Birmingham’s Institutional Review Board.https://www.cms.gov/Medicare/Prescription-Drug-Coverage/PrescriptionDrugCovContra/Downloads/Opioid-Morphine-EQ-Conversion-Factors-Aug-2017.pdf).The primary endpoints for this study were average PACU pain score measured using visual analog scores  and total opioid use in PACU . Using the Medical Administration Record from the electronic medical record in conjunction with the charted PACU admission and discharge times, the amount of opioids given in PACU was obtained and converted to OMEs using the standard CDC conversion table (2 < 92%), and the incidence of post-operative nausea/vomiting and delirium. Time to first requested pain medication and time of required supplemental oxygen were censored at 240 minutes.Secondary endpoints included time until the patient first requested pain medication, total time spent in PACU (or time until the patient was ready for discharge from the PACU), duration for which supplemental oxygen was required post-operatively, number of documented desaturation events (defined as SpOMatchingPatients who received ketamine were matched (1:1) with non-ketamine patients on age (within 10 years), gender, BMI (within five points), race , anesthesia time (within 30 minutes), intraoperative fentanyl dose (within 50 mcg), ketamine dose, and surgery type . Patients receiving ketamine were further stratified according to ketamine dosing as either high-dose ketamine (≥ 50 mg) or low-dose (< 50 mg).Statistical analysisAnalysis was performed using SAS v. 9.4 . Continuous data were summarized as mean and standard error (SE), categorical data were summarized as frequency and percentages, and time-to-event data were summarized as median and interquartile range (IQR). Two sample t-tests (for continuous variables), chi-square tests , and log-rank tests (for time-to-event variables) were used to compare patients who received ketamine intraoperatively with the matched controls. These analyses were conducted on the entire sample as well as after stratifying by ketamine dose and surgery type. A p-value of <0.05 was considered statistically significant.A total of 574 patients were analyzed (287 received ketamine and 287 were matched controls). Demographics and clinical characteristics for the matched sample are shown in Table The incidence of chronic opioid use, as determined by ICD-9 and ICD-10 coding, did not significantly differ between the ketamine and no ketamine groups . Furthermore, among ketamine patients, the incidence of chronic opioid use did not significantly differ according to ketamine dose .Ketamine patients did not significantly differ from non-ketamine patients in pain scores, OME requirements, adverse events, or time until ready for PACU discharge Table .Ketamine patients had significantly longer times to wean to room air than their matched controls (p = 0.038). Only 48.43% of ketamine patients had weaned to room air by 120 minutes post-operatively compared with 56.45% of non-ketamine patients. Kaplan-Meier estimates for the time to wean to room air for the ketamine and non-ketamine groups are shown in Figure Results by doseHigh-Dose Ketamine vs. ControlAmong the ketamine patients, 118 (41%) received high-dose ketamine and 169 (59%) received low-dose ketamine. When comparing the patients who received high-dose ketamine to their matched controls, the increased time to wean to room air was again noted in the ketamine group (p = 0.038). Additionally, the high-dose ketamine patients reported a higher average (SE) pain score, 3.98 (0.32), on arrival to PACU compared with their matched controls, who reported an average (SE) pain score of 3.25 . Despite this difference, these patients did not require a significantly higher amount of opioids to control their pain (p = 0.105) or ask for medication sooner than the non-ketamine patients (p = 0.884). There was no difference noted in the incidence of adverse events or desaturation events between the high-dose ketamine and matched control group, or the time until ready for PACU discharge .When the patients who received high-dose ketamine were further stratified by surgical category, the patients who received high-dose ketamine reported higher pain scores on arrival to PACU for the head/neck  and musculoskeletal/spine  categories Figure ; howeverLow-Dose Ketamine vs. ControlWhen comparing patients who received low-dose ketamine with their matched controls, there was no noted difference in the time to wean to room air (p = 0.246) or time to first opioid (p = 0.887). There was no significant difference in pain scores on arrival to PACU, OME requirements post-operatively, adverse events, or time until ready for PACU discharge .When further divided by surgical category, there was again a difference noted in pain scores on arrival to PACU, with the head/neck  and musculoskeletal/spine  procedure patients who received ketamine reporting higher pain scores than their matched controls Figure . HoweverResults by surgical categoryDue to the small sample sizes, the cardiac (n = 18) and vascular (n = 8) patients were combined. Ketamine patients had significantly higher pain scores than the non-ketamine patients for both head/neck surgeries (p = 0.024) and musculoskeletal/spine surgeries (p = 0.013) Figure .For the musculoskeletal/spine surgeries, ketamine patients also required significantly more OMEs (p = 0.024) Figure . No otheTime to wean to room air was also significantly longer for ketamine patients compared with non-ketamine patients undergoing gastrointestinal/genitourinary (p = 0.025) and head/neck 0.044) surgeries  of 135 patients undergoing laparoscopic cholecystectomy . In compIn an RCT of 80 open abdominal hysterectomy patients, Faiz et al. compared the efficacy of IV acetaminophen versus low-dose ketamine and found ketamine to be less effective for post-operative pain . Aubrun One theory for these findings in OSA patients is that ketamine contributes to sympathetic wind-up in OSA patients by blunting the inhibitory feedback to the central nervous system. In these patients who already have decreased pain tolerance relative to the general population , this coLastly, current recommendations for dosing of ketamine use ideal body weight, but most prior studies are not focused on the use of ketamine in obese patients. Despite Gorlin et al.’s study showing that ketamine at doses < 0.3 mg/kg improved pain scores and opioid requirements , our resPossible confounders include the fact that ketamine is often used selectively for more painful surgeries, and despite matching this could still be an issue. Limitations of this study are those inherent to retrospective studies; data were not available for variables such as the severity of OSA, undiagnosed opioid abuse, and explicit drug or alcohol use, and for other psychosocial factors that could impact a patient’s pain perception in the post-operative period. Matching by intraoperative fentanyl dose also eliminates measurement of potential intraoperative opioid sparing, which is often considered in the measurements of prior studies. Also, ketamine patients typically received midazolam to avoid concern for dysphoria, and more sedating IV medications may have contributed to their increased oxygen needs post-operatively. ERAS (enhanced recovery after surgery) protocols and other multimodal analgesic use could mask the effects of ketamine. Lastly, although no difference in chronic opioid use was observed between the various groups, patients were not matched for chronic opioid use.Further research should be conducted regarding the use of ketamine in OSA patients. Large, randomized controlled trials in specific surgical populations could determine the utility, appropriate dosing, and timing of ketamine to definitively determine its beneficial effects, if any, in this high-risk patient population.