Genome-wide association study on pharmacological outcomes of musculoskeletal pain in UK Biobank.

The pharmacological management of musculoskeletal pain starts with NSAIDs, followed by weak or strong opioids until the pain is under control. However, the treatment outcome is usually unsatisfying due to inter-individual differences. To investigate the genetic component of treatment outcome differences, we performed a genome-wide association study (GWAS) in ~23,000 participants with musculoskeletal pain from the UK Biobank. NSAID vs. opioid users were compared as a reflection of the treatment outcome of NSAIDs. We identified one genome-wide significant hit in chromosome 4 (rs549224715, P = 3.88 × 10-8). Suggestive significant (P < 1 × 10-6) loci were functionally annotated to 18 target genes, including four genes linked to neuropathic pain processes or musculoskeletal development. Pathway and network analyses identified immunity-related processes and a (putative) central role of EGFR. However, this study should be viewed as a first step to elucidate the genetic background of musculoskeletal pain treatment.

Postoperative Pain and Age: A Retrospective Cohort Association Study.

BACKGROUND: As the population ages, the number of elderly people undergoing surgery increases. Literature on the incidence and intensity of postoperative pain in the elderly is conflicting. This study examines associations between age and pain-related patient reported outcomes and perioperative pain management in a dataset of surgical patients undergoing four common surgeries: spinal surgery, hip or knee replacement, or laparoscopic cholecystectomy. Based on the authors' clinical experience, they hypothesize that pain scores are lower in older patients. METHODS: In this retrospective cohort, study data were collected between 2010 and 2018 as part of the international PAIN OUT program. Patients filled out the International Pain Outcomes Questionnaire on postoperative day 1. RESULTS: A total of 11,510 patients from 26 countries, 59% female, with a mean age of 62 yr, underwent one of the aforementioned types of surgery. Large variation was detected within each age group for worst pain, yet for each surgical procedure, mean scores decreased significantly with age (mean Numeric Rating Scale range, 6.3 to 7.3; ß = -0.2 per decade; P ≤ 0.001), representing a decrease of 1.3 Numeric Rating Scale points across a lifespan. The interference of pain with activities in bed, sleep, breathing deeply or coughing, nausea, drowsiness, anxiety, helplessness, opioid administration on the ward, and wish for more pain treatment also decreases with age for two or more of the procedures. Across the procedures, patients reported being in severe pain on postoperative day one 26 to 38% of the time, and pain interfered moderately to severely with movement. CONCLUSIONS: The authors' findings indicate that postoperative pain decreases with increasing age. The change is, however, small and of questionable clinical significance. Additionally, there are still too many patients, at any age, undergoing common surgeries who suffer from moderate to severe pain, which interferes with function, supporting the need for tailoring care to the individual patient.

Relationship Between Postoperative Pain and Overall 30-Day Complications in a Broad Surgical Population: An Observational Study.

OBJECTIVE: The aim of this study was to establish the relationship between postoperative pain and 30-day postoperative complications. BACKGROUND: Only scarce data are available on the association between postoperative pain and a broad range of postoperative complications in a large heterogeneous surgical population. METHODS: Having postoperative pain was assessed in 2 ways: the movement-evoked pain score on the Numerical Rating Scale (NRS-MEP) and the patients' opinion whether the pain was acceptable or not. Outcome was the presence of a complication within 30 days after surgery. We used binary logistic regression for the total population and homogeneous subgroups to control for case complexity. Results for homogeneous subgroups were summarized in a meta-analysis using inverse variance weighting. RESULTS: In 1014 patients, 55% experienced moderate-to-severe pain on the first postoperative day. The overall complication rate was 34%. The proportion of patients experiencing postoperative complications increased from 0.25 [95% confidence interval (CI) = 0.21-0.31] for NRS-MEP = 0 to 0.45 (95% CI = 0.36-0.55) for NRS-MEP = 10. Patients who found their pain unacceptable had more complications (adjusted odds ratio = 2.17 (95% CI = 1.51-3.10; P < 0.001)). Summary effect sizes obtained with homogeneous groups were similar to those obtained from the total population who underwent very different types of surgery. CONCLUSIONS: Higher actual postoperative pain scores and unacceptable pain, even on the first postoperative day, are associated with more postoperative complications. Our findings provide important support for the centrality of personalized analgesia in modern perioperative care.

Acute pain services and postsurgical pain management in the Netherlands: a survey.

BACKGROUND: Acute postoperative pain is still inadequately managed, despite the presence of acute pain services (APSs). This study aimed to investigate the existence, structure, and responsibilities of Dutch APSs and to review the implementation of the Dutch Hospital Patient Safety Program (DHPSP). METHODS: Information was gathered by a digital questionnaire, sent to all 96 Dutch hospitals performing surgical procedures. RESULTS: Completed questionnaires were received from 80 hospitals (83%), of which 90% have an APS. Important duties of the APS are regular patient rounds, checking complex pain techniques (100%), supporting quality improvement of pain management (87%), pain education (100%), and pain research (21%). IMPLEMENTATION OF THE DHPSP: Regular in-hospital pain training is not provided in 46% of the hospitals. Thirteen percent of the hospitals offer no patient information about pain management. CONCLUSIONS: Almost all hospitals have an APS. They differ in both the way they are locally organized, along with the activities they employ. Future research needs to compare the effect of patient and nonpatient-related activities of APSs on outcomes related to pain management.

The association of hemodynamic parameters and clinical demographic variables with acute postoperative pain in female oncological breast surgery patients: A retrospective cohort study.

OBJECTIVES: Appropriate administration of intraoperative analgesia is an essential factor in care and reasonable recovery times. Inappropriate intraoperative analgesia puts the patient at risk of acute postoperative pain (APOP). The absence of an objective standard for intraoperative nociceptive monitoring complicates pain care. Heart rate (HR) and mean arterial blood pressure (MABP) have been suggested as useful parameters during general anesthesia for nociceptive monitoring. However, studies focusing on whether intraoperative heart rate variability (HRv) and mean arterial blood pressure variability (MABPv) during general anesthesia can accurately monitor nociception in patients have remained inconclusive. The current study aimed to (1) identify the association of intraoperative heart rate and blood pressure variability in patients undergoing low-risk surgery with the incidence of APOP in the immediate postoperative setting and (2) evaluate the associations of clinical demographic factors with the incidence of APOP. METHODS: A retrospective observational cohort study was conducted. The outcome was moderate-to-severe APOP, defined as a numeric rating scale score of ≥ 4. HRv, MABPv, and potential confounders, such as age, body mass index, duration of surgery, smoking, depression, preoperative use of analgesics, and type of surgery, were used as independent variables. RESULTS: Data from 764 female oncological breast surgery patients were analyzed. No statistically significant association of HRv and MABPv with APOP was found. Lower age was associated with higher odds of APOP (odds ratio [OR] 0.978, p = 0.001). Increased length of surgery (OR 1.013, p = 0.022) and a history of depression were associated with increased odds of APOP (OR 2.327, p = 0.010). The subtype of surgery was statistically significantly associated with APOP (p = 0.006). CONCLUSIONS: Our results suggest that heart rate and blood pressure variability intraoperatively, in female patients undergoing low-risk surgery, are not associated with, and thus not predictive of, APOP in the immediate postoperative setting.

A systematic review of genome-wide association studies for pain, nociception, neuropathy, and pain treatment responses.

ABSTRACT: Pain is the leading cause of disability worldwide, imposing an enormous burden on personal health and society. Pain is a multifactorial and multidimensional problem. Currently, there is (some) evidence that genetic factors could partially explain individual susceptibility to pain and interpersonal differences in pain treatment response. To better understand the underlying genetic mechanisms of pain, we systematically reviewed and summarized genome-wide association studies (GWASes) investigating the associations between genetic variants and pain/pain-related phenotypes in humans. We reviewed 57 full-text articles and identified 30 loci reported in more than 1 study. To check whether genes described in this review are associated with (other) pain phenotypes, we searched 2 pain genetic databases, Human Pain Genetics Database and Mouse Pain Genetics Database. Six GWAS-identified genes/loci were also reported in those databases, mainly involved in neurological functions and inflammation. These findings demonstrate an important contribution of genetic factors to the risk of pain and pain-related phenotypes. However, replication studies with consistent phenotype definitions and sufficient statistical power are required to validate these pain-associated genes further. Our review also highlights the need for bioinformatic tools to elucidate the function of identified genes/loci. We believe that a better understanding of the genetic background of pain will shed light on the underlying biological mechanisms of pain and benefit patients by improving the clinical management of pain.

The effect of preferred music versus disliked music on pain thresholds in healthy volunteers. An observational study.

Pain is a prevalent and debilitating healthcare problem. Since pharmacological treatments have numerous side-effects, additional treatment could be beneficial. Music has been shown to affect the pain perception and the pain threshold. The objective of this observational study was to evaluate the effect of preferred music as opposed to disliked music on pain (tolerance) thresholds and perceived pain intensity in healthy volunteers. Pain thresholds were measured via quantitative sensory testing. The volunteers were randomly assigned to either handheld pressure algometry to assess the pressure pain threshold to or electrical measurements to assess the electrical pain tolerance threshold while listening to preferred and disliked music. The pain thresholds were administered on the dorsal side of the forearm. The perceived pain intensity was assessed via a numerical rating scale, ranging from 0 (no pain) to 10 (worst pain imaginable). In total 415 volunteers were included in this study. The pressure pain threshold was assessed in 277 volunteers and in the electrical pain tolerance threshold test 138 volunteers were entered. In both groups, preferred music yielded higher pain thresholds than disliked music (P<0.001) and lower perceived pain intensity during the stimulus (P = 0.003). Moreover, the highest pain thresholds of both pressure pain and electrical pain tolerance thresholds were obtained when the preferred music was preceded by disliked music. Listening to preferred music when receiving noxious stimuli leads to higher pain thresholds and lower perceived pain scores in comparison with disliked music. Preferred music could be beneficial for patients with pain or undergoing painful procedures.

Pain predict genetics: protocol for a prospective observational study of clinical and genetic factors to predict the development of postoperative pain.

INTRODUCTION: Postoperative pain remains a challenging medical condition impacting the quality of life of every patient. Although several predictive factors for postoperative pain have been identified, an adequate prediction of postoperative pain in patients at risk has not been achieved yet.The primary objective of this study is to identify specific genetic risk factors for the development of acute and chronic postoperative pain to construct a prediction model facilitating a more personalised postoperative pain management for each individual. The secondary objectives are to build a databank enabling researchers to identify other risk factors for postoperative pain, for instance, demographic and clinical outcome indicators; provide insight into (genetic) factors that predict pharmacological pain relief; investigate the relationship between acute and chronic postoperative pain. METHODS AND ANALYSIS: In this prospective, observational study, patients who undergo elective surgery will be recruited to a sample size of approximately 10 000 patients. Postoperative acute and chronic pain outcomes will be collected through questionnaires at different time points after surgery in the follow-up of 6 months. Potential genetic, demographic and clinical risk factors for prediction model construction will be collected through blood, questionnaires and electronic health records, respectively.Genetic factors associated with acute and/or chronic postoperative pain will be identified using a genome-wide association analysis. Clinical risk factors as stated in the secondary objectives will be assessed by multivariable regression. A clinical easy-to-use prediction model will be created for postoperative pain to allow clinical use for the stratification of patients. ETHICS AND DISSEMINATION: The Institutional Review Board of the Radboud university medical centre approved the study (authorisation number: 2012/117). The results of this study will be made available through peer-reviewed scientific journals and presentations at relevant conferences, which will finally contribute to personalised postoperative pain management. TRIAL REGISTRATION NUMBER: NCT02383342.

Multimodal analgesia practices for knee and hip arthroplasties in the Netherlands. A prospective observational study from the PAIN OUT registry.

INTRODUCTION: Different multimodal pain management strategies following total hip arthroplasty(THA) and total knee arthroplasty (TKA) surgery are used in clinical practice. The optimal pain management strategy, however, remains unclear. This study aims to evaluate the differences in perioperative multimodal pain management strategies for THA and TKA in the Netherlands, and studies the associations between patient- and therapy related factors and pain outcomes. METHODS: Data from the Dutch hospitals in the PAIN OUT network were used in this study. Demographic data, pain management strategy including perioperative medication use and anesthetic techniques were recorded and used in a multivariable regression analysis to study the association with maximum pain intensity, the duration of severe pain, pain interference in bed and postoperative nausea. RESULTS: In 343 hip arthroplasty patients and 301 knee arthroplasty patients in seven hospitals, respectively 28 and 35 different combinations of analgesic regimens were used. The number of different drugs prescribed was not related to postoperative pain intensity. Female sex, younger age and spinal anesthesia were associated with higher postoperative maximum pain scores (Numeric Rating Scale (NRS) > 5). Hip surgery and ketamine use were associated with lower postoperative pain scores. The use of non-steroidal anti-inflammatory drugs (NSAIDs) and gabapentinoids, higher age, higher body mass index (BMI) and male gender were associated with less postoperative nausea (NRS < 3). CONCLUSION: In conclusion, our study demonstrated a large diversity of analgesic strategies following total joint arthroplasties in the Netherlands. Although no ideal strategy was identified, the use of NSAIDs, ketamine and dexamethasone were associated with less pain and less side effects.

Identification of preoperative predictors for acute postsurgical pain and for pain at three months after surgery: a prospective observational study.

Identifying patients at risk is the start of adequate perioperative pain management. We aimed to identify preoperative predictors for acute postsurgical pain (APSP) and for pain at 3 months after surgery to develop prediction models. In a prospective observational study, we collected preoperative predictors and the movement-evoked numerical rating scale (NRS-MEP) of postoperative pain at day 1, 2, 3, 7, week 1, 6 and 3 months after surgery from patients with a range of surgical procedures. Regression analyses of data of 2258 surgical in- and outpatients showed that independent predictors for APSP using the mean NRS-MEP over the first three days after surgery were hospital admittance, female sex, higher preoperative pain, younger age, pain catastrophizing, anxiety, higher score on functional disability, highest categories of expected pain, medical specialty, unknown wound size, and wound size > 10 cm compared to wound size ≤ 10 cm (RMSE = 2.11). For pain at three months, the only predictors were preoperative pain and a higher score on functional disability (RMSE = 1.69). Adding pain trajectories improved the prediction of pain at three months (RMSE = 1.37). Our clinically applicable prediction models can be used preoperatively to identify patients at risk, as well as in the direct postoperative period.

Translation, Cross-Cultural Adaptation, and Validation of the Pain Sensitivity Questionnaire in Dutch Healthy Volunteers.

An increased sensitivity to painful stimuli has been proposed to be related to the development of chronic pain. Therefore, assessment of individual pain sensitivity is useful in clinical practice. However, experimental pain testing may be uncomfortable for patients and requires specific equipment. The Pain Sensitivity Questionnaire (PSQ) has been developed to facilitate assessment of pain sensitivity. In this study, we aimed to translate and cross-culturally adapt the PSQ from its published German and English versions into the Dutch language and to assess validity of the PSQ in healthy volunteers. After translation and cross-cultural adaptation of the PSQ following international guidelines, we validated the PSQ in 394 healthy volunteers by comparing the PSQ-values with two different experimental pain tests: electrical pain tolerance (EPT) and pressure pain threshold (PPT). In addition, ratings of pain intensity during these tests were obtained on the numerical rating scale (NRS, 0-10). We found that the reliability of the PSQ based on internal consistency was good (Cronbach's alpha 0.90). PSQ-scores, adjusted for age and sex, were statistically significant and weakly inversely correlated to EPT (PSQ-moderate: rho = -0.24, p=0.007; PSQ-total: rho = -0.22, p=0.016). No statistically significant correlation between PSQ-scores and PPT was found. Concerning the pain scores, PSQ-scores were weakly to moderately correlated to EPT-NRS (PSQ-minor: rho = 0.21, p=0.021; PSQ-moderate: rho = 0.22, p=0.016; PSQ-total: rho = 0.23, p=0.009) as well as PPT-NRS (PSQ-minor: rho = 0.32, p < 0.001; PSQ-moderate: rho = 0.36, p < 0.001; PSQ-total: rho = 0.37, p < 0.001). Therefore, we concluded that the Dutch version of the PSQ is culturally appropriate for assessing self-reported pain sensitivity in healthy volunteers.

Prevalence and Risk Factors for Acute Postoperative Pain After Elective Orthopedic and General Surgery at a Tertiary Referral Hospital in Tanzania.

BACKGROUND: In Africa, postoperative pain management is still a major problem with a prevalence of postoperative pain in up to 95.2% of the patients. There are little data on the prevalence and potential risk factors for postoperative pain in Tanzania. Therefore, we aimed to investigate these at Kilimanjaro Christian Medical Centre in Northern Tanzania. Our goal is to optimize pain management. METHODS: A prospective cohort study was carried out from December 2016 to April 2017. Patients ≥18 years admitted for elective general or orthopedic surgery were included in the study. Demographic data were collected during a pre-operative visit, and pain was assessed with a numerical rating scale (NRS 0-10) at 4, 24, 36 and 48 hours postoperatively. A NRS >3 was considered as moderate to severe postoperative pain. Potential risk factors for postoperative pain were identified using univariate and multivariable binary logistic regression analyses. RESULTS: A total of 281 patients were included in the study. The prevalence of postoperative pain was 61%, 73%, 67% and 58% at 4, 24, 36 and 48 hours after surgery, respectively. Pethidine was the most frequently prescribed analgesic for postoperative pain management (85.1%) in the first 24 hours postoperatively; only 1% received paracetamol or diclofenac, and 13% received tramadol. In the multivariable model, general anesthesia and intra-operative analgesia (OR = 3.70, 95% CI 1.70-8.04) were significant risk factors for postoperative pain. CONCLUSION: Pain is still inadequately managed at Kilimanjaro Christian Medical Centre leading to a high prevalence (73% on the first day after surgery) of reported postoperative pain in this study. It reflects the need for adequate postoperative analgesia, especially in low- and middle-income countries. Further research identifying risk factors in larger cohorts can be performed if adequate analgesia is given.

Moving beyond pain scores: Multidimensional pain assessment is essential for adequate pain management after surgery.

BACKGROUND: Clinical experience teaches us that patients are willing to accept postoperative pain, despite high pain intensity scores. Nevertheless, relationships between pain scores and other methods of pain assessment, e.g. acceptability of pain or its interference with physical functioning, are not fully established. Our aims were to examine these relationships. METHODS: A cross-sectional study was conducted on patients who underwent major surgery between January 2008 and August 2013. Using logistic regression, we quantified the relationships between movement-evoked pain scores on the numerical rating scale (NRS-MEP) and three dichotomous dependent variables: patient's opinion on acceptability of pain (PO: acceptable or unacceptable pain); nurses' observation of patient's performance of necessary activities to expedite recovery (NO: good or bad performance); a compound measure judging the presence of the clinically desirable situation of acceptable pain associated with good patients' performance (PONO: present or not). Using Receiver Operating Characteristics (ROC) analysis, NRS cut-off points were determined such that they best discriminate between patients having one versus the other outcome for PO, NO and PONO. RESULTS: 15,394 assessments were obtained in 9,082 patients in the first three postoperative days. Nine percent of the patients had unacceptable pain while having an NRS-MEP of 0-4. An estimated 47% (95%CI = 45%-49%) of patients with an NRS-MEP of 7 described their pain as acceptable on day one. Moreover, 33% (31%-35%) performed all required physical activities, and 22% (21%-24%) combined acceptable pain with appropriate movement. NRS cut-off points for PO, NO and PONO were five, four and four, respectively, but had insufficient discriminatory power. CONCLUSIONS: Our results suggest pain management should be guided by the many dimensions of the patient's pain experience, not solely by NRS cut-off points. Future research should evaluate the impact of such multidimensional pain assessment on patients' functional outcome.

Comparison of Epidural or Regional Analgesia and Patient-controlled Analgesia: A Critical Analysis of Patient Data by the Acute Pain Service in a University Hospital.

OBJECTIVES: A large number of patients still experience pain after surgery. This study investigates if epidural or regional analgesia (continuous infusion peripheral nerve blocks [CPNB]) provide superior pain relief compared with patient-controlled analgesia (PCIA) and identifies the incidence of minor and major adverse effects or complications of these techniques. MATERIALS AND METHODS: Prospectively collected data of postoperative patients from an online data registration system of a special dedicated nurse-based acute pain service were analyzed. The acute pain service consultations were documented from January 2008 to August 2013 in a university hospital in The Netherlands. RESULTS: An analysis was applied on data of 12,399 consecutive patients. Results showed that patients who received epidural analgesia and CPNB reported lower pain scores than those who received PCIA, after undergoing the same procedures. In addition, pain scores at rest were significantly lower than movement-evoked pain scores, in abdominal surgery. Severe nausea was mostly observed in patients with PCIA and itching was most common in patients with epidural analgesia. Opioid-induced respiratory depression was found in 5 patients with PCIA. DISCUSSION: Epidural analgesia and CPNB provide better pain relief to patients than PCIA, especially in dynamic pain scores of patients. Evaluating real patient data on every patient visit is important for further improvement of the quality of postoperative pain management. Pain scores may vary widely between patients with similar surgical procedures. Therefore, we recommend that future research focuses on personalized pain measurement and pain management, to improve clinical practice more intensely.