Serum lidocaine (lignocaine) concentrations during prolonged perioperative infusion in patients undergoing breast cancer surgery: A secondary analysis of a randomised controlled trial.

Perioperative lidocaine (lignocaine) infusions are being employed with increasing frequency. The determinants of systemic lidocaine concentrations during prolonged administration are unclear. In the Long-term Outcomes after Lidocaine Infusions for PostOperative Pain (LOLIPOP) pilot trial, the impact of infusion duration and body size metrics on serum lidocaine concentrations was examined with regression models in 48 women undergoing breast cancer surgery. Lidocaine was delivered as an intravenous bolus (1.5 mg/kg) and infusion (2 mg/kg per h) intraoperatively, followed by a 12-h subcutaneous infusion (1.33 mg/kg per h) postoperatively. Dosing was based on total body weight. Wound infiltration with other long-acting local anaesthetics was permitted. Protein binding and pharmacogenomic data were also collected. Lidocaine concentrations (median (interquartile range) (range)) during prolonged administration were in the safe and potentially therapeutic range: post-anaesthesia care unit 2.16 (1.73-2.82) (1.12-6.06) µg/ml; ward 1.41 (1.22-1.75) (0.64-2.81) µg/ml. Concentrations increased non-linearly during the early intravenous phase of administration (mean rise 1.21 µg/ml per hour of infusion, P = 0.007) but reached a pseudo steady-state during the later subcutaneous phase. Higher dose rates received per kilogram of lean (P = 0.004), adjusted (P = 0.006) and ideal body weight (P = 0.009) were associated with higher steady-state concentrations. The lidocaine free fraction was unaffected by the presence of ropivacaine, and phenotypes linked to slow metabolism were infrequent. Serum lidocaine concentrations reached a pseudo steady-state during a 12-h postoperative infusion. Greater precision in steady-state concentrations can be achieved by dosing on lean body weight versus adjusted or ideal body weight (equivalent lean body weight doses: intravenous bolus 2.5 mg/kg; intravenous infusion 3.33 mg/kg per h; subcutaneous infusion 2.22 mg/kg per h.

Evaluating Adherence of Evidence-Based Post-Operative Discharge Opioid Prescribing Guidelines and Patient Outcomes Two Weeks Post-Discharge.

Introduction: There is a growing public health concern regarding inappropriate prescribing practices of discharge analgesia. A tertiary Australian hospital first developed its Postoperative Inpatients Discharge Analgesia Guidelines after an initial audit in 2015. Adherence to the guidelines were evaluated in 2016 and 2017 which show reduced compliance from 93.5% in 2016 to 83.4% in 2017. Aim: To assess ongoing compliance with the guidelines five years following its implementation and to evaluate patient outcome in terms of its clinical impact and minimization of harmful events. Methods: Prescribing data were obtained for discharge analgesic medication for 200 surgical patients from August 2019 to April 2020. Records were assessed against the hospital's Postoperative Inpatients Discharge Analgesia Guidelines and compared with equivalent data from the previous 2015, 2016, and 2017 audits. Patients were interviewed by telephone two weeks after hospital discharge. Results: Prescribing of analgesia was most compliant with overall guidelines for paracetamol (100% unchanged from 2017), followed by celecoxib (98%, up from 96% in 2017), tramadol IR (89% up from 74% in 2017), and pregabalin (89% up from 50% in 2017). Two weeks after discharge, 112 (56%) patients were surveyed and reported a mean pain-score of 2 (95% CI 1.5-2.5) out of 10 at that time. Thirty-two (29%) patients interviewed were still taking pain medication, with 17 (53%) taking medication supplied from the hospital. Seventy-eight (88%) patients stored their pain medication in an unlocked location. Among those no longer taking analgesia, 28 (43%) had unused pain medications, and only two (6%) had returned these to a community pharmacist. Conclusion: This study found that compliance with hospital discharge analgesia prescribing guidelines has increased, although there is room for improvement. Follow-up of the participants reveals high rates of unused opioids, improper storage and disposal of their pain medication.

Successful rotation from long-acting full agonist opioids to sublingual buprenorphine/naloxone using a microdosing approach.

Buprenorphine/naloxone (BPN/NX) is a first-line treatment for opioid use disorder. Conventional treatment guidelines recommend a period of opioid abstinence and the presence of moderate withdrawal before initiation to avoid precipitated withdrawal. A newer approach of "microdosing" removes this requirement and has potential benefits. We present two cases of successful induction of BPN/NX using a microdosing regimen in an inpatient withdrawal unit. Both cases did not result in precipitated withdrawal and did not necessitate prior cessation of other opioids. This case report highlights how the use of microdosing to induct BPN/NX treatment can reduce potential barriers and complications with treatment initiation.

Efficacy and Tolerability of Oral Compared with Sublingual Ketamine Lozenges as Rescue Analgesics in Adults for Acute Pain: The OSKet Trial.

BACKGROUND AND OBJECTIVE: Ketamine is an N-methyl-D-aspartate receptor (NMDA) antagonist used widely as an intravenous analgesic for treatment of acute pain. Its use as oral and sublingual analgesics is not well studied. This study aims to compare the clinical efficacy and tolerability of oral (PO) versus sublingual (SL) ketamine lozenges in adult patients with moderate-to-severe breakthrough pain. METHODS: The study had a randomized, double-blind crossover design in 23 inpatients requiring ketamine as rescue analgesics when pain scores exceeded 4/10 on the Numerical Rating Scales. Each participant received either SL 50 mg ketamine lozenge and PO placebo lozenge or SL placebo lozenge and PO 50 mg ketamine lozenge in two treatment periods with a minimum 24-h washout. Pain scores and adverse effects were documented half hourly for the first 2 h, then one hourly for the next 2 h after treatment. The time to first effect and time to meaningful pain relief were recorded. Patients reported their satisfaction and a global impression of change (GIC) at the end of each treatment period. Data were analysed using random effects regression models. RESULTS: Sixteen subjects completed both days, 7 completed 1 day. Time to first effect was 13.1 min PO versus 6.6 min SL (p = 0.069), time to meaningful pain relief was 29.4 min PO versus 10.8 min SL (p = 0.02). Pain scores were not significantly different at all time points post-treatment. Satisfaction and GIC scores were similar for both groups. Overall, adverse events occurred more often with SL administration (p = 0.02). CONCLUSIONS: Sublingual administration of ketamine led to a faster onset of pain relief (but also a higher adverse event rate), but in all other aspects treatment with ketamine given sublingually and orally produced similar analgesic effects. ACTRN: ACTRN12621000240842, 08/03/2021, retrospectively registered.

Do NSAIDs Really Interfere with Healing after Surgery?

Perioperative analgesia should be multimodal to improve pain relief, reduce opioid use and thereby adverse effects impairing recovery. Non-steroidal anti-inflammatory drugs (NSAIDs) are an important non-opioid component of this approach. However, besides potential other adverse effects, there has been a longstanding discussion on the potentially harmful effects of NSAIDs on healing after surgery and trauma. This review describes current knowledge of the effects of NSAIDs on healing of bones, cartilage, soft tissue, wounds, flaps and enteral anastomoses. Overall, animal data suggest some potentially harmful effects, but are contradictory in most areas studied. Human data are limited and of poor quality; in particular, there are only very few good randomized controlled trials (RCTs), but many cohort studies with potential for significant confounding factors influencing the results. The limited human data available are not precluding the use of NSAIDs postoperatively, in particular, short-term for less than 2 weeks. However, well-designed and large RCTs are required to permit definitive answers.

Pregabalin for neuropathic pain in primary care settings: recommendations for dosing and titration.

Pregabalin is one of the first-line treatments approved for the management of neuropathic pain (NeP). While many patients benefit from treatment with pregabalin, they are often treated with suboptimal doses, possibly due to unfamiliarity around prescribing the drug and/or side effects that can occur with up-titration. This narrative review discusses key aspects of initiating, titrating, and managing patients prescribed pregabalin therapy, and addresses concerns around driving and the potential for abuse, as well as when to seek specialist opinion. To ensure that patients derive maximum therapeutic benefit from the drug, we suggest a 'low and slow' dosing approach to limit common side effects and optimize tolerability alongside patients' expectations. When requiring titration to higher doses, we recommend initiating 'asymmetric dosing,' with the larger dose in the evening. Fully engaging patients in order for them to understand the expected timeline for efficacy and side effects (including their resolution), can also help determine the optimal titration tempo for each individual patient. The 'low and slow' approach also recognizes that patients with NeP are heterogeneous in terms of their optimal therapeutic dose of pregabalin. Hence, it is recommended that general practitioners closely monitor patients and up-titrate according to pain relief and side effects to limit suboptimal dosing or premature discontinuation.

Potential for Harm Associated with Discharge Opioids After Hospital Stay: A Systematic Review.

INTRODUCTION: Mounting evidence highlights the adverse effects of opioids. In spite of this, clinicians often prescribe excessive number of discharge opioids. The aim of this systematic review is to analyse the potential of harm from discharge opioids after inpatient care including excessive prescribing of discharge opioids, improper handling of unused opioids, and unintentional chronic opioid use. METHODS: A systematic search of MEDLINE, EMBASE, and Cochrane databases at the cut-off date of 1 December 2018 was conducted for studies reporting on various harmful effects of discharge opioids after inpatient care. RESULTS: Twenty-eight studies analysed the potential for harm of discharge opioids after various inpatient surgical or medical procedures. On average, patients consumed only 38% of the prescribed discharge opioid pills. Seventy-two percent of patients stored their leftover opioids in an unlocked location, and failure to dispose of unused opioids was reported in 94.5% of patients. These factors may contribute to the increasing rate of opioid misuse and diversion in the community. In addition, discharge opioids contribute to prolonged opioid use; the proportion of opioid-naïve patients still consuming opioids 3 months after hospital discharge is 10.4%. At 6 months, the proportion is 4.4%. Unintentional chronic opioid use is associated with pre-operative opioid use, history of substance use, specific comorbidities, and invasive surgical procedures. CONCLUSION: This systematic review suggests that the current discharge opioid prescribing practices can be improved. Lack of patient education regarding storage and disposal of opioids also contributes to the increasing rate of opioid misuse, diversion, and unintended long-term use. More high-quality research with comparable outcomes is needed. Evidence-based hospital guidelines and public health policies are needed to improve opioid stewardship.

The effect of guideline implementation on discharge analgesia prescribing (two years on).

The provision of appropriate discharge analgesia can be challenging and is often prescribed by some of the most junior members of the medical team. Opioid abuse has been considered a growing public health crisis and physician overprescribing is a major contributor. In 2015 an initial audit of discharge analgesia at the Royal Perth Hospital led to the development of discharge analgesia guidelines. Compliance with these guidelines was assessed by a follow-up audit in 2016, which showed improved practice. This audit assesses discharge analgesia prescribing practices two years following guideline implementation. Dispensing data were obtained for analgesic medication over a three-month period from April to July 2017 and 100 unique patients were chosen using computer generated randomisation. Patients' medical records were assessed against the hospital's Postoperative Inpatients Discharge Analgesia Guidelines. The data collected were then compared with equivalent data from the previous 2015 and 2016 audits. Overall 83.4% of the 170 discharge analgesia prescriptions written were compliant with guidelines. The highest overall compliance rates were achieved for paracetamol (100%, up from 95.9% in 2016), celecoxib (96%, down from 100% in 2016), and oxycodone immediate release (IR) (74%, down from 88.9% in 2016). The quantity of oxycodone IR given on discharge complied with quantity guidelines in only 56% of cases. Overall there has been a significant and sustained improvement in appropriateness of discharge analgesia prescribing since 2015, though the results from 2017 show less compliance than 2016 and that achieving compliance with quantity guidelines is an ongoing challenge. This demonstrates the challenge of obtaining high adherence to guidelines over a longer time period.

The IASP classification of chronic pain for ICD-11: chronic postsurgical or posttraumatic pain.

Chronic pain after tissue trauma is frequent and may have a lasting impact on the functioning and quality of life of the affected person. Despite this, chronic postsurgical and posttraumatic pain is underrecognised and, consequently, undertreated. It is not represented in the current International Classification of Diseases (ICD-10). This article describes the new classification of chronic postsurgical and posttraumatic pain for ICD-11. Chronic postsurgical or posttraumatic pain is defined as chronic pain that develops or increases in intensity after a surgical procedure or a tissue injury and persists beyond the healing process, ie, at least 3 months after the surgery or tissue trauma. In the classification, it is distinguished between tissue trauma arising from a controlled procedure in the delivery of health care (surgery) and forms of uncontrolled accidental damage (other traumas). In both sections, the most frequent conditions are included. This provides diagnostic codes for chronic pain conditions that persist after the initial tissue trauma has healed and that require specific treatment and management. It is expected that the representation of chronic postsurgical and posttraumatic pain in ICD-11 furthers identification, diagnosis, and treatment of these pain states. Even more importantly, it will make the diagnosis of chronic posttraumatic or postsurgical pain statistically visible and, it is hoped, stimulate research into these pain syndromes.

Pilot field testing of the chronic pain classification for ICD-11: the results of ecological coding.

BACKGROUND: A task force of the International Association for the Study of Pain (IASP) has developed a classification of chronic pain for the ICD-11 consisting of seven major categories. The objective was to test whether the proposed categories were exhaustive and mutually exclusive. In addition, the perceived utility of the diagnoses and the raters' subjective diagnostic certainty were to be assessed. METHODS: Five independent pain centers in three continents coded 507 consecutive patients. The raters received the definitions for the main diagnostic categories of the proposed classification and were asked to allocate diagnostic categories to each patient. In addition, they were asked to indicate how useful they judged the diagnosis to be from 0 (not at all) to 3 (completely) and how confident they were in their category allocation. RESULTS: The two largest groups of patients were coded as either chronic primary pain or chronic secondary musculoskeletal pain. Of the 507 patients coded, 3.0% had chronic pain not fitting any of the proposed categories (97% exhaustiveness), 20.1% received more than one diagnosis. After adjusting for double coding due to technical reasons, 2.0% of cases remained (98% uniqueness). The mean perceived utility was 1.9 ± 1.0, the mean diagnostic confidence was 2.0 ± 1.0. CONCLUSIONS: The categories proved exhaustive with few cases being classified as unspecified chronic pain, and they showed themselves to be mutually exclusive. The categories were regarded as useful with particularly high ratings for the newly introduced categories (chronic cancer-related pain among others). The confidence in allocating the diagnoses was good although no training regarding the ICD-11 categories had been possible at this stage of the development.

Procedure-Specific Pain Management (PROSPECT) - An update.

Post-operative pain management protocols may be optimised by examining procedure-specific evidence and outcomes. This recognition led to the formation of the PROcedure-SPECific Pain ManagemenT (PROSPECT) collaboration of anaesthesiologists and surgeons. The aim of PROSPECT is to provide practical and evidence-based recommendations to prevent and treat post-operative pain after specific surgical procedures, thereby overcoming the limitations of generic, non-specific guidelines. Updates in the methodology of PROSPECT in 2017 have placed an increased emphasis on the clinical relevance of studies, including a focus on interventions in the context of multimodal analgesia strategies and consideration of risks and benefits of interventions in specific surgical settings. Evidence-based reviews of analgesic measures, including advice on surgical techniques and adjuvants after diverse surgical procedures, have been completed by the PROSPECT collaboration and are accessible on the website (www.postoppain.org) and published in the peer-reviewed literature. These reviews continue to identify significant gaps in clinically relevant research on post-operative analgesia and are possibly leading to a closing of some of these gaps.

Content validation of a Critical Appraisal Tool for Reviewing Analgesia Studies (CATRAS) involving subjects incapable of self-reporting pain.

INTRODUCTION: This article reports the content validation of a Critical Appraisal Tool designed to Review the quality of Analgesia Studies (CATRAS) involving subjects incapable of self-reporting pain and provide guidance as to the strengths and weakness of findings. The CATRAS quality items encompass 3 domains: level of evidence, methodological soundness, and grading of the pain assessment tool. OBJECTIVES: To validate a critical appraisal tool for reviewing analgesia studies involving subjects incapable of self-reporting pain. METHODS: Content validation was achieved using Delphi methodology through panel consensus. A panel of 6 experts reviewed the CATRAS in 3 rounds and quantitatively rated the relevance of the instrument and each of its quality items to their respective domains. RESULTS: Content validation was achieved for each item of the CATRAS and the tool as a whole. Item-level content validity index and kappa coefficient were at least greater than 0.83 and 0.81, respectively, for all items except for one item in domain 2 that was later removed. Scale-level content validity index was 97% (excellent content validity). CONCLUSIONS: This 67-item critical appraisal tool may enable critical and quantitative assessment of the quality of individual analgesia trials involving subjects incapable of self-reporting pain for use in systematic reviews and meta-analysis studies.

Does perioperative ketamine have a role in the prevention of chronic postsurgical pain: the ROCKet trial.

Identifying operations and individuals with an increased risk of chronic postsurgical pain (CPSP) has led to significant interest in interventions with the potential to achieve primary prevention of this condition. Pharmacological prevention remains controversial with a Cochrane review identifying perioperative ketamine administration as the only intervention with possible benefit although, with only small, heterogeneous studies, the authors called for a large randomised controlled trial (RCT) to confirm the validity of this result. In response to these data, a group of researchers from Australia and Hong Kong designed the ROCKet trial - Reduction Of Chronic Post-surgical Pain with Ketamine, endorsed by the Australian and New Zealand College of Anaesthetists (ANZCA) Clinical Trials Network (CTN).

The safety profile of parecoxib for the treatment of postoperative pain: a pooled analysis of 28 randomized, double-blind, placebo-controlled clinical trials and a review of over 10 years of postauthorization data.

BACKGROUND: Nonselective, nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors are associated with safety issues including cardiovascular, renal, and gastrointestinal (GI) events. OBJECTIVE: To examine the safety of parecoxib, a COX-2 inhibitor, for the management of postoperative pain. DESIGN: Pooled analysis of 28 placebo-controlled trials of parecoxib and review of postauthorization safety data. MAIN OUTCOME MEASURES: Prespecified safety events commonly associated with COX-2 inhibitors and/or NSAIDs. In the clinical trial analysis, the frequency of each event was compared between treatment groups using a chi-square test. In the postauthorization review, the number of confirmed cases, along with outcome, was presented for each event. RESULTS: In the clinical trial analysis, GI-related events occurred in ~0.2% of patients in the parecoxib and placebo groups. Renal failure and impairment was similar between parecoxib (1.0%) and placebo (0.9%). The occurrence of arterial (parecoxib=0.3%; placebo=0.2%) and venous (parecoxib=0.2%; placebo=0.1%) cardiovascular embolic and thrombotic events was similar between groups. Hypersensitivity reactions including anaphylactic reactions (parecoxib=8.7%; placebo=8.6%), hypotension (parecoxib=2.6%; placebo=2.1%), angioedema (parecoxib=2.5%; placebo=2.8%), and severe cutaneous adverse reactions (0% in both groups) were similar between groups. Incision site or other skin/tissue infections occurred in <0.1% of patients in both groups. The occurrence of these events (total reports/serious reports) in the postauthorization database, based on 69,567,300 units of parecoxib, was as follows: GI ulceration-related events (35/35), renal failure and impairment (77/68), cardiovascular embolic and thrombotic events (66/64), hypersensitivity reactions including hypotension-related events (32/25) and severe cutaneous adverse events (17/17), and masking signs of inflammation (18/18). A majority of reported outcomes were classified as recovered or recovering. CONCLUSIONS: Potentially serious safety events occur infrequently with parecoxib, which high-lights its safety in patients with postoperative pain.

Fentanyl Formulations in the Management of Pain: An Update.

Fentanyl is a synthetic, highly selective opioid with many desirable physicochemical properties, including a high lipophilicity and predictable pharmacokinetics. These properties have an established record in the management of pain in a variety of settings, particularly acute pain and breakthrough cancer pain. Fentanyl was initially developed for parenteral use; however, this is invasive and impractical in the outpatient setting. Unfortunately, the high first-pass metabolism of fentanyl makes oral formulations unfeasible. However, its high lipophilicity allows fentanyl to be absorbed via a number of other routes. Thus new formulations were designed to allow non-invasive methods of administration. Transmucosal and transdermal fentanyl formulations are well established, and have proven useful in the settings of breakthrough cancer pain, emergencies and in the paediatric population. The iontophoretic transdermal system was developed to provide a needle-free system of delivering bolus doses of fentanyl on demand, a novel way of delivering patient-controlled opioid analgesia. Transpulmonary administration of fentanyl remains experimental. The aim of this review is to provide an update on current non-parenteral fentanyl formulations, with attention to their particular pharmacokinetics and features relevant to clinical use in pain management.

Effect of Concomitant Pain Medications on Response to Pregabalin in Patients with Postherpetic Neuralgia or Spinal Cord Injury-Related Neuropathic Pain.

BACKGROUND: Patients with neuropathic pain (NeP) often receive combination therapy with multiple agents in the hopes of improving both pain and any comorbidities that may be present. While pregabalin is often recommended as a first-line treatment of NeP, few studies have examined the effects of concomitant medications on the efficacy of pregabalin. OBJECTIVE: To examine the effects of concomitant medications on the efficacy and safety of pregabalin for the treatment of NeP. STUDY DESIGN: Data were derived from 7 randomized placebo-controlled trials of pregabalin (150, 300, 600, and flexible 150 - 600 mg/d) for the treatment of postherpetic neuralgia (PHN) and 2 randomized placebo-controlled trials for the treatment of NeP due to spinal cord injury (SCI-NeP). On each day, patients rated the severity of their pain and pain-related sleep interference (PRSI) over the previous 24 hours on a scale from 0 to 10, with higher scores indicating greater severity. Patients were also continually monitored for the occurrence of adverse events. SETTING: A pooled retrospective analyses of data from randomized clinical trials. METHODS: Changes from baseline in mean weekly pain and PRSI scores were compared between patients who received concomitant NeP medications and patients who did not receive concomitant NeP medications. Results of these comparisons are presented separately for the PHN (through 4, 8, and 12 weeks) and SCI-NeP (through 12 weeks) cohorts. Common adverse events are also presented for each treatment group. RESULTS: Pregabalin significantly improved both pain and PRSI scores relative to placebo at most dose levels and time points examined. Notably, little difference was observed in the extent of therapeutic response to pregabalin between patients who received concomitant NeP medications and patients who did not receive concomitant NeP medications. Additionally, the profile of treatment-emergent adverse events appeared to be largely unaffected by the use of concomitant NeP medications in the pooled patient population. LIMITATIONS: Our analysis is limited in that the original trials of pregabalin were not powered to examine the effects of concomitant NeP medications. CONCLUSIONS: The data presented here demonstrate that therapeutic response to pregabalin and the occurrence of adverse events in patients with NeP are generally unaffected by the concurrent use of other NeP medications.Trial Registration numbers: NCT00159666; NCT00301223; NCT00407745Key words: Pregabalin, neuropathic pain, pain-related sleep interference, concomitant medications, postherpetic neuralgia, spinal cord injury, efficacy, safety.