Genome-wide association study of nociceptive musculoskeletal pain treatment response in UK Biobank

Drug treatment for nociceptive musculoskeletal pain (NMP) follows a three-step analgesic ladder proposed by the World Health Organization (WHO), starting from non-steroidal anti-inflammatory drugs (NSAIDs), followed by weak or strong opioids until the pain is under control. However, effective pain treatment is challenged by inter-individual differences, and unsatisfied pain treatment response (PTR) rates ranging from 34 to 79% in those suffering from NMP. To investigate the underlying genetic component of PTR, we performed a genome-wide association study (GWAS) in ~ 23,000 participants with NMP from the UK Biobank. In our primary analysis, we compared NSAID vs. opioid users as a reflection of (non)response to NSAIDs, adjusting for age, sex, BMI, population substructure, and study-specific covariates. One genome-wide significant hit was identified in an intergenic region on chromosome 4, rs549224715 (P = 3.88x10-8), and seven signals pass the suggestively significant threshold (P < 1x10-6). All identified loci were in non-coding regions, but most variants showed potential regulatory functions. SNPs in LD (r2 > 0.6) with the lead SNPs passing the nominal significant threshold (P < 0.05) were mapped to 28 target genes in FUMA. Eight of these 28 genes are involved in processes linked to neuropathic pain and musculoskeletal development. Pathway and network analyses with Ingenuity resulted in the identification of immunity-related processes and a (putative) central role of EGFR. Genetic correlation analysis including 596 traits resulted in the identification of 67 nominally significant (P < 0.05) genetic correlations, and these traits were significantly enriched for chronic pain and socioeconomic status traits (P = 3.35 x 10-12). Additionally, we conducted a subtype GWAS for inflammatory NMP and a secondary GWAS for participants with NMP disease history, but no significant hits or overlap with the primary analysis were observed. Overall, we identified one genome-wide significant association in this first GWAS focusing on pain treatment using the analgesic ladder as phenotype. However, we realize that this study lacked power and should be viewed as a first step to elucidate the genetic background of NMP treatment.

4 clinical cases of patients in whom the combination of chondroitin and glucosamine should be considered

Osteoarthritis is a chronic disease that affects mainly the elderly. The primary form of therapy is analgesic pharmacotherapy in accordance with the analgesic ladder. Another, still controversial, method is the administration of symptomatic slow-acting drugs for osteoarthritis, the main advantage of which is that they are practically devoid of toxicity. A recent review of papers on the use of this group of drugs has shown that the most potent modifying effect has the combination of glucosamine and chondroitin, which synergistically change the metabolism of the articular cartilage. In this article, we present four clinical cases in which the combination of glucosamine and chondroitin was effective.

Changes in Plasma Beta-Endorphin Levels in Stage III–IV Nasopharyngeal Carcinoma Patients Post World Health Organization 3-Step Analgesic Ladder Therapy

Introduction Nasopharyngeal carcinoma (NPC) is the most common malignancy in the field of otorhinolaryngology, and chronic pain is identical with this malignancy. Pain therapy according to World Health Organization (WHO) recommendations is WHO 3-step analgesic ladder. Pain is subjective and related to the function of beta-endorphin hormone. Objective Analyzing the relationship between the degree of pain and plasma endorphin levels in stage III–IV NPC patients before and after the administration of WHO 3-step analgesic ladder. Materials and Methods The study design used pretest and posttest without control design. Participants were given WHO 3-step analgesic ladder therapy for 3 days. The participants then rated the pain scale using the visual analog scale (VAS) and plasma beta-endorphin levels in venous blood. The statistical test used the dependent t-test, Wilcoxon test, and Spearman test with p < 0.05, confidence interval: 95%. Results There were 14 stage-III NPC patients with moderate pain (78.57%) and 31 stage-IV NPC participants had moderate pain (83.87%; p = 0.071). The VAS value in the moderate pain group before and after therapy was 82.22 and 66.67%, respectively (p < 0.001). The values of plasma beta-endorphin levels before and after therapy were 74.89 ± 69.12 and 72.49 ± 75.53 pg/mL, respectively (p = 0.647). Plasma beta-endorphin levels were −19.20 ± 37.72 pg/mL (mild pain), −4.76 ± 35.30 pg/mL (moderate pain), and −21.67 ± 6.27 pg/mL (severe pain; p = 0.717). Conclusion Pain levels in advanced NPC patients have decreased after the therapy, but plasma beta-endorphin levels have no significant difference.

421 Closed loop analgesia audit, a Single Centre Experience in Raigmore Hospital, Inverness, Scotland

Aim Assess are we following the analgesic step ladder accurately and if not are the reasons clear and documented? Method A closed-loop audit performed on the use of the WHO Analgesic ladder in surgical patients. We looked at the compliance of the analgesic ladder and are the reasons documented or explained when the ladder is not followed. The data was collated, analysed, and presented at an audit meeting. We then implemented changes in the form of educational sessions and information leaflets sharing, as well as email reminders among staff. Post-implementation showed an improvement in the documentation when the analgesic ladder was not followed. Results A total of 103 surgical patients were included. Prior to the implementation of interventions, 83.3% of patients had analgesia prescribed following the analgesic ladder. Of those remaining patients who had analgesia prescribed not according to the analgesic ladder, only 50% documented the indications and reasons. Post-implementation, the analgesic ladder compliance dropped to 50.9% with documentation improvement to 56%. Conclusions All surgical patients have prescribed analgesia when needed. Though WHO ladder compliance has shown reduction compared to the first data sample, the reasons are clinically justified, and improvements have been shown in documentation after intervention though there is still room for improvement for documentation. This is perhaps surgical teams are more aware of the choice of analgesia used post-intervention while taking the analgesic ladder into consideration. Stepwise multimodal analgesia prescribing will improve analgesic effect hence improves post-operative recovery hence reduce the length of hospital stay as part of the ERAS protocol.

695 Analgesic Ladder Compliance by Junior Doctors on Surgical Wards

Introduction Analgesia makes up an integral part of the management of the surgical patient. The World Health Organisation “analgesic ladder” details the escalation of analgesics from paracetamol through to opiates. Over the past decade, opiate prescriptions in the UK have increased by 22% to 40.5 million a year. Method Drug charts were reviewed on the surgical wards prior to presentation of the trust guidelines to surgical juniors. Inclusion criteria was non-cancerous adults who were not on chronic pain medications and had no known allergy or contraindication to NSAIDs. F1/2s were also surveyed on their knowledge of the trust guidelines Results Compliance improved in weak opioids (10.6%) and oramorph (19.1%) but fell in NSAIDs (-2.9%). Paracetamol was prescribed appropriately in 100%. 78% of doctors admitted to not having read the trust guidelines and 89% to not following them despite 100% being aware of the concept of the analgesic ladder. Conclusions We saw a tangible improvement in opiate prescribing by surgical juniors. However, the overall compliance to the analgesic ladder is still relatively poor given the doctors are all aware of the concept of the analgesic ladder, suggesting appropriate analgesic prescribing does not rank as highly in importance as it should.

Introduction of a modified analgesic ladder in the emergency department: Effect on oxycodone use for back pain

Objective: The aim of this study was to assess the introduction of an analgesic ladder and targeted education on oxycodone use for patients presenting to the emergency department (ED).Design: A retrospective pre-post implementation study was conducted. Data were extracted for patients presenting from June to July 2016 (preintervention) and June to July 2017 (post-intervention).Setting: The EDs of a major metropolitan health service and an affiliated community-based hospital.Participants: Patients with back pain where nonpharmacological interventions such as mobilization and physiotherapy are recommended as the mainstay of treatment.Interventions: A modified analgesic ladder introduced in May 2017. The ladder promoted the use of simple analgesics such as paracetamol and nonsteroidal anti-inflammatory drug (NSAIDs) prior to opioids and tramadol in preference to oxycodone in selected patients.Main outcome measure(s): The proportion of patients prescribed oxycodone and total doses administered.Results: There were 107 patients pre and 107 post-intervention included in this study. After implementation of the analgesic ladder, 78 (72.9 percent) preintervention patients and 55 (51.4 percent) post-intervention patients received oxycodone in ED (p = 0.001). The median oxycodone doses administered in the ED was 14 mg (interquartile range: 5-20 mg) and 5 mg (interquartile range: 5-10 mg; p 0.001), respectively. On discharge from hospital, a prescription for oxycodone was issued for 36 (33.6 percent) patients preintervention and 26 (24.3 percent) patients post-intervention (p = 0.13). Conclusions: Among patients with back pain, implementation of a modified analgesic ladder was associated with a statistically significant but modest reduction in oxycodone prescription. Consideration of multifaceted interventions to produce major and sustained changes in opioid prescribing is required.

Independent Research on Cancer Pain Management in the Setting of Early Palliative Care: A Flywheel to Counteract General Opioid Misuse and Abuse

The increased recognition of the high prevalence and important burden of cancer pain and the documentation of a large proportion of patients receiving inadequate analgesic treatment should have reinforced the need for evidence-based recommendations. The World health Organization (WHO) guidelines on cancer pain management—or palliative care—are traditionally based on a sequential, three-step, analgesic ladder according to pain intensity: nonopioids (paracetamol or nonsteroidal anti-inflammatory drugs) to mild pain in step I; weak opioids (eg, codeine or tramadol) to mild-moderate pain in step II; and strong opioids to moderate-severe pain in step. III. Despite the widespread use of this ladder, unrelieved pain continues to be a substantial concern in one third of patients with either solid or hematologic malignancies. The sequential WHO analgesic ladder, and in particular, the usefulness of step II opioids have been questioned but there are no universally used guidelines for the treatment of pain in patients with advanced cancer and not all guideline recommendations are evidence-based. The American Society of Clinical Oncology and the European Society of Medical Oncology have recommended the implementation of early palliative care (EPC), which is a novel model of care, consisting of delivering dedicated palliative service concurrent with active treatment as early as possible in the cancer disease trajectory. Improvement in cancer pain management is one of the several important positive effects following EPC interventions. Independent well-designed research studies on pharmacological interventions on cancer pain, especially in the EPC setting are warranted and may contribute to spur research initiatives to investigate the poorly addressed issues of pain management in non cancer patients.

Analgesic Equivalent Days: A Novel Approach to Assess Chronic Analgesic Use in the Population

Introduction: There is no simple method to compare the use of multiple analgesic products in mild to moderate pain. The aim of this study is to validate a new tool to assess analgesic use. Methods: A measure of Analgesic Equivalent Days (AEDs) was developed using Defined Daily Doses (DDD) and the total mg of each analgesic over a 12 month period. Comparisons were made using analgesic class and all analgesics combined. Results: In a group of newly initiated patients with Osteoarthritis, AEDs values indicated that patients received around 70% of AEDs from paracetamol, 20% from NSAIDs and 10% from opioids. AEDs were similar between the two paracetamol formulations. However, one group took 8 more AEDs of NSAIDs, while the other group took 7 more AEDs of opioids. Conclusion: Even though the total AED scores, there was no significant difference in total analgesic use between the two formulations, differences were found among the analgesic classes. The AED methodology was sufficiently sensitive to demonstrate that one group of patients climbed higher up the analgesic ladder than the other group. AEDs are easy to calculate and seem to produce valid outcomes from both a statistical and a clinically meaningful perspective.