Post‐operative analgesic effects of paracetamol,NSAIDs, glucocorticoids,gabapentinoids and their combinations: a topical review

In contemporary post‐operative pain management, patients are most often treated with combinations of non‐opioid analgesics, to enhance pain relief and to reduce opioid requirements and opioid‐related adverse effects. A diversity of combinations is currently employed in clinical practice, and no well‐documented ‘gold standards’ exist. The aim of the present topical, narrative review is to provide an update of the evidence for post‐operative analgesic efficacy with the most commonly used, systemic non‐opioid drugs, paracetamol, non‐steroidal anti‐inflammatory drugs (NSAIDs)/COX‐2 antagonists, glucocorticoids, gabapentinoids, and combinations of these. The review is based on data from previous systematic reviews with meta‐analyses, investigating effects of non‐opioid analgesics on pain, opioid‐requirements, and opioid‐related adverse effects. Paracetamol, NSAIDs, COX‐2 antagonists, and gabapentin reduced 24 h post‐operative morphine requirements with 6.3 (95% confidence interval: 3.7 to 9.0) mg, 10.2 (8.7, 11.7) mg, 10.9 (9.1, 12.8) mg, and ≥ 13 mg, respectively, when administered as monotherapy. The opioid‐sparing effect of glucocorticoids was less convincing, 2.33 (0.26, 4.39) mg morphine/24 h. Trials of pregabalin > 300 mg/day indicated a morphine‐sparing effect of 13.4 (4, 22.8) mg morphine/24 h. Notably, though, the available evidence for additive or synergistic effects of most combination regimens was sparse or lacking. Paracetamol, NSAIDs, selective COX‐2 antagonists, and gabapentin all seem to have well‐documented, clinically relevant analgesic properties. The analgesic effects of glucocorticoids and pregabalin await further clarification. Combination regimens are sparsely documented and should be further investigated in future studies.     

Nonsteroidal antiinflammatory drugs for postoperative pain management after lumbar spine surgery: a meta-analysis of randomized controlled trials

OBJECT: The authors undertook this meta-analysis to assess the efficacy and safety of nonsteroidal antiinflammatory drugs (NSAIDs) in addition to opioid analgesics on perioperative pain management in lumbar spine surgery. METHODS: The authors searched MEDLINE, Excerpta Medica (EMBASE), The Cochrane Library, CINAHL, PsycINFO, Allied and Complementary Medicine (AMED), and Science Citation Index Expanded databases. In addition, they manually searched key journals and their references. They included randomized trials comparing the use of NSAIDs in addition to opioid analgesics versus opioid analgesics alone after posterior lumbar discectomy, laminectomy, or spinal fusion. Two independent reviewers performed an assessment of the quality of the methods. RESULTS: Seventeen studies comprising 400 patients who received NSAIDs in addition to opioid analgesics and 389 patients receiving opioid analgesics alone were included. Patients receiving NSAIDs in addition to opioid analgesics had lower pain scores and consumed fewer opioids than the group receiving opioid analgesics alone. There was no difference in the incidence of adverse effects. CONCLUSIONS: This meta-analysis provides evidence that the addition of NSAIDs to opioid analgesics in lumbar spine surgery provided better pain control than opioid analgesics alone.     

Association between postoperative opioid use and outpatient surgical adverse events

Background

Opioid-related adverse drug events are common following inpatient surgical procedures. Little is known about opioid prescribing after outpatient surgical procedures and if opioid use is associated with short term risks of outpatient surgical adverse events (AEs).

Analgetikakombinationen zur postoperativen Schmerztherapie

BACKGROUND: The supplementation of an opioid by a non-opioid analgesic is a widely accepted technique for the treatment of postoperative pain. However, it is still unclear whether a combination of different non-opioids has an advantage in terms of an improved analgesia and/or a reduction of the opioid-related adverse effects. METHODOLOGY: A systematic analysis of the literature was performed searching for randomized, controlled trials studying the effects of a combination of two non-opioid analgesics in order to reduce postoperative opioid requirements and/or postoperative pain. Significant reduction of the postoperative opioid requirement and/or postoperative pain were defined as main rating criteria. To facilitate comparisons between the trials, the relative (proportional) reduction of postoperative opioid administration and the relative reduction of postoperative pain were calculated on defined pain scales. RESULTS: A total of 25 trials were identified, mainly studies comparing non-steroidal anti-inflammatory drugs (NSAIDs) with paracetamol. Only 3 trials found a statistically improved analgesic efficacy and 15 studies did not show any relevant improvement or the combination group was only significantly superior to one of the groups receiving monotherapy. A further seven studies could not be evaluated due to methodological issues. There was no evidence for a significant reduction of opioid-induced adverse effects. CONCLUSION: A combination of non-opioid analgesics, in particular NSAIDs with paracetamol, cannot be recommended at present due to the lack of data showing improved effectiveness.     

Single-dose intravenous paracetamol or propacetamol for prevention or treatment of postoperative pain: a systematic review and meta-analysis

Paracetamol is the most commonly prescribed analgesic for the treatment of acute pain. The efficacy and safety of i.v. formulations of paracetamol is unclear. We performed a systematic search (multiple databases, bibliographies, any language, to May 2010) for single-dose, randomized, controlled clinical trials of propacetamol or i.v. paracetamol for acute postoperative pain in adults or children. Thirty-six studies involving 3896 patients were included. For the primary outcome, 37% of patients (240/367) receiving propacetamol or i.v. paracetamol experienced at least 50% pain relief over 4 h compared with 16% (68/527) receiving placebo (number needed to treat=4.0; 95% confidence interval, 3.5-4.8). The proportion of patients in propacetamol or i.v. paracetamol groups experiencing at least 50% pain relief diminished over 6 h. Patients receiving propacetamol or paracetamol required 30% less opioid over 4 h and 16% less opioid over 6 h than those receiving placebo. However, this did not translate to a reduction in opioid-induced adverse events (AEs). Similar comparisons between propacetamol or i.v. paracetamol and active comparators were either not statistically significant, not clinically significant, or both. AEs occurred at similar rates with propacetamol or i.v. paracetamol and placebo. However, pain on infusion occurred more frequently in those receiving propacetamol compared with placebo (23% vs 1%). A single dose of either propacetamol or i.v. paracetamol provides around 4 h of effective analgesia for about 37% of patients with acute postoperative pain. Both formulations are associated with few AEs, although patients receiving propacetamol have a higher incidence of pain on infusion.     

Evaluation of the safety and efficiency of the dorsal slit and sleeve methods of male circumcision provided by physicians and clinical officers in Rakai, Uganda

Study Type – Therapy (outcomes research) Level of Evidence 2c What’s known on the subject? and What does the study add? MC reduces heterosexual acquisition of HIV in men for safe and efficient rapid scale‐up; task shifting from physicians to clinical officers is safe and the use of bipolar cautery will reduce operative time, but is associated with higher adverse events.

OBJECTIVE

? To assess the safety and efficiency of the dorsal slit and sleeve male circumcision (MC) procedures performed by physicians and clinical officers (COs).

PATIENTS AND METHODS

? We evaluated the time required for the MC procedure (efficiency) and moderate/severe adverse events (AEs) for MC (safety) by trained physicians and COs using the sleeve and dorsal slit MC methods in a service programme. ? Univariate and multiple regressions with robust variance estimation were used to assess factors associated with operative duration (linear) and AEs (logistic).

RESULTS

? Six physicians and eight COs conducted 1934 and 3218 MCs, respectively; there were 2471 dorsal slit and 2681 sleeve MC procedures. The overall mean operative duration was 33 min for newly trained providers, whichdecreased to ≈20 min after ≈100 MCs. ? The adjusted mean operative duration for dorsal slit MC was significantly shorter than that for the sleeve MC method (Δ? 2.7 min, P < 0.001). ? The operative duration was longer for COs than physicians for the sleeve procedure, but not the dorsal slit procedure; however this difference reduced with increasing numbers of MCs completed. ? The unadjusted AE rates were 0.6% for dorsal slit MC and 1.4% for the sleeve method (P= 0.006) and 1.5% for physicians and 0.68% for COs (P= 0.003); however, there were no significant differences after multivariate adjustment. ? Use of bipolar cautery significantly reduced operative duration (Δ? 4.0 min, P= 0.008), but was associated with higher AE rates (adjusted odds ratio 2.13, 95% confidence interval 1.26–3.61, P= 0.005).

CONCLUSION

? The dorsal slit MC method is faster than sleeve resection, and can be safely performed by non‐physicians; however, use of bipolar cautery may be inadvisable in this setting.     

Paracetamol and selective and non-selective non-steroidal anti-inflammatory drugs for the reduction in morphine-related side-effects after major surgery: a systematic review

Non-opioid analgesics, paracetamol, non-steroidal anti-inflammatory drugs (NSAIDs), or cyclo-oxygenase 2 (COX-2) inhibitors are often given along with morphine as part of multimodal analgesia after major surgery. We have undertaken a systematic review and a mixed treatment comparison (MTC) analysis in order to determine explicitly which class of non-opioid analgesic, paracetamol, NSAIDs, or COX-2 inhibitors is the most effective in reducing morphine consumption and morphine-related adverse effects. Sixty relevant studies were identified. The MTC found that when paracetamol, NSAIDs, or COX-2 inhibitors were added to patient-controlled analgesia (PCA) morphine, there was a statistically significant reduction in morphine consumption: paracetamol [mean difference (MD) -6.34 mg; 95% credibility interval (CrI) -9.02, -3.65], NSAIDs (MD -10.18; 95% CrI -11.65, -8.72), and COX-2 inhibitors (MD -10.92; 95% CrI -12.77, -9.08). There was a significant reduction in nausea and postoperative nausea and vomiting with NSAIDs compared with placebo (odds ratio 0.70; 95% CrI 0.53, 0.88) but not for paracetamol or COX-2 inhibitors, nor for NSAIDs compared with paracetamol or COX-2 inhibitors. There was no statistically significant difference in sedation between any intervention and comparator. On the basis of six trials (n=695), 2.4% of participants receiving an NSAID experienced surgical-related bleeding compared with 0.4% with placebo. The MTC found that there is a decrease in 24 h morphine consumption when paracetamol, NSAID, or COX-2 inhibitors are given in addition to PCA morphine after surgery, with no clear difference between them. Similarly, the benefits in terms of reduction in morphine-related adverse effects do not strongly favour one of the three non-opioid analgesics.     

Multimodal analgesia for postoperative pain control.

Pain is one of the main postoperative adverse outcomes. Single analgesics, either opioid or nonsteroidal antiinflammatory drugs (NSAIDs), are not able to provide effective pain relief without side effects such as nausea, vomiting, sedation, or bleeding. A majority of double or single-blind studies investigating the use of NSAIDs and opioid analgesics with or without local anesthetic infiltration showed that patients experience lower pain scores, need fewer analgesics, and have a prolonged time to requiring analgesics after surgery. This review focuses on multimodal analgesia, which is currently recommended for effective postoperative pain control.     

Pharmacology of systemic analgesics

Systemic administration of analgesic drugs is still the most widely used method for providing pain relief in acute painful situations. Opioids may be selected on the basis of their physicochemical characteristics and their diffusion index to the brain. But in clinical practice, their very steep concentration-analgesic effect relationship remains a critical aspect of opioid therapy. Thus, small fluctuations in plasma concentrations of opioids may lead to profound fluctuations in analgesic effect when their plasma and effect-site concentrations are near the minimum effective analgesic concentration (MEAC). Combining drugs acting on different mechanisms of nociceptive modulation offers benefits from additive/synergistic effects and will decrease the incidence of their adverse effects. Evidence-based reviews showed that effective pain relief using non-opioid analgesics relied on paracetamol supplemented with non-steroidal anti-inflammatory drugs (NSAIDs). The role of COX-2 selective inhibitors (CSIs) in acute pain relief still requires further evaluation. NSAIDs, CSIs and paracetamol share the property of morphine sparing in situations of severe (post-operative) pain. CSIs may be beneficial in patients in whom post-operative bleeding is a major surgical risk as the effects of NSAIDs on coagulation may last for days. Finally, low-dose ketamine infusions remain a worthwhile addition to opioid therapy. Analgesic concentrations of ketamine are 1/5th to 1/10th the anaesthetic concentration and exert significant inhibition on N-methyl-d-aspartate (NMDA) receptor activation.     

Adverse events from targeted therapies in advanced renal cell carcinoma: the impact on long-term use

What’s known on the subject? and What does the study add? The side‐effect of targeted agents is known. The clinician should be aware of the side‐effects of targeted agents and how to prevent/diminish them, particularly in sequential and combination therapies. The aim of this review is to help physicians tailor targeted treatments for advanced renal cell carcinoma to suit patient needs and ensure maximum overall duration of response to therapy by providing a summary of the frequency and time of onset of adverse events (AEs) and by raising awareness of AE profiles. A PubMed literature search was performed, and papers on targeted therapy‐related AEs were reviewed. The frequency, severity and management of targeted therapy‐related AEs are discussed. Manageable AEs commonly reported with all the approved targeted agents include: fatigue, gastrointestinal disorders (diarrhoea, nausea, vomiting), hypertension, skin and subcutaneous tissue disorders. Life‐threatening AEs are less common than manageable AEs and are usually class specific. Data suggest that long‐term treatment with well‐established targeted agents does not result in increased or unexpected AEs. Caution is required with regard to the long‐term use of newer targeted agents for which there are no long‐term tolerability data or clinical experience. Studies have reported that the type and frequency of observed AEs associated with sequential tyrosine kinase inhibitor (TKI) use are similar to those reported in the literature for TKI monotherapy. Having an awareness of the AE profiles of targeted agents allows the development of effective management strategies. Generally, more extensive clinical experience has accumulated, and AE profiles are more predictable, for well‐established targeted agents.     

Thirty-day postoperative death rate at an academic medical center

OBJECTIVE: To improve understanding of perioperative deaths at an academic medical center. SUMMARY BACKGROUND DATA: Because published data have typically focused on specific patient populations, diagnoses, or procedures, there are few data regarding surgical deaths and complications in institutional or regional studies. Specifically, surgical adverse events and errors are generally not studied comprehensively. This limits the overall understanding of complications and deaths. METHODS: Data from all operations performed in the main operating suite of the University of Virginia Health Sciences Center from January 1 to June 30, 1999, were compared with state death records to gain a dataset of patients dying within 30 days of surgery. All clinical records from patients who died were screened for adverse events and subsequently reviewed by three surgeons who identified adverse events and errors and performed comparisons with survivors. RESULTS: One hundred nineteen deaths followed 7,379 operations performed on 6,296 patients, yielding a patient death rate of 1.9%. Patients dying within 30 days of surgery were older and had higher American Society of Anesthesiologists scores. Of 119 deaths, 86 (72.3%) were attributable to the patient's primary disease. Twenty-three patient deaths (19.3% of all deaths, 0.37% of all patients) could not be attributed to the patient's primary disease and thus were suspicious for an adverse event (AE) as the cause of the death. Of the 23 deaths suspicious for AE, 15 (12.6% of all deaths, and 65.2% of AE deaths) followed an error in care and thus were classified as potentially preventable, affecting 0.24% of the study population. CONCLUSIONS: Overall, the 30-day postoperative death rate was low in the total surgical population at an academic medical center. Errors and AEs were associated with 12.6% and 19.3% of deaths, respectively. Retrospective review inadequately characterized the nature of AEs and failed to determine causality. Prospective audits of outcomes will enhance our understanding of surgical AEs.     

Post-operative analgesia

High-risk patients undergo simple operations as well as complicated ones. Optimal analgesia for simple procedures can be deduced from systematic reviews. For simple drug treatments we know that oral non-steroidal anti-inflammatory drugs (NSAIDs) are the most effective and that injected opioids need to be given at higher doses to beat the oral NSAIDs. For patients who cannot take NSAIDs combinations of paracetamol and opioid are the next best choice. For high-risk surgery spinals and epidurals using combinations of local anaesthetic and opioid may enable radical change in hospital stay and morbidity from the procedure. Against this must be set any risk from the spinal or epidural itself.     

Adverse reactions following injection with a permanent facial filler polyacrylamide hydrogel (Aquamid): causes and treatment

Background Polyacrylamide hydrogel (Aquamid), an atoxic non-immunogenic gel of the non-resorbable type, has gained widespread popularity as an injectable filler for facial augmentation. However, adverse events (AEs) have occurred, the nature of which seems obscure because of negative findings on culture and a pattern of foreign-body response on microscopy.Design This is a prospective study of case reports provided by physicians injecting Aquamid during the period 21 May 2001 to 15 September 2003.Materials Among 40,000 persons injected, 55 were reported to have experienced AEs. Information from questionnaires distributed along with the product and follow-up information from involved physicians was collected into a database.Results AEs occurring mainly in lips and nasolabial folds were reported in 55 patients, with 51 requiring treatment. The time from the last gel injection to the debut of the AE varied from 2 to 364 days, with a median of 12 days. Seventeen patients presented with different types of reaction to the injection, and the exact cause of the AE was established in another 19. A complete follow-up until full recovery was available in only 43 cases (84%). A broad-spectrum antibiotic in high dosage was effective for a short time. Steroids and non-steroidal anti-inflammatory drugs (NSAIDs) tended to aggravate symptoms and to prolong treatment time.Conclusions AEs presenting clinically as nodules or swellings later than 1 week and less than 1 year after the injection of polyacrylamide hydrogel (Aquamid) should be treated immediately with a broad-spectrum antibiotic (quinolone) in high dosage. Steroids or NSAIDs are contraindicated.The authors have no relevant financial interest in this study     

Anti-inflammatory drugs, analgesics and the risk of perforated colonic diverticular disease

BACKGROUND: Acute perforated colonic diverticular disease has a mortality rate of up to 30 per cent, but little is known about its aetiology. The aim of this study was to test the hypothesis that three classes of drugs, namely non-steroidal anti-inflammatory drugs (NSAIDs), opioid analgesics and corticosteroids, are risk factors for perforated diverticular disease. METHODS: All patients with confirmed perforated colonic diverticular disease were identified over a 5-year period in two hospitals in Norfolk, UK. Two control groups were selected and matched for age, sex and hospital of admission. Data on medication use were obtained from hospital records. Odds ratios for each drug were calculated using conditional logistic regression. RESULTS: Opioid analgesics, NSAIDs and corticosteroids were all positively associated with perforated colonic diverticular disease. The odds ratio for opioid analgesics was 1.8 (95 per cent confidence interval (c.i.) 1.1 to 3.0) in the analysis with ophthalmology controls and 3.1 (95 per cent c.i. 1.8 to 5.5) in that with dermatology controls. Respective odds ratios for NSAIDs were 4.0 (95 per cent c.i. 2.1 to 7.6) and 3.7 (95 per cent c.i. 2.0 to 6.8), and those for corticosteroids were 5.7 (95 per cent c.i. 2.2 to 14.4) and 7.8 (95 per cent c.i. 2.6 to 23.3). CONCLUSION: Opioid analgesics, NSAIDs and corticosteroids are all positively associated with perforated colonic diverticular disease. The consistency of these associations, together with plausible biological mechanisms, suggests that these drugs may have a causative role in this condition.     

Adverse event profile of a mature voluntary medical male circumcision programme performing PrePex and surgical procedures in Zimbabwe

Introduction : The frequency of adverse events (AEs) is a widely used indicator of voluntary medical male circumcision (VMMC) programme quality. Though over 11.7 million male circumcisions (MCs) have been performed, little published data exists on the profile of AEs from mature, large‐scale programmes. No published data exists on routine implementation of PrePex, a device‐based MC method. Methods : The ZAZIC Consortium began implementing VMMC in Zimbabwe in 2013, supporting services at 36 facilities. Aggregate data on VMMC outputs are collected monthly from each facility. Detailed forms are completed describing the profile of each moderate and severe AE. Bivariate and multivariable analyses were conducted using log‐binomial regression models. Results : From October 2014 through September 2015, 44,868 clients were circumcised with 156 clients experiencing a moderate or severe AE. 96.2% of clients had a follow‐up visit within 14 days of their procedure. AEs were uncommon, with 0.3% (116/41,416) of surgical and 1.2% (40/3,452) of PrePex clients experiencing a moderate or severe AE. After adjusting for VMMC site, we found that PrePex was associated with a 3.29‐fold (95% CI: 1.78–6.06) increased risk of experiencing an AE compared to surgical procedures. Device displacements, when the PrePex device is intentionally or accidentally dislodged during the 7‐day placement period, accounted for 70% of PrePex AEs. The majority of device displacements were intentional self‐removals. Overall, infection was the most common AE among VMMC clients. Compared to clients aged 20 and above, clients aged 10–14 were 3.07‐fold (95% CI: 1.36–6.91) more likely to experience an infection and clients aged 15–19 were 1.80‐fold (95% CI: 0.82–3.92) more likely to experience an infection, adjusted for site. Conclusions : This exploratory analysis found that clients receiving PrePex were more likely to experience an AE than surgical circumcision clients. This is largely attributable to the occurrence of device displacements, which require prompt access to corrective surgical MC procedures as part of their clinical management. Most device displacements were self‐removals which are preventable if client behaviour could be modified through counselling interventions. We also found that infection after MC is more common among younger clients, who may benefit from additional counselling or increased parental involvement.     

Cytochrom-P450-Enzyme und ihre Bedeutung für Medikamenteninteraktionen

One of the factors that can alter the response to drugs is the concurrent administration of other drugs. There are several mechanisms by which drugs may interact, but most can be categorised as pharmacokinetic (absorption, distribution, metabolism, excretion), pharmacodynamic, or combined toxicity. Knowledge of the mechanism by which a given drug interaction occurs is often clinically useful and may help to avoid serious adverse events and perioperative morbidity. Although every tissue has some ability to metabolise drugs, the liver is the principal organ of drug metabolism and at the subcellular level the cytochrome P450 enzyme system is the main source of drug interaction. This article reviews the basic principles of drug metabolism and the role of cytochrome P450 in this scenario. Drugs frequently used in anaesthesia and critical care medicine such as benzodiazepines, opioid analgesics, antihypertensive and antiarrhythmic agents, antibiotics and antifungal drugs, antiemetics, histamine-receptor-antagonists, theopylline and paracetamol will be considered. The development of methods and tools which are practical and also economic, are of utmost importance since drug interaction is predictable if the metabolic pathway and the activity (genetic polymorphism) of the enzyme is known.     

SO14PPERIOPERATIVE OUTCOMES OF CYTOREDUCTIVE SURGERY AND PERIOPERATIVE INTRAPERITONEAL CHEMOTHERAPY FOR NON‐APPENDICEAL PERITONEAL CARCINOMATOSIS FROM A PROSPECTIVE DATABASE

Purpose Cytoreductive surgery and perioperative intraperitoneal chemotherapy has expanded its application in the management of peritoneal carcinomatosis from gastrointestinal and ovarian malignancies. An accurate assessment of perioperative outcomes is crucial for integration of this combined procedure into clinical practice. Methodology A prospective study of 80 patients undergoing the combined treatment for non‐appendiceal peritoneal carcinomatosis was conducted. Forty‐seven adverse events by 8 organ‐systems were rated from Grade I to IV with increasing severity. Grade I morbidity was self‐limiting; Grade II required medical treatments; Grade III required an invasive intervention; and Grade IV required returning to the operating room or intensive care management. Results One patient (1.3%) died postoperatively. Postoperative adverse events affected genitourinary system (38%), haematological system (31%), gastrointestinal system (25%), infection (20%), intravenous catheters status (15%), pulmonary system (14%), cardiovascular system (11%), and neurological system (4%). Thirty‐six patients (45%) experienced 49 Grade III adverse events. Six patients (8%) experienced 8 Grade IV adverse events. More than 4 peritonectomy procedures (p = 0.010), and length of hospital stay of more than 21 days (p = 0.007) were strongly associated with Grade III and/or Grade IV morbidity. Conclusions The morbidity and mortality rates after the combined treatment for non‐appendiceal peritoneal carcinomatosis were within the acceptable range of surgical treatments for other gastrointestinal cancers. A standardized prospective database is required for an accurate assessment of perioperative outcomes.     

NSAIDs and anastomotic leak: What's the evidence?

Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesics and may be a valuable component of opioid-sparing perioperative analgesic strategies following colorectal surgery. However, NSAIDs may also impair wound healing and have been associated with an increased risk of anastomotic leak in some reports. In this chapter we will review the benefits of NSAIDs in managing postoperative pain, and review and critique the body of evidence on the association between NSAIDs and anastomotic leaks after colorectal surgery.