Beneficial actions attributed to NSAIDs in the appropriate management of postoperative pain [16, 17]
\r\n\tIn sum, the book presents a reflective analysis of the pedagogical hubs for a changing world, considering the most fundamental areas of the current contingencies in education.
",isbn:"978-1-83968-793-8",printIsbn:"978-1-83968-792-1",pdfIsbn:"978-1-83968-794-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"b01f9136149277b7e4cbc1e52bce78ec",bookSignature:"Dr. María Jose Hernandez-Serrano",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10229.jpg",keywords:"Teacher Digital Competences, Flipped Learning, Online Resources Design, Neuroscientific Literacy (Myths), Emotions and Learning, Multisensory Stimulation, Citizen Skills, Violence Prevention, Moral Development, Universal Design for Learning, Sensitizing on Diversity, Supportive Strategies",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 14th 2020",dateEndSecondStepPublish:"October 12th 2020",dateEndThirdStepPublish:"December 11th 2020",dateEndFourthStepPublish:"March 1st 2021",dateEndFifthStepPublish:"April 30th 2021",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Phil. Maria Jose Hernandez Serrano is a tenured lecturer in the Department of Theory and History of Education at the University of Salamanca, where she currently teaches on Teacher Education. She graduated in Social Education (2000) and Psycho-Pedagogy (2003) at the University of Salamanca. Then, she obtained her European Ph.D. in Education and Training in Virtual Environments by research with the University of Manchester, UK (2009).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"187893",title:"Dr.",name:"María Jose",middleName:null,surname:"Hernandez-Serrano",slug:"maria-jose-hernandez-serrano",fullName:"María Jose Hernandez-Serrano",profilePictureURL:"https://mts.intechopen.com/storage/users/187893/images/system/187893.jpg",biography:"DPhil Maria Jose Hernandez Serrano is a tenured Lecturer in the Department of Theory and History of Education at the University of Salamanca (Spain), where she currently teaches on Teacher Education. She graduated in Social Education (2000) and Psycho-Pedagogy (2003) at the University of Salamanca. Then, she obtained her European Ph.D. on Education and Training in Virtual Environments by research with the University of Manchester, UK (2009). She obtained a Visiting Scholar Postdoctoral Grant (of the British Academy, UK) at the Oxford Internet Institute of the University of Oxford (2011) and was granted with a postdoctoral research (in 2021) at London Birbeck University.\n \nShe is author of more than 20 research papers, and more than 35 book chapters (H Index 10). She is interested in the study of the educational process and the analysis of cognitive and affective processes in the context of neuroeducation and neurotechnologies, along with the study of social contingencies affecting the educational institutions and requiring new skills for educators.\n\nHer publications are mainly of the educational process mediated by technologies and digital competences. Currently, her new research interests are: the transdisciplinary application of the brain-based research to the educational context and virtual environments, and the neuropedagogical implications of the technologies on the development of the brain in younger students. Also, she is interested in the promotion of creative and critical uses of digital technologies, the emerging uses of social media and transmedia, and the informal learning through technologies.\n\nShe is a member of several research Networks and Scientific Committees in international journals on Educational Technologies and Educommunication, and collaborates as a reviewer in several prestigious journals (see public profile in Publons).\n\nUntil March 2010 she was in charge of the Adult University of Salamanca, by coordinating teaching activities of more than a thousand adult students. She currently is, since 2014, the Secretary of the Department of Theory and History of Education. Since 2015 she collaborates with the Council Educational Program by training teachers and families in the translation of advances from educational neuroscience.",institutionString:"University of Salamanca",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Salamanca",institutionURL:null,country:{name:"Spain"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"23",title:"Social Sciences",slug:"social-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"301331",firstName:"Mia",lastName:"Vulovic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/301331/images/8498_n.jpg",email:"mia.v@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6942",title:"Global Social Work",subtitle:"Cutting Edge Issues and Critical Reflections",isOpenForSubmission:!1,hash:"222c8a66edfc7a4a6537af7565bcb3de",slug:"global-social-work-cutting-edge-issues-and-critical-reflections",bookSignature:"Bala Raju Nikku",coverURL:"https://cdn.intechopen.com/books/images_new/6942.jpg",editedByType:"Edited by",editors:[{id:"263576",title:"Dr.",name:"Bala",surname:"Nikku",slug:"bala-nikku",fullName:"Bala Nikku"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"46303",title:"Multimodal Analgesia for the Management of Postoperative Pain",doi:"10.5772/57401",slug:"multimodal-analgesia-for-the-management-of-postoperative-pain",body:'The US Congress declared the 10-year period between January 1st, 2001, and December 31st, 2010, the decade for the control and treatment of pain, while the IASP (International Association for the Study of Pain) declared the period ending in October 2011, the year dedicated to acute pain. In spite of this measure, we must recognize that this effort has been insufficient, and that pain is one of the main health problems in the 21st century [1]. There is no ideal analgesic regimen, as none encompasses the characteristics of a fast onset of action, good cost-effectiveness profile, absence of short and long-term adverse effects, nil interaction with other drugs and/or metabolites, and ease of administration, both for the patients and healthcare personnel. Furthermore, technical deficiencies in the drug-delivery systems have contributed to a worsening of this situation, which is why, over the past few years, new and more precise mechanisms have appeared to allow us to improve the overall quality of analgesic regimens, “making old drugs new”, especially those in the opioids family [2].
In spite of advances in the knowledge of the neurobiology of nociception and the physiology of systemic and spinal analgesic drugs, postoperative pain remains undertreated. Hospitalized postoperative patients should have the best access to analgesia, nevertheless, more than 1/3 of these patients experience moderate to severe pain in the first 24 h after their procedure [2]. Further, around 60% of current surgery can be ambulatory, but in reality, almost 80% of patients complain about moderate postoperative pain. Inadequate treatment leads to an extension of the recovery time, an increase in the length of the hospitalization stay, of healthcare costs, and greater patient dissatisfaction [3].
The gap between the knowledge of the mechanism of pain production and the application of an effective treatment is great, and ever growing. Neither acute, nor chronic pain usually receives adequate treatment due to several reasons relating to culture, attitude, education, politics and logistics. The correct treatment of pain is considered a fundamental right of the patient; in fact, lawsuits have been launched due to the under-treatment of pain, as well as an indicator of good clinical practice and quality of care [4]. The ideal analgesic regimen must assess the risks against the benefits and consider the patient’s preference, as well as the clinician’s prior experience, and will be framed within a multimodal approach in order to facilitate postsurgical recovery. Effectiveness in the management of postoperative pain entails a multimodal approach involving several drugs with different mechanisms of action so as to achieve a synergistic effect and thus minimize the adverse effects of the different routes of administration [5].
The main objective of this review is to explain the multimodal approach to postoperative pain, defining the benefits and risks of the combination of the most common used analgesic drugs and techniques as well as the latest improvements in this field and experts’ recommendations. For this purpose, a review on Ovid-Medline was carried out until December 2012, with the keywords: “postoperative pain”, “postoperative convalescence”, “multimodal analgesia”, “non-steroidal anti-inflammatory drugs”, “regional analgesia” and “opioids”, focusing on systematic reviews with or without meta-analysis, randomized controlled trials and expert opinion articles concerning several controversial points.
The study of the neurophysiology of pain [6] has produced important advances in the knowledge of the mechanism of the production of painful stimuli in the perioperative period, describing a dynamic system where multiple nociceptive afferent pathways, together with other downstream modulation mechanisms, are of relevance. Surgical incision triggers deep responses of an inflammatory nature and from the sympathetic system, which determines a first stage of peripheral sensitization that, if it is maintained over time, amplifies the transmission of the stimulus until it conditions a second stage of central sensitization. As a consequence, it leads to an increased release of catecholamines and increased oxygen consumption, with increased neuroendocrine activity, translating into hyperactivity in many organs and systems. This translates into cardiovascular, pulmonary, endocrine-metabolic, gastrointestinal, immunological and psychological complications.
There is a direct association between processes with a severe degree of postsurgical pain and the proportion of the appearance of chronic pain, such as with limb amputation (30-83%), thoracotomy (36-56%), gall bladder or breast surgery (11-57%), inguinal hernia (37%) and sternotomy (27%) or abdominal hysterectomy (3-25%) [7]. Chronic pain can be severe in about 2-10% of these patients representing a major largely unrecognized clinical problem. Iatrogenic neuropathic pain is probably the most important cause of long-term postsurgical pain and consequently surgical techniques that avoid nerve damage should be applied whenever possible. Also, early and aggressive pain therapy during the postoperative setting should be administered since the intensity of acute pain correlates with the risk of developing a persistent pain state. Finally, the role of genetic factors should be studied, since only a certain proportion of patients with intraoperative nerve damage develop chronic pain [8]. Many clinical trials have demonstrated the effectiveness of gabapentin and pregabalin administration in the perioperative period as an adjunct to reduce acute postoperative pain. However, very few clinical trials have examined their use in the prevention of chronic postsurgical pain (CPSP). Eight studies were included in a recent meta–analysis, the six of the gabapentin trials demonstrated a moderate–to–large reduction in the development of CPSP (pooled odds ratio [OR] 0.52; 95% confidence interval [CI], 0.27 to 0.98; P=0.04), and the two pregabalin trials found a very large reduction in the development of CPSP (pooled OR 0.09; 95% CI, 0.02 to 0.79; P=0.007). This review supports the view that the perioperative administration of gabapentin and pregabalin is effective in reducing the incidence of CPSP but better–designed clinical trials are needed to confirm these early findings [9].
We must hence carry out a thorough treatment of dynamic postoperative pain, as it is not enough to only treat pain at rest, and to avoid other predicting factors, such as pain more than one month prior to the intervention, aggressive or repeated surgery, associated nerve injury or prior psychopathological factors [10]. Moreover, factors predisposing patients to a greater postoperative pain are young age and the type of surgery, such as orthopaedic surgery (due to the involvement of periosteum, which has a very low pain sensitivity threshold) and thoraco-abdominal surgery (due to the large involvement of the functions of the corresponding organs) [10]. The concept of pre-emptive analgesia is based on the administration, prior to surgical incision, of an analgesic in order to mitigate or prevent central hypersensitivity phenomena, aiming to reduce analgesic consumption in the postoperative period and chronic pain. However, there is great controversy regarding its efficacy. In a meta-analysis [11], sixty-six studies with data from 3, 261 patients were analysed. Fixed-effect model combined data were used and the effect size index (ES) was used as the standardized mean difference. When the data from all three-outcome measures were combined, the ES was the most pronounced for the pre-emptive administration of epidural analgesia (ES, 0.38; 95% confidence interval [CI], 0.28-0.47), local anaesthetic wound infiltration (ES, 0.29; 95% CI, 0.17-0.40), and non-steroidal anti-inflammatory-drugs (NSAIDs) administration (ES, 0.39; 95% CI, 0.27-0.48). Whereas pre-emptive epidural analgesia resulted in consistent improvements in all three-outcome variables, pre-emptive local anaesthetic wound infiltration and NSAIDs administration improved analgesic consumption and time to first rescue analgesic request, but not postoperative pain scores. The least proof of efficacy was found for systemic NMDA antagonist (ES, 0.09; 95% CI, -0.03 to 0.22) and opioid (ES, -0.10; 95% CI, -0.26 to 0.07) administration, and the results remain equivocal. Epidural analgesia begun prior to the surgical stimulus and maintained for several days (2-4) in the postoperative period has previously shown to be effective in this setting, either for amputations or thoracotomy and laparotomy, focusing on the timing of the perioperative analgesia [12].
Hyperalgesia can occur after surgery either due to nervous system sensitization caused by surgical nociception (nociception-induced hyperalgesia) or as an effect of anaesthetic drugs, particularly opioids (opioid-induced hyperalgesia - OIH). Both are potentially undesirable and can share similar underlying mechanisms such as the involvement of excitatory amino acids via the N-methyl-D-aspartate (NMDA) receptors [13]. Hyperalgesia is characterized by a deviation down and to the left of the curve that associates the intensity of the stimulus to the degree of pain observed, so that a usually painful stimulus is perceived as a pain of greater intensity, and likewise, another stimulus that is not painful is perceived as painful (allodynia). This effect may be seen both in the peripheral and central nervous systems. Primary hyperalgesia is a consequence of the sensitization of peripheral nociceptors during the inflammatory phase which is sustained by the local ischemia and acidosis caused by thermal or mechanical stimuli in areas close to the surgical incision. Secondary hyperalgesia is, in turn, due to central sensitization by a painful afferent stimulus sustained over time that triggers a spontaneous increase in the neuronal activity of the posterior horn of the spinal cord, only manifesting when faced with mechanical stimuli in tissues far from the lesion [14].
The clinical importance of hyperalgesia lies, on the one hand, in the increased intensity of the pain, in the consumption of analgesics, in the morbidity and in the discomfort in the postoperative period, and also, in the greater presence of chronic pain, and a greater probability of developing a complex regional pain syndrome that has even been suggested [15]. Furthermore, the greatest inconvenience lies in how hard it is to quantify; this should be done against electrical stimuli on the region of the skin, as it is not usually reflected in traditional subjective pain assessment scales (visual or numeric analogic scales), and objective neuroplasticity assessment tests (Von Frey filaments) that provide complementary information for a correct adjustment of the treatment. This should be based on neuromodulator drugs like gabapentinoids (gabapentin or pregabalin), ketamine, or NSAIDs. Finally, effective perioperative blocking of nociceptive inputs from the wound with regional analgesia as well as the use of antihyperalgesic and analgesic drugs in a multimodal combination, seem to be the best way to prevent central sensitization [14, 15].
The acceptance of the concept of multimodal analgesia and the appearance of parenteral preparations has increased the popularity of NSAIDs in the management of postoperative pain [16]. The potential beneficial effects are summarized in Table I.
The mechanism of action involves the peripheral and central inhibition of cyclooxygenase (COX) and to the reduced production of prostaglandins from arachidonic acid. Two isoenzymes have been described [17], COX-1: Constitutive, responsible for platelet aggregation, haemostasis and the protection of the gastric mucosa, but it also increases by 2-4 times in the initial inflammatory process and in the synovial fluid of chronic processes such as rheumatoid arthritis and COX-2: Induced, causing pain (by increasing by 20-80 times in the inflammation), fever and carcinogenesis (by facilitating tumour invasion, angiogenesis and metastasis). However, both forms are constitutive in the dorsal root ganglion and in the grey matter of the spinal cord. Therefore, although the spinal administration of COX-1 inhibitors has not shown to be effective, COX-2 inhibitors (Coxib) may play an important role in central sensitization and in the anti-hyperalgesic effect by blocking the constitutive form at the medullary level and by reducing the central production of prostaglandin E-2. Although Coxib drugs present with a lower risk of gastrointestinal haemorrhage and a nil effect on platelet function, they have not been demonstrated to reduce renal complications (hypertension, oedema, nephrotoxicity) and the effects on osteogenesis, compared to non-selective NSAIDs are still controversial [16, 17, 18]. It has been proposed that COX-2 is a cardioprotective enzyme and that the cardiovascular risk associated with its inhibition is due to an alteration in the balance between prostacyclin I-2 (endothelial) and thromboxane A-2 (platelet) in favour of the latter which leads to platelet aggregation, vasoconstriction and vascular proliferation. Coxib drugs improve the side effect profile and maintain a similar analgesic power; however, the duration of the treatment with these drugs in at-risk patients, their adverse effects, cost/effectiveness and efficacy compared to that of conventional NSAIDs associated with gastric protectors and their reliability in patients who usually take anti-aggregate drugs have not yet been defined [17, 18]. On the basis of many human studies, one may conclude that perioperative COX-2 inhibitors, in standard doses, decrease opioid consumption, but it is not clear whether they decrease adverse events related to the opioids. Future investigations with different multimodal techniques may help elucidate and clarify the true benefits of perioperative COX-2 inhibitors in acute pain management strategies [18].
Celecoxib is a sulphonamide with a large volume of distribution (400 litres/200 mg), large tissue penetration, degradation through the cytochrome P450 2C9/3A4 system, and a half-life of 11 h, with inactive metabolites. Rofecoxib is a sulphone with a volume of distribution of 86-litres/25 mg, it is metabolized by cytosolic reduction, without interacting with the cytochrome system, and its half-life is of 17 h, with active metabolites. The equipotent dose for the treatment of acute pain is 400 mg of celecoxib/50 mg of rofecoxib. This would explain the differences between COX-2/COX-1 selectivity, and the differences found in the incidence of cardiovascular adverse effects, which are greater for rofecoxib [19, 20]. The decision to withdraw this drug from the US market in September 2004 was based on a three year controlled clinical trial on the prevention of adenomatous polyposis, in which an increased relative risk of cardiovascular effects such as ischemia or myocardial infarction was found in patients who were on treatment for more than 18 months. The risk of myocardial infarction varies with individual NSAIDs. An increased risk was observed for diclofenac and rofecoxib, the latter having a clear dose-response trend. There was a suggestion of a small increased risk with ibuprofen. Data also suggest a small-reduced risk for naproxen present only in non-users of aspirin, mainly people free of clinically apparent vascular disease [20].
Etoricoxib is a selective cyclo-oxygenase-2 (COX-2) inhibitor licensed for the relief of chronic pain in osteoarthritis and rheumatoid arthritis, and acute pain in some jurisdictions. This class of drugs is believed to be associated with fewer upper gastrointestinal adverse effects than conventional non-steroidal anti-inflammatory drugs (NSAIDs). Single dose oral etoricoxib produces high levels of good quality pain relief after surgery and the incidence of adverse events did not differ from the placebo. The 120 mg dose is as effective as, or better than, other commonly used analgesics [21].
Parecoxib is a pro-drug used in Europe for parenteral administration in the treatment of moderate-to-severe postoperative pain. The IV administration of 40 mg produces analgesia at 14 min. and as it is rapidly hydrolysed in the liver into valdecoxib, it is not detected in urine. Its analgesic peak is detected after 2 h and its duration varies from between 5-22 h. Its usefulness in reducing pain after dental, gynaecological, abdominal, orthopaedic and cardiac surgery has been proven. The analgesic efficacy of 40 mg IV is similar to that of ketorolac 30 mg IV. The maximum daily dose recommended is of 80 mg [22]. Parecoxib is contraindicated in patients with ischaemic heart disease or established cerebrovascular disease, in patients with congestive heart failure (NYHA classes II-IV), as well as in the treatment of postoperative pain after coronary by-pass surgery.
The efficacy of paracetamol or acetaminophen [23] has been proven in the treatment of moderate postoperative pain and in many other types of acute pain. It appears it could act by blocking the COX-3 detected in the cerebral cortex, thus reducing pain and fever. This third isoenzyme, which is similar to the mRNA of COX-1, has a retained intron-1 that alters its genetic expression in humans, and it may lead to questions as to whether this is the pathway for its therapeutic action, which, centrally, could be favoured for its lower presence of endoperoxides in nerve cells. The main analgesic mechanism appears to be due to a modulation of the serotonergic system, and it is possible that it increases noradrenalin concentrations in the CNS and peripheral β-endorphins. Thus, even if the mechanism of action is not clearly understood, there is now evidence that paracetamol acts within the CNS, by inhibiting the prostaglandin synthesis, whereas it has very weak antiplatelet and anti-inflammatory effects at recommended dosages. It manifests with a potentiating effect on NSAIDs and opioids and at therapeutic doses it does not present with relevant adverse effects. It presents with a very favourable efficacy/tolerability ratio, which is why it has been turned into the first-line of treatment in postoperative multimodal analgesia regimens. Its peak effect in the CSF is achieved at 1-2 h and its concentration in this compartment remains above that of plasma after repeated doses. It has been suggested that better analgesia could be obtained with a 2 g starting dose instead of with the recommended dose of 1 g. Its maximum daily dose is 4 g, but 3 g per day should not be exceeded in alcohol abusers or patients with a coexisting disease causing glutathione depletion. The usual scheme of administration (1 g every 6 hours) has a less than 10 mg sparing effect on 24 hour morphine consumption and consequently does not significantly reduce morphine side effects [24]. In a meta-analysis, seven prospective randomized controlled trials, involving 265 patients in the group with PCA (patient-controlled-analgesia) morphine plus acetaminophen and 226 patients in the group with PCA morphine alone, were selected. Acetaminophen administration was not associated with a decrease in the incidence of morphine-related adverse effects or an increase in patient satisfaction. Adding acetaminophen to PCA was associated with a morphine-sparing effect of 20% (mean, -9 mg; CI -15 to -3 mg; P=0.003) over the first postoperative 24 h [24]. In a recent systematic review, it has been verified how the association of paracetamol with other NSAIDs (diclofenac, ibuprofen, ketoprofen, ketorolac, tenoxicam, rofecoxib and aspirin) improved the efficacy of paracetamol administered alone (85% of the studies), as well as that of anti-inflammatories (64% of the studies) [25]. The antinociception induced by the intraperitoneal co-administration of combinations of paracetamol with the NSAIDs; diclofenac, ibuprofen, ketoprofen, meloxicam, metamizole, naproxen, nimesulide, parecoxib and piroxicam was studied by isobolographic analysis in the acetic acid abdominal constriction test in mice (writhing test). As shown by isobolographic analysis, all the combinations were synergistic, the experimental ED50s being significantly smaller than the theoretically calculated ED50s. The results of this study demonstrate potent interactions between paracetamol and NSAIDs and validate the clinical use of combinations of these drugs in the treatment of pain conditions [26].
Metamizole or dipyrone is another powerful analgesic and antipyretic agent, with limited anti-inflammatory power, that is broadly used in Spain, Russia, South America and Africa, but that is not marketed in the US or the United Kingdom due to the possible risk of agranulocytosis and aplastic anaemia. Other inconveniences of metamizole include the possibility of episodes of severe allergic reactions and of hypotension after its administration via IV [16]. It presents with a spasmolytic action and an efficacy that is superior to that of salicylates, which is why it is indicated in moderate to severe postoperative pain and in colic-type pain. In a systematic review [27], over 70% of participants experienced at least 50% pain relief over 4 to 6 hours with 500 mg of oral dipyrone compared to 30% with a placebo in five studies (288 participants). Fewer participants needed rescue medication with dipyrone (7%) than with the placebo (34%; four studies, 248 participants). There was no difference in participants experiencing at least 50% pain relief with 2.5 g intravenous dipyrone and 100 mg intravenous tramadol (70% versus 65%; two studies, 200 participants). No serious adverse events were reported.
Diclofenac is an anti-inflammatory with a great analgesic capacity, especially after orthopaedic and traumatological surgery, due to its great penetration into inflamed tissues and synovial fluid. It is also of use in pains of a colic nature, such as renal pain. The maximum daily dose is of 150 mg, distributed in 2 doses, and it is important to remember that some countries only approve it for deep intramuscular use [28]. Its greatest contraindication is kidney failure and gastrointestinal bleeding disorders. A new formulation of the non-selective NSAID diclofenac sodium suitable for intravenous bolus injection has been developed using hydroxypropyl beta-cyclodextrin as a solubility enhancer (HPbetaCD diclofenac). HPbetaCD diclofenac intravenous bolus injection was shown to be bioequivalent to the existing parenteral formulation of diclofenac containing propylene glycol and benzyl alcohol as solubilizers (PG-BA diclofenac), which is relatively insoluble and requires slow intravenous infusion over 30 minutes. For patients with acute moderate and severe pain after abdominal or pelvic surgery, repeated 18.75 mg and 37.5 mg doses of HPβCD diclofenac provided significant analgesic efficacy, as compared to a placebo. Significant analgesic efficacy was also provided by the active comparator ketorolac. Both HPβCD diclofenac and ketorolac significantly reduced the need for opioids [29].
Dexketoprofen trometamol is one of the most potent “in vitro” inhibitors of prostaglandin synthesis; it is a soluble salt of the (S)-(+) right-handed enantiomer of ketoprofen. It is administered at doses of 12.5-25 mg orally, with a fast absorption with an empty stomach, and recently has been administered at 50 mg IV with a maximum daily dose of 150 mg for only 48 h, binding strongly to albumin, and with a renal excretion of inactive metabolites after glucuronidation. Ketoprofen at doses of 25 mg to 100 mg is an effective analgesic in moderate to severe acute postoperative pain with an NNT for at least 50% pain relief of 3.3 with a 50 mg dose. This is similar to that of commonly used NSAIDs such as ibuprofen (NNT 2.5 for a 400 mg dose) and diclofenac (NNT 2.7 at a 50 mg dose). The duration of action is about five hours. Dexketoprofen is also effective with NNTs of 3.2 to 3.6 in the dose range 10 mg to 25 mg. Both drugs were well tolerated in single doses and its main indication is acute postoperative pain and nephritic colic [30].
Ketorolac is an anti-inflammatory with a great analgesic power, equitable to that of meperidine and even morphine, but with a roof therapeutic effect. It is absorbed orally, by IM, IV and topically through the eye, as it is well tolerated by all human tissues. It binds to plasma proteins to a degree of 99%, and it´s eliminated by the renal pathway as an active drug and metabolites. It is very useful in postoperative pain, of the renal colic and spastic bladder-type. It has also been used successfully in IV regional anaesthesia together with lidocaine [31]. The recommended doses are 10 mg orally or 30 mg parentally, with a maximum duration of five and two days, respectively. Its main adverse effects are dyspepsia and nausea, although it must be used cautiously in patients with a history of gastrointestinal bleeding. A European multicentre study that compared ketorolac with ketoprofen and naproxen used postoperatively (≤ 5 days) evaluated the risk of death (0.17%), surgical bleeding (1.04%), gastrointestinal bleeding (0.04%), acute kidney failure (0.09%) and allergic reactions (0.12%) on 11, 245 patients, and found no significant differences among them [32].
It is a proven fact that NSAIDs are effective in the postoperative treatment of moderate to severe pain, but it is yet to be verified what systematic reviews suggest: that they can be as effective as opioids [5, 16, 33]. (See Table II, Oxford Listing about the efficacy of single-dose analgesics based on Systematic Reviews. NOTE: The lower the NNT, the greater the potency)
\n\t\t\t\tNSAIDS\n\t\t\t | \n\t\t\t\n\t\t\t\tNSAIDS + OPIOIDS\n\t\t\t | \n\t\t\t\n\t\t\t\tOPIOIDS\n\t\t\t | \n\t\t
\n\t\t\t\tEtoricoxib PO\n\t\t\t\t 60 mg NNT 2.2 (1.7-3.2) 80 mg NNT 1.6 (1.5-1.8) 180-240 mg NNT 1.5 (1.3-1.7) \n\t\t\t\tValdecoxib PO\n\t\t\t\t 40 mg NNT 1.6 (1.4-1.8) 20 mg NNT 1.7 (1.4-2.0) \n\t\t\t\tParecoxib IV\n\t\t\t\t 40 mg NNT 1.7 (1.3-2.4) 20 mg NNT 2.5 (2.0-4.8) \n\t\t\t\tCelecoxib PO\n\t\t\t\t 200 mg NNT 3.5 (2.9-4.4) 400 mg NNT 2.1 (1.8-2.1) \n\t\t\t\tRofecoxib PO\n\t\t\t\t 50 mg NNT 2.2 (1.9-2.4) | \n\t\t\t\n\t\t\t\tParacetamol 1 g + Codeine 60 mg PO\n\t\t\t\t NNT 2.2 (1.7-2.9) \n\t\t\t\tParacetamol 500 mg + Oxycodone IR 5 mg NNT 2.2 (1.7-3.2) \n\t\t\t\tParacetamol 500 mg + Oxycodone IR 10 mg NNT 2.6 (2.0-3.5) \n\t\t\t\tParacetamol 650 mg + Tramadol\n\t\t\t\t75 mg PO NNT 2.6 (2.0-3.0) \n\t\t\t\tParacetamol 1000 mg + Oxycodone IR 10 mg PO NNT 2.7 (1.7-5.6) \n\t\t\t\tParacetamol 650 mg + Tramadol 112 mg PO NNT 2.8 (2.1-4.4) | \n\t\t\t\n\t\t\t\tOxycodone PO 15 mg\n\t\t\t\t NNT 2.4 (1.5-4.9) | \n\t\t
\n\t\t\t\tDiclofenac PO, IM\n\t\t\t\t 100 mg NNT 1.8 (1.5-2.1) 50 mg NNT 2.3 (2.0-2.7) 25 mg NNT 2.8 (2.1-4.3) | \n\t\t\t\n\t\t\t\tParacetamol 1000 mg + Oxycodone IR 5 mg PO NNT 3.8 (2.1-20.0) | \n\t\t\t\n\t\t\t\tMorphine IM 10 mg\n\t\t\t\t NNT 2.9 (2.6-3.6) | \n\t\t
\n\t\t\t\tKetoprofen PO\n\t\t\t\t 50 mg 3.3 (1.6-4.5) Dexketoprofen 10 mg PO NNT 3.2 (2.8-3.4) 25 mg PO NNT 3.6 (2.6-4.2) 50 mg IV similar to diclofenac IM | \n\t\t\t\n\t\t\t | \n\t\t\t\tMeperidine IM 100 mg\n\t\t\t\t NNT 2.9 (2.3-3.9) | \n\t\t
\n\t\t\t\tIbuprofen PO\n\t\t\t\t 400 mg + Paracetamol 1 g NNT 1.5 (1.4-1.7) 200 mg + Paracetamol 500 mg NNT 1.6 (1, 5-1.8) 600 mg NNT 2.4 (1.9-3.3) 400 mg NNT 2.7 (2.5-3.0) 200 mg NNT 3.3 (2.8-4.0) \n\t\t\t\tFlurbiprofen PO\n\t\t\t\t 100 mg NNT 2.5 (2.0-3.1) 50 mg NNT 2.7 (2.3-3.3) \n\t\t\t\tMetamizole PO, IV\n\t\t\t\t 500 mg NNT 2.4 (1.9-3.2) 2 g IV similar to 100 mg tramadol | \n\t\t\t\n\t\t\t\tParacetamol 600/650 mg + Codeine 60 mg\n\t\t\t\tPO NNT 4.2 (3.4-5.3) \n\t\t\t\tParacetamol 650 mg +\n\t\t\t\t \n\t\t\t\tDextropropoxifen 65 mg PO\n\t\t\t\t NNT 4.4 (3.5-5.6) | \n\t\t\t\n\t\t\t\tTapentadol PO:\n\t\t\t\t - Bunionectomy pain (50, 75, 100 mg) NNT 3.6 -3.8 -2.5 - Dental pain (50, 75, 100, 200 mg) NNT 13, 5, 2, 3 | \n\t\t
\n\t\t\t\tKetorolac PO 10 mg\n\t\t\t\t NNT 2.6 (2.3-3.1) \n\t\t\t\tKetorolac IM 30 mg\n\t\t\t\t NNT 3.4 (2.5-4.9) | \n\t\t\t\n\t\t\t\tAspirin 650 mg + Codeine 60 mg PO\n\t\t\t\t NNT 5.3 (4.1-7.4) | \n\t\t\t\n\t\t\t\tTramadol PO 100 mg\n\t\t\t\t NNT 4.8 (3.4-8.2) \n\t\t\t\tTramadol PO 50 mg\n\t\t\t\t NNT 7.1 (4.6-18) | \n\t\t
\n\t\t\t\tNaproxen Na PO 550 mg\n\t\t\t\t NNT 2.6 (2.2-3.2) \n\t\t\t\tPiroxicam 20 mg PO\n\t\t\t\t NNT 2.7 (2.1-3.8) | \n\t\t\t\n\t\t\t\tParacetamol 325 mg + Oxycodone IR\n\t\t\t\t5 mg PO NNT 5.5 (3.4-14.0) \n\t\t\t | \n\t\t\t\n\t\t\t\tDextropropoxifen PO 65 mg\n\t\t\t\t NNT 7.7 (4.6-22) | \n\t\t
\n\t\t\t\tParacetamol PO\n\t\t\t\t 1 g NNT 3.8 (3.4-4.4) 650 mg NNT 5.3 (4.1-7.2) \n\t\t\t\tAspirin PO\n\t\t\t\t 1200 mg NNT 2.4 (1.9-3.2) 1 g NNT 4.0 (3.2-5.4) 650 mg NNT 4.4 (4.0-4.9) | \n\t\t\t\n\t\t\t\tParacetamol 300 mg + Codeine 30 mg PO NNT 5.7 (4.0-9.8) | \n\t\t\t\n\t\t\t\tDihydrocodeine PO 30 mg\n\t\t\t\t NNT 8.1 (4.1-540) \n\t\t\t\tCodeine PO 60 mg\n\t\t\t\t NNT 9.1 (6.0-23.4) | \n\t\t
Relative efficacy of several analgesics according to the nnt in acute pain [5, 16, 33] (NNT: Number of patients necessary to treat in order to achieve a 50% relief of moderate to severe postoperative pain after a single dose)
PO: Per Os (orally)
IM: Intramuscularly
IV: Intravenously
IR: Immediate release
(Between brackets after NNT: 95% confidence interval)
Opioids are the drugs with the greatest known analgesic efficacy. This is because their action is the result of a combined interaction on four types of receptors in turn divided into several subtypes (μ1-3, δ1-2, κ1-3, ORL-1) that are located at different levels of the nerve axis, from the cerebral cortex to the spinal cord, and in some peripheral locations, and that intervene both in afferent and efferent mechanisms of nociceptive sensitivity. They are also a part of the endogenous neuromodulator system of pain, and are associated with the adrenergic, serotonergic and GABAergic system [16].
Opioids produce a high degree of analgesia, without a roof effect, but are limited by the appearance of side effects such as respiratory depression, nausea and itching. Their parenteral use in moderate to severe pain achieves a good analgesic effect in a short period of time; the intravenous route being preferable to the intramuscular route due to their greater bioavailability. The oral route with sustained-release drugs is also showing its usefulness in this setting [34, 35]. The features of the main parenteral opioids are summarized in table III.
\n\t\t\t\tOPIOIDS\n\t\t\t | \n\t\t\t\n\t\t\t\tOnset of action (min)\n\t\t\t | \n\t\t\t\n\t\t\t\tPeak effect (min)\n\t\t\t | \n\t\t\t\n\t\t\t\tDuration of the clinical effect (h)\n\t\t\t | \n\t\t\t\n\t\t\t\tPotency compared to morphine\n\t\t\t | \n\t\t\t\n\t\t\t\tIV-PCA bolus dose\n\t\t\t | \n\t\t\t\n\t\t\t\tTime of closure of IV-PCA (min)\n\t\t\t | \n\t\t\t\n\t\t\t\tContinuous IV infusion *\n\t\t\t\t\n\t\t\t | \n\t\t
Morphine ** Hydromorphone Meperidine *** Fentanyl Sufentanil Tramadol Methadone | \n\t\t\t2-4 2-3 10 1-2 1 10 2-3 | \n\t\t\t15-20 10-15 30 5 5 35 5-6 | \n\t\t\t2 2 3-4 1-2 1 4-6 6-12 | \n\t\t\t1 5 1/10 100 1000 1/10 1 | \n\t\t\t1-2 mg 0.2-0.4mg 10-20 mg 20-50 µg 4-6 µg 10-20 mg 0.5 mg | \n\t\t\t6-10 6-10 6-10 5-10 5-10 6-10 10-15 | \n\t\t\t0-2 mg h-1 0-0.4 mg h-1 0-20 mg h-1 0-60 µg h-1 0-8 µg h-1 0-20 mg h-1 0-0.5 mg h-1 | \n\t\t
* Not recommended for initial programming except in patients undergoing chronic treatment with opioids or insufficient analgesia with PCA alone.
**Not recommended in patients with serum creatinine levels > 2 mg/dL, due to an accumulation of the active metabolite morphine-6-glucuronide.
*** Contraindicated in patients with kidney failure, convulsive disorders (due to their neurotoxic metabolite normeperidine), or patients who take MAOIs due to the risk of malignant hyperthermia syndrome. Only recommended in patients with intolerance to all other opioids.
Tramadol [36] is a synthetic opioid with a weak affinity for receptor µ (6, 000 times lower than morphine) and also for receptors κ and σ; it presents with a non-opioid mechanism, as it inhibits the central reuptake of serotonin and adrenaline, and has mild properties as a local peripheral anaesthetic. It produces a smaller number of side effects, such as nausea, due to a lower potency compared to morphine (1/5-1/10 depending on whether its administration is oral or parenteral) and it has an active metabolite [M1 (mono-O-desmethyltramadol)] with a greater affinity for opioid receptors than the original compound, which is why it contributes to the overall analgesic effect. It has shown its usefulness in a large variety of processes with moderate pain, with a dose of 100 mg /8 h IV recommended in the postoperative period. The efficacy of tramadol for the management of moderate to severe postoperative pain has been demonstrated in both inpatients and day surgery patients. Most importantly, unlike other opioids, tramadol has no clinically relevant effects on respiratory or cardiovascular parameters. It may prove particularly useful in patients with poor cardiopulmonary function, including the elderly, the obese and smokers, in patients with impaired hepatic or renal function, and in patients in whom NSAIDs drugs are not recommended or need to be used with caution. Parenteral or oral tramadol has proved to be an effective and well-tolerated analgesic agent in the perioperative setting.
Oxycodone [37] is a semisynthetic pure agonist derived from the natural opioid alkaloid thebaine, which is becoming the most used opioid in North America for the treatment of moderate to severe pain, as its pharmacodynamics are similar to those of morphine. Because its chemical structure only varies in a CH3 group in position 3, and an oxygen in position 6, it has certain pharmacokinetic advantages over morphine. Its administration, aside from analgesia, produces anxiolysis, euphoria, a sensation of relaxation, and inhibits coughing. It is available as immediate-release and sustained-release oral tablets, releasing 38% during the first two hours and the rest during the following 6-12 h, which is why they must be swallowed without chewing, to avoid an overdose. It differs from morphine in terms of its greater oral bioavailability (60-87% in the retarded form, and almost 100% in the immediate-release form), a slightly greater half-life (3-5 h) and in its liver metabolism, which occurs by means of the cytochrome P-450 (CPY2D6) rather than by glucuronidation, which is why it can interact with sertraline and fluoxetine, potent inhibitors of said enzyme. It reaches a plasma steady state after 24-36 h of treatment. It is metabolized mainly into noroxycodone, which has a relative analgesic potency of 0.6 and to a lesser extent, in oxymorphone which has a high analgesic power, both of which are eliminated by the kidney. The plasma clearance for adults is of 0.8 L/min, and about 40% binds to proteins. Its administration must not be adjusted with respect to age, although it is reduced by 20-50% in patients with liver or kidney failure and concomitant treatment with other CNS depressants, such as benzodiazepines. A better risk/benefit ratio in the postoperative period appears to be associated with the use of ibuprofen or paracetamol and it has a neuropathic pain efficacy due to its “κ-agonist” action. As a treatment guide, 10 mg of oxycodone are equal to 20 mg of oral morphine. Oxycodone is highly effective and well tolerated in different types of surgical procedures and patient groups, from preterm to aged patients. In the future, the use of trans mucosal administration and enteral oxycodone-naloxone controlled-release tablets is likely to increase, and an appropriate concurrent use of different enteral drug formulations will decrease the need for more complex administration techniques, such as intravenous patient-controlled analgesia [38].
Tapentadol [39] is a new mixed analgesic of dual central action, μ-opioid agonist and noradrenalin reuptake inhibitor. It is 2-3 times less potent than morphine, but it is in turn, twice as potent as tramadol. It was approved in November 2008 by the FDA for the treatment of moderate to severe pain in adult patients. It is available in immediate-release (IR) tablets of 50, 75, 100, 150 mg, with a half-life of 4-6 h and a maximum daily dose of 600 mg. A 12-h sustained-release presentation has recently been marketed for the management of chronic pain. It has a better safety profile for nausea and/or vomiting and constipation compared to oxycodone IR and also has a significantly lower rate of treatment discontinuation. It has been successfully tested after otorhinolaryngological and dental surgery, in chronic osteoarticular pain, both of the rachis and is associated with knee and hip arthrosis. The observed efficacy across different pain models and favourable gastrointestinal tolerability profile associated with tapentadol IR indicate that this novel analgesic is an attractive treatment option for the relief of moderate-to-severe acute pain [40].
Good pain control after surgery is important in preventing negative outcomes such as tachycardia, hypertension, myocardial ischemia, decrease in alveolar ventilation and poor wound healing. Exacerbations of acute pain can lead to neural sensitization and the release of mediators both peripherally and centrally. Clinical wind up occurs as a consequence of the processes of N-Methyl D-Aspartate (NMDA) activation, wind up central sensitization, the long-term potentiation of pain and transcription-dependent sensitization. Advances in the knowledge of molecular mechanisms have led to the development of multimodal analgesia and new pharmaceutical products to treat postoperative pain. They include extended-release epidural morphine and analgesic adjuvants such as capsaicin, ketamine, gabapentin, pregabalin, dexmedetomidine and tapentadol. Newer postoperative patient-controlled analgesia (PCA) in modes such as intranasal, regional, transdermal, and pulmonary presents another interesting avenue of development [41].
NMDA-antagonist drugs are used as modulators of pain, hyperalgesia and allodynia after surgical trauma. Ketamine is involved in opioid, cholinergic and monoaminergic systems; it may act on sodium channels, although the optimal dose and route of administration are yet to be defined. It has been tested as an analgesic potentiation drug, and in a systematic review on 2, 240 patients [42], it was verified that, in the treatment of acute postoperative pain at sub anaesthetic doses (0.1-0.25 mg/kg), either IV, IM or epidural (0.5-1 mg/kg), it is effective in reducing morphine consumption during the first 24 h after surgery, and reducing nausea and vomiting with a low incidence of side effects. Further, intravenous ketamine is an effective adjunct for postoperative analgesia. Particular benefit was observed in painful procedures, including upper abdominal, thoracic and major orthopaedic surgeries. The analgesic effect of ketamine was independent of the type of intraoperative opioid administered, the timing of ketamine administration, and the ketamine dose [43]. Despite using less opioid, 25 out of 32 treatment groups (78%) experienced less pain than the placebo groups at some point postoperatively when ketamine was efficacious. This finding implies an improved quality of pain control in addition to decreased opioid consumption. Hallucinations and nightmares were more common with ketamine but sedation was not. When ketamine was efficacious for pain, postoperative nausea and vomiting were less frequent in the ketamine group. The dose-dependent role of ketamine analgesia could not be determined. Dextromethorphan (40-120 mg IM) and amantadine (200 mg IV) are other drugs of this group that have been used with varying efficacy [16].
Agonists of α2–adrenergic receptors, such as clonidine (2-8 μg/kg IV) and dexmedetomidine (2.5 μg/kg IM) enhance the analgesic and sedative effects of opioids centrally, at the level of the locus coeruleus and of the posterior medullary horn, respectively, but its side effects such as hypotension and bradycardia limit their routine use intravenously or through the medulla. A very recent systematic review and meta-analysis [44], looked at 30 relevant studies (1, 792 patients, 933 received clonidine or dexmedetomidine). There was evidence of postoperative morphine sparing at 24 h; the weighted mean difference was -4.1 mg (95% confidence interval, -6.0 to -2.2) with clonidine and -14.5 mg (-22.1 to -6.8) with dexmedetomidine. There was also evidence of a decrease in pain intensity at 24 h; the weighted mean difference was -0.7 cm (-1.2 to -0.1) on a 10 cm visual analogic scale with clonidine and -0.6 cm (-0.9 to -0.2) with dexmedetomidine. The incidence of early nausea was decreased with both (number needed to treat, approximately nine). Clonidine increased the risk of intraoperative (number needed to harm, approximately nine) and postoperative hypotension (number needed to harm, 20). Dexmedetomidine increased the risk of postoperative bradycardia (number needed to harm, three). Recovery times were not prolonged. No trial reported on chronic pain or hyperalgesia.
Gabapentin and pregabalin, structural analogues of γ–amino butyric acid, are the first-line treatment for neuropathic pain, and their usefulness in postoperative pain is due to their action on the α2δ-1 subunit of voltage-dependent calcium channels of the posterior medullary horn. Their oral administration, and their central adverse effects, such as dizziness and somnolence, limit their use. Which is why their effective dose and treatment duration are yet to be defined. Their greatest usefulness lies in their ability to reduce the consumption of opioids in the postoperative period, as well as to reduce pain in movement and quality of sleep, which is why it is being used successfully in orthopaedic surgery, improving rehabilitation [45]. They are also useful in patients who are used to opioids by reducing their consumption in the postoperative period. They have also recently shown their usefulness in the prevention of postsurgical chronic pain [9]. In a recent meta-analysis [46], pregabalin administration reduced the amount of postoperative analgesic drugs (30.8% of non-overlapping values - odds ratio=0.43). There was no effect with 150, and 300 or 600 mg/day provided identical results. Pregabalin increased the risk of dizziness or light-headedness and of visual disturbances, and decreased the occurrence of postoperative nausea and vomiting (PONV) in patients who did not receive anti-PONV prophylaxis. The authors concluded that the administration of pregabalin during a short perioperative period provides additional analgesia in the short term, but at the cost of additional adverse effects. The lowest effective dose was calculated as 225-300 mg/day.
Postoperative nausea and vomiting are the most common complications after anaesthesia and surgery, and both female sex and laparoscopic technique are risk factors. It is certainly of a remarkably high incidence after laparoscopic gynaecological surgery, which is reported as being at nearly 70% within the first postoperative 24 hours. Corticoids have analgesic and anti-inflammatory properties due to the joint inhibition of cyclooxygenase and lipoxygenase, and it has been shown that the preoperative use of dexamethasone (4-8 mg IV) also prevents the appearance of postoperative vomiting and nausea, especially after laparoscopy. In a recent meta-analysis [47], prophylactic dexamethasone administration decreased the incidence of nausea and vomiting after laparoscopic gynaecological operations in post-anaesthesia care units and within the first postoperative 24 hours. In a review of the current mechanisms for reducing postoperative pain, nausea and vomiting, epidural anaesthesia did not reduce the length of a hospital stay or the incidence of PONV despite reducing pain intensity and ileus. NSAIDs are more effective than paracetamol in reducing postoperative opioid consumption and PONV, while dexamethasone and 5-HT3 antagonists are both effective in reducing PONV [48]. Dehydrobenzperidol is also used as a first-line agent in the treatment of postoperative vomiting and in a quantitative systematic review of randomized controlled trials of 2, 957 patient´s doses below 1mg was determined as the optimal IV dose. Two patients receiving 0.625 mg of droperidol had extrapyramidal symptoms. Cardiac toxicity data were not reported. The authors concluded that because adverse drug reactions are likely to be dose-dependent, there is an argument to stop using doses of more than 1 mg [49].
In a meta-analysis of 1, 754 patients, it has been verified that the perioperative infusion of lidocaine [50] reduced the intensity of pain and the consumption of opioids postoperatively, the incidence of paralytic ileus and of nausea and vomiting, as well as the length of hospital stay. The efficacy was greater in patients who underwent abdominal surgery. Considering that in some cases, toxic levels were detected, and that adverse effects were not collected systematically in all the studies, we must establish a safety range before recommending their systematic use. In another recent systematic review of 764 patients, having open and laparoscopic abdominal surgery, as well as ambulatory surgery patients [51], intravenous perioperative infusion of lidocaine resulted in significant reductions in postoperative pain intensity and opioid consumption. Pain scores were reduced at rest and with coughing or movement for up to 48 hours postoperatively. Opioid consumption was reduced by up to 85% in lidocaine-treated patients when compared with controls. The infusion of lidocaine also resulted in earlier return of bowel function, allowing for earlier rehabilitation and a shorter duration of hospital stay. First flatus occurred up to 23 hours earlier, while first bowel movement occurred up to 28 hours earlier in the patients treated with lidocaine. The duration of the hospital stay was reduced by an average of 1.1 days in the patients treated with lidocaine. The administration of an intravenous lidocaine infusion did not result in toxicity or clinically significant adverse events. Lidocaine had no impact on postoperative analgesia in patients undergoing tonsillectomy, total hip arthroplasty or coronary artery bypass surgery. Systemic lidocaine also improves the postoperative quality of recovery in patients undergoing outpatient laparoscopy. In a recent study [52], patients who received lidocaine had less opioid consumption, which was translated to a better quality of recovery. The authors concluded that lidocaine is a safe, inexpensive and effective strategy for improving the quality of recovery after ambulatory surgery.
IV Magnesium has been reported to improve postoperative pain, however, the evidence is inconsistent. The objective of a very recent quantitative systematic review was to evaluate whether or not the perioperative administration of IV magnesium can reduce postoperative pain. Twenty-five trials comparing magnesium with a placebo were identified. Apart from the mode of administration (bolus or continuous infusion), perioperative magnesium reduced cumulative IV morphine consumption by 24.4% (mean difference: 7.6 mg, 95% CI -9.5 to -5.8 mg; p < 0.00001) at 24 h postoperatively. Numeric pain scores at rest and on movement at 24 h postoperatively clearly improved and both were reduced by 4.2 (95% CI -6.3 to -2.1; p < 0.0001) and 9.2 (95% CI -16.1 to -2.3; p = 0.009) out of 100, respectively. The authors concluded that perioperative IV magnesium reduces opioid consumption and, to a lesser extent, pain scores, in the first 24 h postoperatively, without any reported serious adverse effects [53].
Non-pharmacological techniques, such as transcutaneous electrical nerve stimulation (TENS), which works by activating the opioid receptors and thick Aβ fibres, auricular acupuncture, music therapy or psychotherapy, may also be useful in the postoperative period, but more studies are needed to verify their efficacy as coadjutant to pharmacological therapy [54].
Relief of acute pain during the immediate postoperative period is an important task for anaesthesiologists. Morphine is widely used to control moderate-to-severe postoperative pain and the use of small IV boluses of morphine in the post-anaesthesia care unit (PACU) allows for a rapid titration of the dose needed for adequate pain relief. The essential principle of a titration regimen must be to adapt the morphine dose to the pain level. Although morphine would not appear to be the most appropriate choice for achieving rapid pain relief, this is the only opioid assessed in many studies of immediate postoperative pain management using titration. More than 90% of the patients achieve pain relief using a protocol of morphine titration (2-3 mg/ 5 min.) and the mean dose required to obtain pain relief is 12 mg, after a median of four boluses. Sedation is frequent during IV morphine titration and should be considered as a morphine-related adverse event and not evidence of pain relief. The incidence of respiratory depression is very low when the criteria for limiting the dose of IV morphine are enforced. Morphine titration can be used with caution in elderly patients, in children, or in obese patients. In real practice, morphine titration allows the physician to meet the needs of individual patients rapidly and limits the risk of overdose making this method the first step in postoperative pain management [55].
The introduction of patient-controlled analgesia (PCA) has provided us a very useful tool in the adjustment of opioid doses within a broad range of postoperative needs, in turn minimizing adverse effects. Patients can self-administer a rescue dose, with or without a background regimen, thus maintaining plasma therapeutic levels. The basis of the treatment consists of a period of closure after the administered bolus in which a new administration is not allowed, thus avoiding the appearance of side effects, such as excessive sedation or respiratory depression [35].
In a practical sense [35], it is advised to administer 2-4 mg of morphine IV every 5-10 min. in the post anaesthetic recovery unit until the pain is controlled, and then start with 1 mg every 6-8 min, without a baseline infusion. If the patient does not achieve an adequate analgesia, the dose of the bolus will be increased to 1.5-2 mg and, as a last resort, a continuous infusion of 1-2 mg/h will be implemented, as long as it does not constitute > 50% of the total administered dose (see fig. nº1). In case of patients with chronic opioid treatment, this opioid infusion could be of up to 80%. The total dose to be scheduled may be calculated according to the rule mg/day/morphine = 100 - age. The systematic review showed a better analgesic quality, together with a lesser morbidity, compared to other analgesic IV regimens without PCA, but there were no differences in the total consumption of opioids, side effects or days of hospital stay. The incidence of adverse effects, such as respiratory depression (< 0.5%) does not seem to differ from other routes of opioids administration, such as the parenteral or neuraxial routes, and it is lower in the pure form of IV PCA.
Titration of IV morphine in bolus or PCA in the PACU [35, 55]
Transdermal Iontophoresis [56] is a drug delivery system by which a molecule with an electrical charge penetrates through the skin in the presence of an electric field. There is a need for an active infusion system, either local or systemic, that delivers lipophilic drugs, composed of small, positively charged particles. It has been tested with transdermal fentanyl in a system similar to a credit card, with an autonomous battery, and a button for the administration of boluses, placed on the arm or on the chest. The administered dose is prefixed at 40 μg, with a closure of 10 min, and with a limit of 80 doses a day and/or 24 h of treatment, whichever occurs first. The on-demand dosing and pharmacokinetics of this system differentiate it from the passive transdermal formulation of fentanyl designed for the management of chronic pain. Its results appear to be comparable to morphine in IV PCA in the treatment of acute postoperative pain, with a good-excellent overall satisfaction of 74-80%, and with a similar incidence of adverse effects, being nausea the most frequent in almost 40% of the patients The use of this system may serve as an alternative modality for the management of acute pain without increasing such adverse effects as bleeding, intravenous catheter infiltration, or manual pump malfunction.
There is also the possibility of carrying out a patient controlled intranasal analgesia (PCINA) [57] with a rapid absorption of opioids. Intranasal drug administration is an easy, well-tolerated, non-invasive trans mucosal route that avoids first-pass metabolism in the liver. The nasal mucosa provides an extensive, highly vascularized surface of pseudo stratified ciliated epithelium. It secretes mucus that is subjected to mucociliary movement that can affect the duration of the contact between the drug and the surface. Absorption is influenced by anatomical and physiological factors as well as by properties of the drug and the delivery system. The drug most used is fentanyl at similar doses to intravenous route, but other opioids have been used to treat acute pain like meperidine, diamorphine and butorphanol. The adverse systemic effects are similar to those described for intravenous administration, the most common being drowsiness, nausea and vomiting. Local effects reported are a burning sensation with meperidine and a bad taste.
Patient-controlled regional analgesia (PCRA) [58] encompasses a variety of techniques that provide effective postoperative pain relief without systemic exposure to opioids. Using PCRA, patients control the application of pre-programmed doses of local anaesthetics, most frequently ropivacaine or bupivacaine (occasionally in combination with an opioid), via an indwelling catheter, which can be placed in different regions of the body depending on the type of surgery. Infusions are controlled either by a staff-programmed electronic pump (similar to that used for IV PCA) or a disposable elastomeric pump. An elastomeric pump is a device that has a distensible bulb inside a protective bulb with a built-in filling port, delivery tube and bacterial filter. Analgesia can be delivered directly into a surgical incision (incisional PCRA), intra-articular (IA), tissue (IA PCRA), or perineural site (perineural PCRA).
In recent years, continuous peripheral nerve blockade has gained increasing acceptance as a safe and effective technique that provides better analgesia than opioids. A meta-analysis [59] that compared systemic opioids with regional peripheral techniques confirms a superior analgesia in the latter; regardless of whether they are used in the form of a single bolus or in a continuous infusion. In this review, perineural analgesia provided better postoperative analgesia compared with opioids (P < 0.001). This effect was seen for all time periods measured for both mean visual analogic scale (VAS) and maximum VAS at 24 h (P < 0.001), 48 h (P < 0.001), and 72 h (mean VAS only) (P < 0.001) postoperatively. Perineural catheters provided superior analgesia to opioids for all catheter locations and time periods (P < 0.05). Nausea/vomiting, sedation and pruritus all occurred more commonly with opioid analgesia (P < 0.001). A reduction in opioid use was noted with perineural analgesia (P < 0.001). In spite of this, the overall benefit to the prognosis of postoperative patients has not been statistically proven.
Patient-controlled epidural analgesia (PCEA) allows for an individualized postoperative regimen that reduces pharmacological requirements, improves the degree of satisfaction and provides a higher analgesic quality. In series of more than 1, 000 patients, 90% were satisfied, with a VAS score of 1 at bed rest to 4 in motion. The presence of side effects was similar to the continuous epidural technique, standing out: itching (16.7%), nausea (14.8%), sedation (13.2%), hypotension (6.8%), motor block (2%) and respiratory depression (0.3%). The specific site of action of LAs is located at the level of the sheath of spinal nerve roots, the ganglion of the dorsal root and through the meninges in the spinal cord itself. The LAs most used are bupivacaine (≤ 0.125%), ropivacaine (≤ 0.20%), and levobupivacaine (≤ 0.125%), together with fentanyl (2-5 μg/mL) or sufentanil (0.5-1 μg/mL) which enhance their analgesic action and allow for a reducing of their total dose [60]. This route of administration has proven to be superior to the IV PCA formula with opioids. Continuous epidural techniques include the benefits of the metameric localized delivery of analgesic drugs with extended delivery in infusion and the capability to adjust the optimal degree of quality and depth in each patient, producing a sensitive postoperative block, with a minimal compromise to movement [61]. The combined use of regional-general anaesthesia improves the immediate recovery after surgery, and allows for an analgesic control of a higher quality than that offered by systemic opioids [62]. The location of the epidural catheter must be, whenever technically possible, metameric to the surgical zone, as it has been demonstrated that a thoracic catheter for thoraco-abdominal surgery reduces cardiorespiratory morbidity and mortality, improves analgesic quality and reduces the incidence of adverse effects such as urine retention and motor block [63].
A broad meta-analysis of data from 141 randomized controlled trials, which studied a total of 9, 559 patients, showed that the use of epidural or spinal anaesthesia was associated with a 30% decrease in 30 day mortality, in addition to other beneficial effects such as a 55% decrease in the incidence of pulmonary embolism, a 39% decrease in pneumonia, a 50% decrease in transfusion requirements, and a 44% decrease in deep venous thrombosis. There was also evidence of further benefits such as a decrease in the risk of respiratory depression, myocardial infarction and renal failure [64]. However, data from more recent studies in patients undergoing major surgery failed to show any decrease in mortality with perioperative epidural analgesia when compared with a combination of general anaesthesia and the use of systemic opioids [65]. Further, an Australian multicentre study (The Master Trial), on epidural anaesthesia in abdominal surgery in high-risk patients, on 888 cases collected over six years (1995-2001) did not show such beneficial effects. There was no reduction in the morbidity in the group receiving epidural administration compared to the control group with opioids and parenteral administration, and the mortality at 30 days was similar (4.3% in the control versus 5.1% in the group with epidural administration). Only acute respiratory failure (ARF) was less frequent in the epidural group (23% in epidural versus 30% in the control, p = 0.02). An NNT of 15 patients was calculated to achieve the prevention of an ARF episode. The pain score was lower and statistically significant in the epidural group, although the VAS was only reduced by 1 cm in the scale 0-10 cm [66].
For catheter placement, the loss of resistance using saline has become the most widely used method. Patient positioning, the use of a midline or paramedian approach, and the method used for catheter fixation can all influence the success rate. When using equipotent doses, the difference in clinical effect between bupivacaine and the newer isoforms levobupivacaine and ropivacaine appears minimal. With continuous infusion, the dose is the primary determinant of epidural anaesthesia quality, with volume and concentration playing a lesser role. The addition of adjuvants, especially opioids and epinephrine, may substantially increase the success rate of epidural analgesia. The use of patient-controlled epidural analgesia (PCEA) with background infusion appears to be the best method for postoperative analgesia [67].
In spite of what was demonstrated above, the thoracic epidural with a local anaesthetic and opioid is the technique of choice for reducing the consumption of IV opioids in the postoperative period for high-risk patients, patients undergoing open vascular and major thoraco-abdominal surgery [68], but some authors question the routine use of this mode of analgesia in the postoperative period for patients having abdominal surgery [69] or thoracic surgery in favour of a paravertebral blockade (PVB)[70]. There is also some evidence that the use of epidural analgesia may decrease the risk of cancer recurrence [71] and surgical site infection [72], although the published data supporting these effects is not yet convincing [73]. More controlled studies are needed to confirm these potentially exciting findings.
Paravertabral blockades (PVB) have been used to achieve unilateral analgesia for surgical and traumatic processes in the chest and abdomen. Its analgesic capacity is compared to the gold standard for this setting, which is thoracic epidural analgesia, always at the expense of the administration of more volume and a greater concentration of LA although adverse effects such as hypotension, urinary retention and vomiting are much less. Its greatest inconvenience is the variable distribution of LA after the single injection technique, with a measure of four sensitive levels blocked after the initial recommended dose of 0.2-0.3 mL/kg of 0.5% bupivacaine with adrenaline, as well as the time to the peak onset of action, which is 40 min and therefore it cannot be used as a preventive analgesia [74]. The failure rate for this technique is lower than that of the thoracic epidural and it is estimated to be above 6-10%, although the use of a stimulator helps improve the success rate. A systematic review and meta-analysis [75] on 520 patients in which both techniques were compared reflected a similar anaesthetic quality with a better profile of adverse effects and pulmonary complications in favour of a paravertebral block. Moreover, it is advantageous in patients who receive anti-aggregation and are under general anaesthesia. Its advantages for use with video thoracoscopy have not been well demonstrated, but they have been demonstrated in breast surgery [76].
In a review by Scarci et al., [70] PVB was found to be of equal efficacy to epidural anaesthesia in patients undergoing thoracotomy surgery, but with a favourable side effect profile, and a lower complication rate. The reduced rate of complication was most marked for pulmonary complications and was accompanied by a quicker return to normal pulmonary function. The epidural block was associated with frequent side effects [urinary retention (42%), nausea (22%), itching (22%) and hypotension (3%) and, rarely, respiratory depression (0.07%)]. Additionally, it prolonged operative time and was associated with technical failure or displacement (8%). Epidurals were also related to a higher complication rate (atelectasis/pneumonia) compared to the PVB.
The spinal administration of an opioid drug does not guarantee selective action and segmental analgesia in the spine. Evidence from experimental studies in animals indicates that bioavailability in the spinal cord biophase is negatively correlated with liposolubility, and is higher for hydrophilic opioids, such as morphine, than lipophilic opioids, such as fentanyl, sufentanil and alfentanil. All opioids administered produce part of their analgesic effect via spinal selectivity, although lipophilic opioids also rapidly reach higher centres of the brain due to their good vascular uptake and redistribution. Clinical trials have demonstrated that the administration of lipophilic opioids by continuous epidural infusion does not produce analgesia due to a spinal mechanism, nevertheless, by strengthening local anaesthesia they enable total doses to be reduced. This contrasts with single epidural injections of fentanyl, which with sufficiently high quantities of the drug can reach specific areas at the spinal level [77].
Morphine [78] is probably the opioid with the greatest medullary selective action after epidural (3-5 mg/day) or intradural administration. Morphine is the most used epidural opioid, and it could be considered the gold standard of spinal drugs (which does not imply it is the ideal one), because, due to its medullary selectivity, the epidural dose used is much lower than the parenteral dose (1/5-1/10), with a recommended daily maximum dose of 10 mg. It can be administered both in the form of boluses (30-100 µg/kg) and in a continuous infusion (0, 2-0, 4 mg /h), as the latter appears to induce a greater analgesic quality, and as a single drug or together with LAs, because these two drugs potentiate the global analgesic effect by means of a synergistic action, resulting in a postoperative analgesia of great quality and duration, but at the expense of a greater incidence of adverse effects. Despite epidural morphine being regarded as an effective drug via a route of administration that is just as effective, its use as a single dose is limited by its effective half-life of less than 24 h, a short duration compared with that of postoperative pain. Liposomes are spherical particles formed by an external phospholipid layer and an internal aqueous chamber, where the drug is located. This is why in 2004, the FDA approved extended release epidural morphine (EREM) liposome injections only for lumbar epidural use, with a half-life of 48 h after a single injection, delaying the peak concentration in the CSF by up to 3 h, without the problems associated with the catheter and with the expectation of improving the global failure rate by close to 30% of the continuous epidural technique. The basic points for its use include administration prior to surgery or after clamping the umbilical cord during a caesarean section and at least 15 min. after the epidural test dose of LA and that no more epidural drugs be given for 48 h, since the continuous infusion of LA increase the release of morphine. The formulation must not be injected through a filter as the particles may be disrupted [79]. As with all opioids, the chief hazard is respiratory depression especially in elderly and debilitated patients and in those with compromised respiratory function. In a meta-analysis on the risk of respiratory depression compared to intravenous morphine in patient-controlled analgesia (PCA), an odds ratio (OR) of 5.80 (95% CI 1.05 - 31.93; p = 0.04) was estimated for the use of EREM [80].
The continuous, solely epidural administration of fentanyl and sufentanil [77] offers very few advantages compared to its intravenous administration, which is why it is used with LAs to reduce its minimum effective analgesic concentration improving overall patient satisfaction. Lipophilic opioids such as fentanyl and sufentanil produce an analgesic effect mainly through systemic reuptake and their administration as a single drug does not offer any advantages compared to the parenteral route. However, their use with LAs enhances the analgesic effect, reducing the total dose of each of the drugs, as well as their adverse effects, such as hypotension and motor block. Fentanyl and sufentanil given epidurally or intradurally are the drugs of choice in obstetrics and ambulatory surgery, and are the coadjutants most commonly used together spinally with local anaesthetics in the perioperative period, improving analgesia without prolonging motor blockade. The spinal administration of alfentanil produces analgesia through systemic reuptake and redistribution to cerebral opioid receptors, as it has the greatest volume of distribution. Only fentanyl in bolus appears to present a specific medullary action in the group of lipophilic opioids in the epidural route at a concentration > 10 μg/ml. Finally, [78] epidural methadone and hydromorphone are suitable alternatives for analgesia in the postoperative period, given that they have intermediate pharmacokinetic characteristics with respect to the two aforementioned groups of opioids.
The components of an ideal epidural solution for the control of postoperative pain are yet to be defined, as none achieves a total relief of the baseline pain at rest and of the breakthrough pain of a dynamic nature, without adverse effects such as hypotension, motor block, nausea, itching or sedation. However, from the studies published to date (clinical, randomized, controlled trials), we may draw the following conclusions with a high level of clinical evidence associated with the use of epidural adrenalin [81]:
The combination of adrenalin with a mixture of low doses of bupivacaine (0.1 %) and fentanyl (2 µg/ml) has proven to be very effective in continuous infusion after major thoracoabdominal surgery, reducing the consumption of two other epidural drugs, as well as reducing their vascular absorption from the epidural space and improving the overall analgesic quality, efficacy and safety.
The minimum analgesic concentration of adrenalin has been estimated to be 1.5 µg/ml.
Ropivacaine has proven to be equipotent to bupivacaine in the same epidural mix.
The location of the epidural catheter must be metameric at the level of the thorax, as there is not enough scientific evidence to recommend the use of adrenalin in continuous infusion at the lumbar level.
Clonidine (5-20 μg/h) enhances the analgesic effect of the epidural mix, but the appearance of side effects such as hypotension, bradycardia or sedation limits its routine use. Neostigmine, a cholinesterase inhibitor, has been described as a strong analgesic coadjutant when using this route, at doses of 1-10 µg/kg after orthopaedic surgery to the knee, abdominal and gynaecological surgery, although it is limited by adverse effects such as sedation and nausea [82].
The objectives of a very recent quantitative systematic review were to assess both the analgesic efficacy and the safety of neuraxial magnesium. Eighteen published trials, comparing magnesium with placebos, have examined the use of neuraxial magnesium in its use as a perioperative adjunctive analgesic since 2002, with encouraging results. However, concurrent animal studies have reported clinical and histological evidence of neurological complications with similar weight-adjusted doses. The time to first analgesic request increased by 11.1% after intrathecal magnesium administration (mean difference: 39.6 min; 95% CI 16.3-63.0 min; p = 0.0009), and by 72.2% after epidural administration (mean difference: 109.5 min; 95% CI 19.6-199.3 min; p = 0.02) with doses of between 50 and 100mg. Four trials were monitored for neurological complications: of the 140 patients included, only a 4-day persistent headache was recorded. The authors concluded that despite promising perioperative analgesic effects, the risk of neurological complications resulting from neuraxial magnesium has not yet been adequately defined [83].
Intrathecal opioid administration can provide an excellent method of controlling acute postoperative pain and is an attractive analgesic technique since the drug is injected directly into the CSF, close to the structures of the central nervous system where the opioid acts. The procedure is simple, quick and has a relatively low risk of technical complications or failure. It is ever more frequent to associate opioids of different characteristics in the intradural route, a lipophilic opioid, such as fentanyl (20-40 μg), and/or a hydrophilic opioid such as morphine (100-300 μg), in the form of a bolus prior to surgery, together with LA, in order to guarantee coverage both during the immediate (2-4 h) and the late (12-24 h) postoperative period. Thus, associating a lipophilic opioid with bupivacaine or lidocaine leads to a shortening of the onset of the block and to an improvement of intraoperative analgesia as well as during the first hours of the postoperative period without prolonging the motor block or lengthening the time to discharge making it a good choice for ambulatory surgery [84].
In an excellent review by Rathmell JP et al. [85] on the use of intrathecal drugs in the treatment of acute pain, a maximum effective dose of morphine was advised, the negative effects of which seem to surpass the beneficial effects; after doses > 300 μg, nausea and itching usually appear, as well as severe urinary retention, and in studies on healthy volunteers, all of them presented with respiratory depression when the doses went beyond 600 µg.
In a meta-analysis [86] of 27 studies (15 concerning cardiothoracic, nine abdominal, and three spinal surgery) on a total of 645 patients who received doses between 100 and 4000 μg, it was demonstrated that among those given intrathecal morphine VAS at rest, on a scale of 10cm, was 2cm lower at 4 h and 1cm lower at 12 and 24 h, and this effect was more pronounced with movement, the relative improvement being more than 2cm throughout the period of monitoring. This lower score on a VAS was significantly better than the outcome with other analgesic techniques such as the administration of IV ketamine at low doses (scores fell by 0.4cm), a regimen of postoperative NSAID (scores fell by 1cm), and even the continuous epidural infusion technique (scores fell by 1cm), as assessed by the same authors previously [87]. The doses of opioids required intra- and postoperatively up to 48 h were lower among those given intrathecal morphine and the use of morphine up to 24 h was significantly lower in the abdominal surgery group (−24.2mg, CI: −29.5 to −19) than the cardiothoracic surgery group (−9.7mg, CI: −17.6 to −1.80). This more marginal benefit in the latter group makes the use of intrathecal morphine in thoracic surgery questionable, as a similar reduction in the amount of morphine required intravenously can be achieved using other strategies, such as the use of intraoperative ketamine (−16 mg/24 h) or postoperative NSAID (−10 to 20 mg/24 h) and even 4mg of IV paracetamol may be able to avoid using up to 8mg of morphine in the first day after surgery [88]. The adverse effects were indeed more common in the group given intrathecal morphine with an odds ratio of 7.8, 3.8 and 2.3 for respiratory depression, pruritus and urine retention, respectively, although interestingly there was not a higher rate of nausea or vomiting. Further, a recent meta-analysis has demonstrated that the addition of clonidine to intrathecal morphine extends the time to the first rescue analgesia in a postoperative setting by more than 75min. compared with morphine alone and it also reduces the amount of postoperative morphine by a mean of 4.45mg (95% CI: 1.40-7.49). However, as the effects are small, and the results are heavily influenced by a study in which intrathecal fentanyl was also given, the authors concluded that this must be balanced with the increased frequency of hypotension [89].
Attempts have been made to define the optimal doses and drugs for a series of surgical procedures with the following recommendations [84-86]:
Sufentanil 5-12.5 μg, or fentanyl 10-25 μg for orthopaedic, ambulatory surgery and caesarean section, and fentanyl 5 μg and sufentanil 2.5-5 μg for pain in labour, as sufentanil doses > 7.5 μg are associated with foetal bradycardia.
Morphine: 50-500 µg (Summarized in Figure nº2)
Recommended intrathecal morphine dosage for various surgical procedures in adults [84-86]
Key points for choosing the correct dose of intradural opioids [84-89]:
- Correct patient selection and minimum effective dose for each surgical procedure.
- Do not use morphine for ambulatory patients. Lyophilic opioids such as fentanyl and sufentanil are a better choice.
- Morphine DOSES ≥ 300 μg → have an elevated risk of late respiratory depression 6-12 h.
- Morphine DOSES < 300 μg have a similar risk to the parenteral administration of opioids.
- Monitored surveillance is recommended in the recovery or waking room or a mínimum monitoring for respiratory rate, oxygen levels (pulse oxymetry, if necessary) and above all, to monitor the level of consciousness for 12-24 h after intradural morphine and 4-6 h after fentanyl or sufentanil.
Peri-incisional analgesia is experiencing a great increase due to its ease of placement by the surgeon and its low profile of complications in the hospitalization ward (rate of infections < 0.7%, without the systemic toxicity risk of LA). It is carried out using a multi-perforated catheter of a similar length to the surgical wound, with an infusion of a long action LA without a vasoconstrictor, in a variable location in the literature, but predominantly in a subcutaneous or subfascial location. It has advantages in a large variety of processes with incisions of 7 to 15cm in length, with a lower VAS score, both at rest and in motion, as well as a lower consumption of opioids and a greater satisfaction for the patients, without affecting the hospital stay [16]. A systematic review, including 16 RCTs of patients undergoing major orthopaedic surgery and 15 RCTs undergoing cardiothoracic surgery, showed that postoperative pain management by wound catheter infusion was associated with decreased pain scores at rest and activity, opioid rescue dose, incidence of PONV and increased pain satisfaction [90]. However, a more recent meta-analysis was far less positive [91]. A total of 753 studies primarily fitted the search criteria and 163 were initially extracted. Of these, 32 studies were included in the meta-analysis. Wound catheters provided no significant analgesia at rest or during activity, except in patients undergoing gynaecological and obstetric surgery at 48 h (P=0.03). The overall morphine consumption was lower (≈13 mg) during 0-24 h (P<0.001) in these patients. No significant differences in side effects were found, except for a lower risk of wound breakdown (P=0.048) and a shorter length of hospital stay (P=0.04) in patients receiving LA. Some authors disagree about these results arguing that these conclusions were due to the exclusion of orthopaedic patients and patients in whom catheters were not actually placed in the surgical wound [92].
A recent study has evaluated the efficacy of the preperitoneal continuous wound infusion (CWI) of ropivacaine for postoperative analgesia after open colorectal surgery in a multicentre randomized controlled trial. Over the 72-hour period after the end of surgery, CWI analgesia was not inferior to continuous epidural analgesia (CEA). The difference of the mean VAS score between CEI and CWI patients was 1.89 (97.5% confidence interval = -0.42, 4.19) at rest and 2.76 (97.5% confidence interval = -2.28, 7.80) after coughing. Secondary end points, morphine consumption and rescue analgesia, did not differ between groups. Time to first flatus was 3.06 ± 0.77 days in the CWI group and 3.61 ± 1.41 days in the CEI group (P = 0.002). Time to first stool was shorter in the CWI than the CEI group (4.49 ± 0.99 versus 5.29 ± 1.62 days; P = 0.001). The mean time to hospital discharge was shorter in the CWI group than in the CEI group (7.4 ± 0.41 and 8.0 ± 0.38 days, respectively). More patients in the CWI group reported an excellent quality of postoperative pain control (45.3% versus 7.6%). The quality of night sleep was better with CWI analgesia, particularly at the postoperative 72-hour evaluation (P = 0.009). Postoperative nausea and vomiting were significantly less frequent with CWI analgesia at the 24 hours (P = 0.02), 48 hours (P = 0.01), and 72 hours (P = 0.007) after surgery evaluations [93].
Appropriate catheter positioning is important, as it seems that preperitoneal placing is associated with better analgesia in patients undergoing open colorectal surgery, whilst subfascial placing provides good analgesia after caesarean section. The evidence-based PROSPECT recommendations include wound infiltration for inguinal herniotomy, laparoscopic cholecystectomy, hysterectomy, open colon surgery (preperitoneal infusion), total knee arthoplasty and haemorrhoidectomy [94]. This technique is also recommended by the ASA (American Society of Anesthesiology) practice guidelines as a part of a multimodal analgesia strategy for the management of postoperative pain [95].
Due to the large variability of surgical interventions and the multiplicity of factors involved in postoperative pain, two initiatives have been put forward for drafting a practical guideline based on clinical evidence, specific for each process, and both are available on the Internet. One of them comes from the Veterans Health Administration of the US, in collaboration with the Defence Department and the University of Iowa (www.oqp.med.va.gov/cpg/cpg.htm), and the other from a working group of European anaesthesiologists and surgeons, the Prospect Working Group (www.postoppain.org). In the latter, the level of recommendation for each drug or medical acts for all of the perioperative periods are defined, and it currently contains 10 surgical procedures [94]. The Prospect Group helps physicians choose the most adequate drugs and technique combinations based on the published medical evidence and they are specialized in providing evidence-based and procedure-specific recommendations and clinical decision support for the management of postoperative pain. These are some examples for postoperative pain management:
This is the modus operandi of the Prospect Group:
Procedure-specific recommendations take into consideration the differences in character, location and severity of pain associated with different surgical procedures.
Evidence from a systematic review is supplemented with transferable evidence and expert knowledge from a Working Group of surgeons and anaesthesiologists.
Consensus recommendations are formulated by the Prospect Working Group, using established methods for group decision-making (Delphi method, Nominal Group Process).
Recommendations are graded to indicate the strength of recommendations (A–D).
Recommendations are provided with an explanation of the evidence on which they are based, including the level (LoE 1–4) and source of evidence (procedure-specific or transferable).
All evidence from systematic reviews, as well as transferable evidence, is summarized and abstracts of all references are provided.
Studies included in the reviews are assessed and assigned a level of evidence: study design, quality, consistency and directness are taken into consideration.
Procedure-specific evidence, transferable evidence and clinical practice information (expert opinion) are clearly separated.
Benefits and harms of different interventions are indicated with a system of ticks and crosses, and the balance of benefits and harms is considered in formulating the recommendations.
Evidence and recommendations are freely accessible on the Internet at www.postoppain.org (Consult the original website for clarification of each level of recommendation)
Recommendations for colonic surgery:
Continuous thoracic epidural anaesthesia and analgesia at a level appropriate to the site of incision are recommended for routine use, based on superior postoperative analgesic and safety benefits compared with systemic techniques, if there is no contraindication for epidural administration. (Grade A)
Where epidural techniques are used, it is recommended that a combination of strong opioid and LA must be used because of the increased analgesic efficacy compared with a strong opioid alone and to reduce the dose of opioids and their associated side effects. (Grade A)
Preoperative administration of a single-shot epidural analgesia produces a similar postoperative analgesic efficacy to postoperative administration
Continuous epidural anaesthesia and postoperative analgesia are recommended for routine use in colonic resection (Grade A), based on their benefits for reducing postoperative pain, systemic opioid use and improving bowel recovery time [(Level of evidence 1 (LoE 1)]
A combination of epidural local anaesthetic (LA) and strong opioid is recommended for epidural analgesia (Grade A), based on procedure-specific evidence of their combined efficacy, in reducing postoperative pain and systemic opioid use, compared with LA alone (LoE 1). However, the addition of opioid to epidural LA results in an increase in time to the first bowel movement. (LoE 1)
Where epidural techniques are used, it is recommended that the epidural catheter be inserted preoperatively because this is the most practical timing for insertion. (Grade D, LoE 4)
COX-2-selective inhibitors (Grade B) (only for patients who do not receive epidural analgesia)
Continuous administration of pre/intraoperative IV lidocaine if continued during the immediate postoperative period (Grade B), when epidural analgesia is not feasible or contra-indicated.
Spinal analgesia is not recommended in combination with epidural anaesthesia (Grade B), based on the lack of benefit in reducing postoperative pain in colonic resection (LoE 2). Moreover, it introduces a greater level of complexity. (LoE 4)
The decision concerning the type of operative technique or incision to use for colonic resection should be primarily based on factors other than the management of postoperative pain, e.g., malignancy versus benign disease operative risk factors of the patient, risk of wound infection, and availability of surgical expertise (Grade D)
Laparoscopic colonic resection is recommended over open colon surgery for reducing postoperative pain, if the conditions outlined above allow (Grade A)
A horizontal/curved (transverse) incision is recommended over a vertical incision for analgesic and other benefits if the operative conditions allow (Grade B). In addition, the horizontal/curved incision is preferred for its cosmetic benefits (Grade D)
Diathermy is recommended over the scalpel (Grade C)
Maintenance of normothermia is recommended for improved clinical outcomes, but it is not helpful for reducing postoperative pain (Grade A)
Postoperative Recommended Systemic Analgesia:
COX-2-selective inhibitors (Grade B) (only for patients who are not receiving epidural analgesia or upon the cessation of epidural analgesia)
Conventional NSAIDs (Grade A) (only for patients who are not receiving epidural analgesia or upon the cessation of epidural analgesia)
IV lidocaine (Grade B) (when epidural is not feasible or contra-indicated)
Strong opioids (Grade B) (for high-intensity pain)
Weak opioids (Grade B) in association with other non-opioid analgesics (for moderate- or low-intensity pain), or if non-opioid analgesia is insufficient or contra-indicated
Paracetamol (Grade B) for moderate- or low-intensity pain (only for patients who do not receive epidural analgesia, or after the cessation of epidural analgesia)
Recommendations for post-thoracotomy pain:
Pre- and intraoperative thoracic epidural or Paravertebral Blockade (PVB) are recommended based on the reduction in pain compared with postoperative administration alone. (Grade A)
PVB LA or thoracic epidural LA plus a strong opioid is recommended as a preoperative bolus followed by an infusion continued for 2–3 days postoperatively, based on a reduction in pain compared with systemic analgesia. (Grade A)
There are not enough data to recommend one specific combination of LA over another, or a specific concentration or volume.
There are not enough data to recommend lipophilic opioids in preference to hydrophilic opioids or vice versa, in combination with LA.
Thoracic epidural LA plus an opioid is recommended in preference to a spinal strong opioid based on evidence that the analgesic effect of thoracic epidural analgesia has a longer duration than 24 h. (Grade A)
A preoperative single bolus of a spinal strong opioid is recommended as part of a multi-analgesic regimen (Grade A), when epidural analgesia or paravertebral blocks are not possible for any reason (Grade D). Repeated perioperative doses via the spinal route are not recommended because they are not considered to be safe or practical. (Grade D)
Spinal opioids are recommended in preference to intravenous PCA opioids, based on a greater reduction in pain for up to 24 hours, with no difference in respiratory function. (Grade A)
Lumbar epidural strong opioid is not recommended as the first choice based on evidence that the thoracic epidural route is more effective for pain relief (Grade A). However, there is procedure specific evidence that lumbar hydrophilic strong opioid reduces pain compared with systemic analgesia.
Epidural epinephrine is recommended if a low dose of epidural LA and/or opioid is used (Grade B).
Intercostal nerve block with LA (bolus at the end of surgery, followed by continuous infusion), if thoracic epidural analgesia and paravertebral blocks are not possible (Grade D)
Postoperative Recommended Systemic analgesia:
Conventional NSAIDs, if regional analgesia is inadequate (Grade A)
COX-2-selective inhibitors, if regional analgesia is inadequate (Grade B)
Intravenous PCA strong opioid, if regional analgesic techniques fail or are not possible (Grade D)
Weak opioids for moderate- (VAS>30<50 mm) or low- (VAS<30 mm) intensity pain in the late postoperative period, only if conventional NSAIDs/COX-2-selective inhibitors plus paracetamol are insufficient or contra-indicated (Grade D)
Paracetamol, if regional analgesia is inadequate, as part of a multianalgesic regimen (Grade D)
Recommendations for Abdominal Hysterectomy:
General anaesthesia, or single dose spinal anaesthesia with or without light general anaesthesia in low-risk patients (grade D)
Epidural anaesthesia combined with light general anaesthesia or combined spinal-epidural anaesthesia, in high-risk patients (grade A)
Strong opioids administered in time to secure sufficient analgesia when the patient wakes up (grade A)
Wound infiltration before closure (grade A)
LAVH or VH rather than abdominal hysterectomy, only if allowed by the surgical requirements (based on technical feasibility, patient indication for hysterectomy and risk factors) (grade A)
Pfannenstiel incision, only if allowed by the surgical requirements (based on technical feasibility, patient indication for hysterectomy and risk factors) (grade B)
Diathermy incision (grade B)
Active patient warming in high-risk patients (grade A)
Intraoperative music (grade A)
Postoperative Recommended Systemic Analgesia:
COX-2 selective inhibitors or conventional NSAIDs, in combination with strong opioids for high-intensity pain (VAS>50mm) or with weak opioids for moderate- (VAS<50>30) or low-intensity pain (VAS<30 mm) (grade A)
Strong opioids via IV PCA or via fixed IV dosing titrated to pain intensity (grade A)
Paracetamol for moderate- (VAS>30<50) or low-intensity (VAS<30 mm) pain, in combination with COX-2 inhibitors or conventional NSAIDs (grade A)
Recommendations for total hip arthroplasty:
COX-2-selective inhibitors or conventional NSAIDs (grade A) in combination with paracetamol and/or strong opioids for high-intensity pain (grade A) or with paracetamol and/or weak opioids for moderate- or low-intensity pain (grade D)
Strong opioids in combination with non-opioid analgesia to manage high-intensity pain (grade A), in time to provide analgesia in the early postoperative recovery period, administered by IV patient-controlled analgesia (grade A) or IV titrated for pain intensity (grade D)
Weak opioids for moderate- or low-intensity pain if conventional NSAIDs or COX-2-selective inhibitors are insufficient or are contra-indicated (grade D)
Paracetamol (grade A) in combination with conventional NSAIDs or COX-2-selective inhibitors, with or without rescue opioids (grade B)
Epidural infusion with local anaesthetic plus opioid for cardiopulmonary risk patients (grade B), in time to provide analgesia in the early postoperative recovery period (grade D)
Posterior lumbar plexus block (psoas sheath blocks) (grade A) or femoral nerve block (grade B) or single-bolus spinal morphine as a part of spinal anaesthesia (grade B), depending on the balance of efficacy and risks for the individual patient
Intraoperative, high-volume, low-concentration wound infiltration (LIA) (grade A)
Recommendations for total knee arthroplasty:
Pre or postoperative Femoral nerve block is recommended (Grade A) based on evidence of a reduction in pain scores and supplemental analgesia (procedure-specific evidence, LoE 1)
No recommendation can be made concerning continuous femoral infusion techniques versus a single bolus because of the heterogeneity in the study design and the inconsistency of procedure-specific data (LoE 4).
Spinal LA + opioid is recommended (Grade A, LoE 1), but not as the first choice of analgesic technique because of a greater potential for adverse events compared with femoral nerve block (transferable evidence, LoE 3)
Morphine is recommended as the opioid in the spinal LA + opioid combination (Grade A) based on evidence for a longer duration of analgesic effect than other opioids (procedure-specific evidence, LoE 1)
Preoperative epidural analgesia (LA and/or opioid) is not recommended as the first choice but it can be used if a femoral blockade is not possible (Grade B).
There is also overall scientific evidence published on the treatment of APP, which is summarized in figure nº3 [97]. In the case of ambulatory surgery, [98] multimodal or balanced regimens of analgesia based on non-opioid drugs have been imposed in order to reduce adverse effects such as nausea and/or vomiting. Moreover, preventive analgesia has been promoted which aims to achieve better control of postoperative pain, as it is one of the most important factors for readmission. It has been proven that a combined regimen of dexamethasone at a single preoperative dose, incision LA (at the beginning or at the end of the surgery) and a postoperative regimen of 3-5 days of NSAIDs (COXIB or non-selective NSAIDs) achieved the best results in the control of pain and in the reduction of the time of convalescence. The association of paracetamol, gabapentinoids and the continuous infusion of peri-incisional LA in an ambulatory setting have also achieved a beneficial effect in patients. In the case of a poor control of pain, opioid rescue medication, such as tramadol or oral oxycodone could be necessary.
Analgesic strategies with the Evidence Level (EL) in APP [97]:
(Ia) meta-analysis, including at least one controlled and randomized study with a large number of cases, (Ib) the same, but with fewer cases, (II) well designed cohort or case-control studies, (III) well designed descriptive, non-experimental studies (IV) studies based on expert opinions or committees, (V) insufficient evidence to reach an opinion.
It is normal daily practice to combine analgesics in order to improve the overall quality and patient satisfaction, but this does not mean we always meet our goal. Based on the studies that included controlled clinical trials or systematic reviews, that compare one drug with a combination of the same drug with one or more additional drugs via the same route of administration, Curatolo M et al. obtained the conclusions summarized in table IV [96].
The data currently available show that a multimodal programme of postoperative physical therapy and rehabilitation [99] can reduce the length of hospital stay, improve the control of dynamic pain and reduce the morbidity and mortality associated with the surgical procedure. We must begin with postoperative care that includes pain as the fifth vital sign, the use of regional analgesia to decrease opioid consumption, a responsible fluid therapy, maintaining normal body temperature, early mobilization, shortening the return to oral intake, avoiding motion-restriction factors such as drains, as well as improving postoperative sleep and stress, as they play a key role in reducing convalescence. This has led to the creation of ambulatory surgery units requiring coordination between all the healthcare specialists involved. Acute postoperative pain units are the key starting point for setting these programmes into motion.
Among the variety of surgical procedures, the recovery programme for colorectal surgery is one of the most studied and evaluated in the last decade. A recent meta-analysis concluded that the implementation of four or more elements of the Enhance Recovery After Surgery (ERAS) pathway leads to a reduction in the length of hospital stay by more than two days and an almost 50% reduction in complication rates in patients undergoing major colonic/colorectal surgery [100]. However, on the other hand, a Cochrane review of fast track surgery versus conventional recovery strategies for colorectal surgery concluded that the quality of the trials and the lack of other sufficient outcomes parameters do not justify the implementation of fast-track surgery as the standard for care [101].
Efficacy of pharmacological combination in acute postoperative pain (APP) [96]
In 2007, a review was published on the clinical evidence of the effect of postoperative analgesia on the major postoperative complications with the following conclusions [102]: the positive effects of epidural analgesia on cardiovascular events or on lung function are limited to high-risk patients or to major vascular surgery, which, in some cases, is irrelevant when using an endovascular technique, and those that are beneficial in the presence of paralytic ileus can be minimized by laparoscopic techniques and fast-track programmes. Moreover, they found no evidence that the perineural or peri-incisional administration of LA, the administration of opioids by PCA, or the programmes of postoperative multimodal analgesia had any positive beneficial effects on postoperative complications, although they do improve overall patient satisfaction.
Indeed, many authors have questioned the use of epidural analgesia as the first choice of technique in the recovery protocols after mayor surgery. Rawal N. [103] thinks that epidural analgesia is a well-established technique that has commonly been regarded as the gold standard in postoperative pain management. However, newer, evidence-based outcome data show that the benefits of epidural analgesia are not as significant as previously believed, and that there are some benefits by decreasing the incidence of cardiovascular and pulmonary complications, but these benefits are probably limited to high-risk patients undergoing major abdominal or thoracic surgery who receive thoracic epidural analgesia with local anaesthetic drugs only. In the review, it was demonstrated that there is increasing evidence that less invasive regional analgesic techniques are as effective as epidural analgesia. These include paravertebral block for thoracotomy, femoral block for total hip and knee arthroplasty, wound catheter infusions for caesarean delivery and colon surgery, and local infiltration analgesia techniques for lower limb joint arthroplasty. Wound infiltration techniques and their modifications are simple and safe alternatives for a variety of other surgical procedures. The author also argues that although pain relief associated with epidural analgesia can be outstanding, clinicians expect more from this invasive, high-cost, labour-intensive technique and that the number of indications for the use of epidural analgesia seems to be decreasing for a variety of reasons. The main conclusion is that the decision about whether to continue using epidural techniques should be guided by regular institutional audits and careful risk-benefit assessment rather than by tradition.
Finally, practice guidelines for acute postoperative pain management have been recently published. The experts recommend anaesthesiologists who manage perioperative pain to use therapeutic options such as epidural or intrathecal opioids, systemic opioid PCA, and regional techniques after thoughtfully considering the risks and benefits for the individual patient. These modalities should be used in preference to IM opioids ordered “as needed”. Consultants and ASA members also strongly agree that the therapy selected should reflect the individual anaesthesiologist’s expertise, as well as the capacity for the safe application of the modality in each practiced setting. Special caution should be taken when continuous infusion modalities are used, as drug accumulation may contribute to adverse events. [95]
Although great work is being carried out in the area of postoperative pain, there is still a long way to go. It is necessary to apply a multimodal approach to pain that includes the routine use of regional techniques, a combination of analgesics such as paracetamol, non-specific or COX-2 NSAIDs and opioids by different routes, making a responsible choice for the type of patient, the surgical management and the predicted adverse effects. The true role of coadjutant drugs and non-pharmacological therapies is yet to be seen, and in the future, it will be essential to have a practical guide based on clinical evidence for each process, that includes postsurgical rehabilitation.
We must delve into the pathophysiology of pain, and in the direct application of this knowledge to new drugs and new systems for drugs delivery that achieve a lower number of postoperative complications, as well as a better overall recovery and general well-being of the patients. Healthcare professionals must be trained in the field of pain and their work must be coordinated within an acute postoperative pain unit, the structure of which must be stable and multidisciplinary, so as to arrive at agreed analgesic regimens with surgical and nursing departments. In the future, the goal must be to also cover the late postoperative period with the creation of postsurgical acute and chronic pain units.
From the pioneering work of Boutonnet et al. [1], the synthesis of nanoparticles in microemulsions has been widely investigated with a variety of technical applications in catalysis [2, 3, 4], photonics [5], and energy conversion and storage devices [6, 7, 8]. The microemulsion route allows to control the size and composition of nanoparticles. A microemulsion consists of nanometer-sized water droplets dispersed in the oil phase and stabilized by a surfactant film. Reactants can be dissolved in the nano-sized water droplets or reverse micelles and can be exchanged between them by direct material transfer during an interdroplet collision [9]. The intermicellar exchange allows the reactants to be carried by the same droplet, so the chemical reaction can proceed inside the nanoreactor. Due to the space limitation inside the micelle, nucleation and growth of the particle are restricted, so it can result in the formation of size-controlled particles. In spite of the complexity of the reaction medium, microemulsion route has several advantages when compared to traditional methods. The first one is that nanoparticle size is directly controlled by the water/surfactant ratio, so narrow size distributions can be obtained. Another advantage is that surfactants around the nanoparticles can be removed with ease and nanoparticles can be prepared at room temperature. In addition, the confinement of reactants inside micelles induces important changes in reactant concentrations, which strongly affect the reaction rates. Finally, in relation to catalysis, nanoparticles obtained by the microemulsion route present an improved catalytic behavior than particles with the same composition which are synthesized by traditional procedures [10, 11].
\nA variety of nanomaterials, ranging from metals [12, 13, 14], bimetallic structures [15, 16, 17], other inorganic nanoparticles [18, 19, 20], and organic compounds [21, 22], has been prepared by this approach. In the field of catalysis, microemulsion approach was successfully used to prepare different nanostructured catalytic materials [2, 10, 17, 23, 24, 25].
\nNevertheless, microemulsion route present a challenge due to the difficulty in managing the material intermicellar exchange. As mentioned above, reactants are distributed in separate nanoreactors, so the whole process (chemical reaction, nucleation, and subsequent growth to build up final particles) is conditioned by the material exchange between them. This exchange is mainly dictated by the surfactant, which is located on the interface between water and oil phases. The hydrophilic portion of the surfactant is anchored into water and the lipophilic one into oil, forming a film which surrounds the micelle surface. It is believed that, when a micelle-micelle collision is violent enough, the surfactant film breaks up, allowing the material exchange. As a consequence, the rate of intermicellar exchange controls the reactants encounter and therefore plays a key role in chemical kinetics in microemulsions. The ease with which intermicellar channels are established as well as their size and stability are determined by the microemulsion composition, which in turn has been shown to affect final nanoparticle properties [26, 27, 28].
\nIn the paper at hand, we are focused on the study of Pt/M (M = Au, Rh) nanoparticles synthesized in microemulsions. Platinum-based nanoparticles (NPs) exhibit remarkable electrocatalytic activity in many important chemical and electrochemical reactions including oxygen reduction reaction (ORR) and direct methanol oxidation [29]. Apart from the inherent chemical and physical properties of the constitutive metals, the catalytic activity, which is one of the more relevant applications of bimetallic nanoparticles, relies notably on the metal distribution, that is, on the intraparticle nanoarrangement [30]. Bimetallic nanoparticles can show four main mixing patterns: (a) core-shell structures, in which one metal forms the core and the second metal covers the first one forming the surrounding shell; (b) mixed structures, which are often called alloys; (c) multilayer structures [31]; and (d) sub-cluster segregated structures, characterized by a small number of heteroatomic bonds [12]. So, the control of bimetallic intrastructure, mainly within the first atomic layers from the surface [25, 32], is key for performance enhancement of bimetallic catalysts. Furthermore, the optimal metal distribution depends on the particular chemical reaction. Au-core/Pt-shell nanocatalyst exhibits an improved activity to catalyze formic acid electro-oxidation [33] or oxygen reduction reaction [34, 35]. On the contrary, an alloyed Pt-Au is better for electro-oxidation of methanol [36]. Therefore, an in-depth study aimed at tailoring well-defined structures will be of great interest.
\nAlthough the simultaneous reduction of the two metals by the microemulsion route is one of the most common procedures to control the size and composition of bimetallic nanoparticles [24, 37], the prediction of the resulting metal arrangement is complicated, as far as the current state-of-the-art is concerned. As a matter of fact, many studies designed to produce new nanoarrangements via microemulsions come from trial-and-error experiments, mainly due to the high number of involved synthetic variables and to their interaction with the inherent complexity of the reaction media. A robust tool for elucidating the interplay between the different factors concerning final bimetallic nanoarrangements is computer simulation. With the aim of understanding the different factors affecting final nanostructures, we perform a comprehensive kinetic analysis of coreduction of different couple of metals in the light of the interplay between three kinetic parameters: intermicellar exchange rate, chemical reduction rates of the two metals, and reactants concentration. The particular combination of these factors determines the reaction rate of each metal, which in turn defines the final metal arrangement.
\nA model was developed to simulate the kinetic course of the two chemical reductions (see Ref. [38] for details). The reaction medium is a microemulsion, which is described as a set of micelles. The one-pot method is reproduced by mixing equal volumes of three microemulsions, each of which contains one of the three reactants (two metal precursors and the reducing agent R). This pattern of mixing reactants recreates the one-pot method, by which the two metal salts are simultaneously reduced.
\nReactants are initially distributed throughout micelles using a Poisson distribution, that is, the occupation of all micelles is not similar. In this study, we present results using different values of metal precursors concentration, but keeping a proportion 1:1 of the two metals: 〈cAuCl4−〉 = 〈cPtCl62−〉 = 〈c〉 = 2, 16, 32, and 64 metal precursors in each micelle, which corresponds to 0.01, 0.08, 0.16, and 0.40 M, respectively, in a micelle with a radius of 4 nm. Au and Rh precursors (AuCl4− and RhCl63−) are represented by M+. Calculations have been made under isolation conditions, that is, reducing agent R is in excess: (〈cR〉 = 10〈cPtCl62−〉).
\nMicelles move and collide with each other. The intermicellar collision is a key feature in kinetics in microemulsions, because upon collision micelles are able to establish a water channel, which allows the exchange of their contents (metal precursors, reducing agent, metallic atoms, and/or growing particles). The material intermicellar exchange makes possible the reactant encounter inside micelles and, as a consequence, it is determinant of chemical reactions to occur. The intermicellar collision is simulated by choosing a 10% of micelles at random. These selected micelles collide, fuse (allowing material intermicellar exchange), and then redisperse. One Monte Carlo step begins in each intermicellar collision and ends when the quantity of species carried by colliding micelles is revised in agreement to the exchange criteria described below.
\nThe reduction rate of a metal A (vA) can be related to the standard potential (ε0A) by means of the Volmer equation:
where jA is the current density, nA is the number of electrons, F is the Faraday constant, kred,A is the chemical rate constant, βA is the transfer coefficient, cO,A is the concentration of oxidized A, R is the gas constant, and T is temperature. When two metals A and B, initially at the same concentration (cO,A = cO,B), are reduced simultaneously to synthesize an A/B bimetallic nanoparticle, this equation can be simplified by assuming the following approximations: the number of electrons (nA = nB = n), the transfer coefficients (βA =βA = β), and the chemical rate constants (kred,A = kred,B = kred) are equal. (One must keep in mind that main factor governing reduction rates is by electrochemical potential.) Under this condition, a simple relation between the rates of electron transfer of two species A and B and their standard potentials can be deduced.
This equation supports the rule according to which the higher the difference between the standard potentials of the two metals, the higher the ratio between both reduction rates is.
\nOn the basis of Eq. (2), to simulate the reduction rate of Au/Pt nanoparticles, the standard reduction potential must be taken into account. When the Au precursor is AuCl4−, the standard reduction potential is ε0(AuCl4−) = 0.926 V, which is higher than that of Pt precursor ε0(PtCl62− = 0.742 V). This results in a faster formation rate of Au particles. In fact, Au is reduced so quickly that kinetics cannot be studied by conventional methods, so stopped flow techniques were needed [39]. The color change occurs instantaneously, so Au reduction was simulated as fast as possible, that is, 100% of Au precursors located in colliding micelles react to produce Au atoms, whenever the amount of reducing agent was enough. The reduction rate parameter of a metal A (vA) is the percentage of reactants inside colliding micelles which are reduced during a collision to give rise to products (A atoms). Regarding to Pt, its reduction rate was successfully simulated by using vPt = 10%, that is, only a 10% of Pt precursor reacts in each collision (vPt = 10%) [40]. In this way, Au/Pt nanoparticle formation is simulated by a reduction rate ratio vAu/vPt = 100/10 = 10, that is, Au reduction is 10 times faster than Pt.
\nThe two reductions can take place simultaneously within the same micelle. The metal precursors and/or reducing agent that did not react remain behind in the micelle and will be exchanged or react later.
\nIn order to research the influence of another metal in the pair Pt/M on Pt reduction, a metal whose reduction rate would be 10 times slower than Pt was chosen. In this manner, the reduction rate ratio is the same as used to simulate Au/Pt nanoparticles, so the possible differences in the kinetic behavior and the final metal distributions cannot be supported by the difference between the standard potentials. Therefore, the reduction rate of Pt is the same as that of Au/Pt pair (vPt = 10%), but now Pt is the faster metal. Taking into account the standard reduction potential of RhCl63−, ε0(RhCl63−) = 0.44 V, this Rh precursor is a good candidate to be simulated as vRh = 1% (only a 1% of RhCl63− located in the colliding micelles will be reduced (vPt/vRh = 10/1 = 10)).
\nThe number of each species located within each micelle is adjusted at each step in agreement with the possibility of chemical reduction and the intermicellar exchange criteria (see below). As the metallic atoms are produced in each micelle, they are assumed to be deposited on nanoparticle seed. That is, unlike for reactants, which are isolated within the micelle, all metal atoms inside a micelle are aggregated forming a growing nanoparticle. In order to calculate the metal distribution in the final bimetallic nanoparticle, the sequence of metals which are reduced is monitored in each micelle as a function of time.
\nTwo different intermicellar exchange criteria are implemented depending on the nature of exchanged species. Metal precursor, reducing agent, and free metal atoms are isolated species, which will be redistributed between two colliding micelles in accordance with the concentration gradient principle: they are transferred from the more to the less occupied micelle. The exchange parameter kex quantifies the maximum amount of isolated species that can be exchanged during an intermicellar collision. As a result of this redistribution, the metal salts (PtCl62− and/or M+) and the reducing agent R can be located within the same micelle. At this stage, chemical reduction can occur at a rate which depends on the nature of the metal.
\nAs the reductions take place, metal atoms are produced within micelles. It is assumed that metal atoms are deposited on nanoparticle seed, so all metal atoms inside a micelle are considered to be aggregated forming a growing nanoparticle. The larger size of a growing nanoparticle leads to a second interdroplet exchange protocol. It is assumed that the exchange of growing particles is restricted by the size of the channel connecting colliding micelles. The ease with which this channel can be established as well as the channel size is mainly determined by the flexibility of the surfactant film. The flexibility parameter (f) specifies the maximum particle size for transfer between micelles. The exchange criterium of growing particles also takes into account Ostwald ripening, which assumes that larger particles grow by condensation of material, coming from the smaller ones that solubilize more readily than larger ones. This feature is included in the model by considering that if both colliding micelles carry a growing particle, the smaller one is exchanged towards the micelle carrying the larger one, whenever the channel size would be large enough.
\nAs the synthesis advances, micelles can contain simultaneously reactants and growing particles. In this situation, autocatalysis can take place. Thus, if one of the colliding micelles is carrying a growing particle, the reaction always proceeds on it. If both colliding micelles contain particles, reaction takes place in the micelle containing the larger one, because it has a larger surface, so a higher probability of playing as catalyst.
\nBased on these simple criteria for material interdroplet exchange, surfactant film flexibility can be characterized as follows. There are two main requirements for material intermicellar exchange to occur: the size of the channel connecting colliding micelles must be large enough and the dimer formed by colliding micelles must be stable, that is, they must remain together long enough. Isolated species (reactants and free metals) traverse the intermicellar channel one by one, so one can assume that the key factor determining their exchange is the dimer stability. That is, when the two micelles stay together longer (higher dimer stability), a larger quantity of species can be exchanged. Channel size would not be relevant in this case. Based on this, kex, which quantifies how many units of isolated species can be exchanged during a collision, is related to the dimer stability. Conversely, when the transferred material is a particle constituted by aggregation of metal atoms, which travels through the channel as a whole, channel size becomes decisive. This kind of material exchange will be restricted by the intermicellar channel size (f parameter). From this picture, the flexibility of the surfactant film is simulated by means of these two parameters, kex (dimer stability) and f (intermicellar channel size).
\nA rigid film, such as AOT/n-heptane/water microemulsion, was successfully reproduced considering a channel size f = 5, associated to kex = 1 free atoms exchanged during a collision [26]. In case of flexible film, both factors rise together, because a more flexible film produces more stable dimer and larger channel size, allowing a quicker exchange of isolated species as well as an exchange of larger particles [41]. That is, a flexible film is associated to a faster material intermicellar exchange rate. A more flexible microemulsion, such as 75% Isooctane/20% Tergitol/5% water microemulsion, was successful compared to simulation data using the values f = 30, kex = 5 [42].
\nThe composition of each nanoparticle is revised at each step and monitored as a function of time. When all metal precursors were reduced and the content of all micelles remains constant over time, nanoparticle synthesis is considered to be finished. At this stage, the sequence of metal deposition of each particle (which is stored as a function of time) is stabilized. One simulation run produces a set of micelles, each one of them can carry one particle with different composition or be empty. At the end of each run, the averaged nanoparticle is calculated. Finally, results are averaged over 1000 runs.
\nThe intrastructure of each particle is calculated by analyzing the sequence in which the two metals are deposited on the nanoparticle surface. So that, each sequence is arranged in 10 concentric layers, assuming that final nanoparticle is spherical. Then, the averaged percentage of each metal is calculated layer by layer. The final bimetallic distribution is represented by histograms, in which the layer composition is described by a color grading, as stated in the following pattern: Au, Pt, and Rh are represented by red, blue, and green, respectively. As the proportion of pure metal in the layer is higher, the color becomes lighter. In order to illustrate the heterogeneity of nanoparticle composition, the number of particles with a given percentage of the faster reduction metal (Au in Au/Pt and Pt in Pt/Rh nanoparticles) in each of 10 layers is also represented in the histograms. This analysis is reproduced layer by layer, from the beginning of the synthesis (inner layer or core) to the end (outer layer or surface). To simplify, the metal distribution is also shown by means of concentric spheres, whose thickness is proportional to the number of layers with the same composition, keeping the same color pattern.
\nThe simulation model was successfully validated by comparison with experimental results. Au/Pt nanoparticles were synthesized in a 75% Isooctane/20% Tergitol/5% water microemulsion [42] (which can be characterized as flexible microemulsion)using different precursor concentrations. (〈cAuCl4−〉 = 〈cPtCl62−〉 = 〈c〉 = 0.01, 0.08, 0.16, and 0.40 M. The resulting Au/Pt particles were studied by HR-STEM and their structures were revealed by cross sections scanned with EDX analysis. The studied conditions were reproduced by simulation, using concentrations 〈cAuCl4−〉 = 〈cPtCl62−〉 = 〈c〉 = 2, 16, 32, and 64 metal precursors in each micelle, which corresponds to 0.01, 0.08, 0.16, and 0.40 M, respectively, in a micelle with a radius of 4 nm. As mentioned above, Au/Pt pair was characterized as vAu/vPt = 10 reduction rate ratio, and the 75% Isooctane/20% Tergitol/5% water microemulsion was simulated as a flexible surfactant film (f = 30, kex = 5).
\nThe left column in Figure 1 shows the simulated nanostructures obtained at each concentration. In order to compare the experimental and simulated nanostructures, the quantity of each metal crossed by a beam of 2 Å (approximate EDX beam size) was computed from each simulated final nanoparticle, and the theoretical STEM profiles were calculated. The STEM profiles of the average particle for each concentration are shown in center (theoretical) and right (experimental) columns of Figure 1. For a better comparison, experimental x-axis was changed from nm to counts, and the two kind of profiles were normalized to 1. Both profiles show the expected behavior: the surface (outer layers) is enriched in Pt, because of its slower reduction rate, and Au, which is reduced faster, accumulates in the core (inner layers). As concentration increases (see Figure 1 from the top to the bottom), deeper Pt profiles are obtained. This means that the final nanostructure shows an improved metal segregation as concentration is higher. It is clearly observed in the histograms, which evolve from Au core covered by a mixed shell obtained at a low concentration to a more mixed Au core covered by a pure Pt shell as concentration increases (see decreasing red bar on the left and increasing blue bar on the right in histograms of Figure 1). This means that the nanostructure can be fine-tuned with sub-nanometer resolution, just by changing concentration.
\nLeft column: simulated histograms for different initial concentrations (Au:Pt = 1:1). The proportion of pure metal in the layer is higher as the color becomes lighter (red: 100% Au, blue: 100% Pt, gray: 50% Au-Pt). Centre column: calculated STEM profiles for the average nanoparticle. Right column: measured STEM profiles for Au/Pt nanoparticles synthesized in a water/tergitol/isooctane microemulsion. Simulation parameters: flexible film (kex = 5, f = 30); reduction rate ratio (vAu/vPt = 100/10); and reducing agent concentration 〈cR〉 = 10〈M+〉. Adapted with permission from Ref. [42]. Copyright (2015) American Chemical Society.
A good agreement between experimental and theoretical results was attained, upholding the validity of the simulation model to predict the atomic structure of bimetallic nanoparticles. On this basis, the model becomes a strong tool to further enhance our knowledge of the complex mechanisms governing reactions in microemulsions and the impact of compartmentalization on final nanostructures.
\nThe better metal segregation obtained as concentration increases is also observed when the two reductions are slowing down, as shown in Figure 2. This figure shows the final nanostructures obtained for the pair Pt/Rh (vPt/vRh = 10/1 = 10), under the same synthetic conditions as used in Figure 1 to prepare Au/Pt nanoparticles. The better metal separation cannot be attributed to a larger reduction rate ratio, because in both cases the faster metal is 10 times faster than the slower one (vAu/vPt = 100/10 = 10). The better metal separation obtained for Pt/Rh pair is more evident at low concentration, where an alloy is obtained for Au/Pt and a core-shell structure for Pt/Rh (compare histograms when <c>= 2 in Figures 1 and 2). This means that, although the reduction rate ratio is similar, when the reduction rate of the faster metal slows down as in Pt, the other metal (Rh) is delayed even more. As a consequence, both reactions take place at different stages of the synthesis, resulting in better segregated structures.
\nHistograms show the number of particles with a given percentage of the faster reduction metal (Pt) in each layer at different concentrations. In all cases, 〈cR〉 = 10〈cPtCl62−〉, and cPtCl62−:RhCl63− is in 1:1 proportion. Reduction rates: vPt = 10%, vRh = 1% (vPt/vRh = 10); flexible film (f = 30, kex = 5). Scheme color: Pt and Rh are represented by blue and green bars, respectively. Lighter colors mean less mixture. The nanostructure is also shown by colored concentric spheres, keeping the same color pattern.
The difference between the standard potentials of the two metal precursors is believed to be the most relevant factor to determine the kinetics and the resulting bimetallic arrangement [43]. As established in Eq. (2), the higher the difference between the standard potentials of the two metals, the higher the ratio between both reduction rates is. It results in the earlier reduction of the faster reduction metal, which builds up the core and becomes the seed for the subsequent deposition of the slower metal, which forms the surrounding shell. On the contrary, when the two reduction rates are almost similar, a mixed nanoalloy is expected. In spite of this argumentation was initially proposed for reactions in homogeneous media, and it does not take into account the confinement of reactants within micelles, it is frequently applied to explain results in microemulsion. As a rule, it is observed a tendency from nanoalloy to core-shell structure as difference in reduction potential is increased (see Table 1 in Ref. [44]). Previous simulation studies allow to clearly observe a better separation of the two metals as reduction rate ratio is larger (for a deeper discussion, see Ref. [28]).
\nTo isolate the effect of microemulsion composition on nanoparticle structure, a particular pair of metals must be chosen and analyze if a change in the microemulsion composition leads to a different metal segregation. For example, Pt/Ru nanoparticles were obtained as nanoalloy, both for rigid (water/Brij-30/n-heptane [45]) and flexible films (water/Berol 050/isooctane 80 [46] or water/NP5-NP9/cyclohexane [47]). But in this couple, the small difference in reduction potentials leads to quite similar reduction rates, which hinder metal segregation, even with a slow intermicellar exchange rate. As a matter of fact, when couples with higher reduction rate ratio are studied (such as Au/Ag, Au/Pt, and Au/Pd), an increase in surfactant flexibility results in the expected transition from a core-shell to a nanoalloy. As an example, alloyed Au/Pt nanoparticles were prepared using a flexible film such as water/Tergitol 15-S-5/isooctane [17] or water/TritonX-100/cyclohexane [48]. On the contrary, rigid films (water/AOT/isooctane [39] and water/Brij 30/n-heptane [49]) lead to segregated structures. The simulation model also predicts this result, as shown in Figure 3, in which different Au/Pt (vAu/vPt = 10) arrangements were obtained by employing different values of surfactant film flexibilities. The ability of the microemulsion to minimize the difference between the reduction rates is clearly reflected in the progressive mixture of Au and Pt as increasing the intermicellar exchange rate (for a deeper discussion, see the following sections).
\nNumber of particles with a given percentage of the faster reduction metal (Au) in each layer using three different microemulsion compositions (different f and kex parameters). 〈cAuCl4−〉 = 〈cPtCl62−〉 = 4; 〈cR〉 = 10〈cPtCl62−〉 reduction rates: vAu = 100%, vPt = 10%. Scheme color: Au and Pt are represented by red and blue bars, respectively. Lighter colors mean less mixture. Adapted with permission from Ref. [44].
The results shown in previous figures were obtained under isolation conditions, that is, the reducing agent concentration is much higher than stoichiometry, so the change in R concentration during the course of the reaction is negligible. As a result, the metal reduction, which is a bimolecular reaction, appears to be first order, when the reaction media is homogeneous. In order to study how the confinement of reactants inside micelles would affect chemical kinetics, the depletion of the number of metal precursors M+ (M+ = AuCl4−, PtCl6−2−, RhCl63−) was monitored as the synthesis advances. The logarithmic plot of M+ concentration versus time is shown in Figure 4 using different initial reactant concentrations. Left and right columns show results for Au/Pt and Pt/Rh couples, respectively. Au, Pt, and Rh are represented by dashed, solid, and dashed-dotted lines, respectively. Figure 4A and B was obtained by simulating a flexible film and C and D a rigid one. At first sight, metal reductions obey first-order kinetics in both Au/Pt and Pt/Rh synthesis, as expected. Nevertheless, it is important to note that, with the exception of Rh, a time lag is required to reach the linear regime. Two points must be highlighted: First, the higher the concentration, the longer the time lag between the beginning of the synthesis and the achievement of the linear behavior. On the second hand, the time lag strongly depends on the intermicellar exchange rate, being longer as the exchange rate is slower (rigid film). Both factors (concentration and film flexibility) suggest that the rate-determining step is the intermicellar exchange rate at earlier reaction times, as explained as follows. The synthesis starts when the microemulsions containing the reactants are mixed. In order to be able to react, reactants must be located inside the same micelle. The reactants redistribution between micelles is dictated by the rate with which reactants can go through the channels communicating colliding micelles, that is, the intermicellar exchange rate. So, a slow exchange rate only allows the exchange of few reactants in each collision, which implies that more collisions are required to redistribute reactants and allow the reactants encounter. Therefore, a rigid film requires much longer lag times than a flexible one (compare Figure 4AwithB and CwithD, for any value of concentration). Apart from that, reactants redistribution is also affected by concentration, because the number of reactants which can traverse the intermicellar channel during an effective collision is restricted. Therefore, if concentration within micelle is large, more collisions (i.e., more time) are needed to make possible reactants redistribution. Finally, it is interesting to point out that this delay in reaching linear behavior disappears when a very slow chemical reduction takes place, as shown by Rh kinetics in right column of Figure 4 (see dashed-dotted lines), which is linear from the beginning, at any concentration value. This behavior can be taken as indication that the reduction rate is so slow (only a 1% of reactants give rise to products) that the limiting step is the reduction itself.
\nPlot of ln M+ (number of metal salt) against time (in Monte Carlo step, mcs) using different initial concentration c (metal salts/micelle). Solid, dashed, and dashed-dotted represent Au, Pt, and Rh, respectively. A and B shows results for a flexible surfactant film (kex = 5, f = 30) and C and D for a rigid one (kex = 1, f = 5). Au/Pt pair (vAu/vPt = 100/10 = 10) is represented in A and C and Pt/Rh pair (vPt/vRh = 10/1 = 10) in B and D. Stars indicate the half-life (red, blue, and green means Au, Pt and Rh, respectively).
Summarizing, the time lag required to achieve linear behavior in Figure 4 reflects the time it takes for reactants to encounter. This time lag can be determinant of final metal segregation, because the inner layers of nanoparticle are building up during this stage.
\nPseudo-first-order rate constants, kobs, can be calculated from linear regime of the logarithmic plot as shown in Figure 4. The values of the pseudo-first-order rate constants are represented in Figure 5 as a function of concentration. One can observe that the slopes of Au reduction are always higher than the slopes of Pt, which in turn is faster that Rh, as expected. Classical chemical kinetics in a homogeneous reaction medium establishes that kobs in bimolecular reactions does not depend on precursors concentrations. This is the case for Pt and Rh, whose kobs values did not depend neither on the concentration nor on the intermicellar exchange rate. In contrast, kobs values of Au are strongly influenced by both factors. To explain this behavior, one have to take into account that the limiting step in Au chemical reduction is the intermicellar exchange [38, 50], because of the extremely fast Au reduction rate. One can observe that the dependence of kobs on concentration decreases as intermicellar exchange rate is faster, until reaching an almost constant value at very fast intermicellar exchange rate (see gray line in Figure 5), as expected. In comparison, Pt and Rh reductions are so slow that their rates are not limited by the exchange rate.
\nkobs (slopes of the linear parts from the plots in Figure 3) as a function of concentration for different microemulsion compositions and different metals. vAu = 100, vPt = 10, vRh = 1. Lines are only a guide to the eye.
One can conclude from Figure 5 that intermicellar exchange rate exerts a different degree of influence depending on the reduction rate of the metal in comparison to the intermicellar exchange rate. This means that the compartmentalization of reaction medium takes part in chemical kinetics more or less depending on the metal nature. This different interplay between exchange rate and reduction rate has to be reflected in the metal segregation of final nanoparticle. It was proposed that if the intermicellar exchange rate can only modify the rate of metals whose reduction is very fast [38], such as Au, only bimetallic nanoparticle including Au could be prepared with different metal distributions as a function of microemulsion composition (intermicellar exchange rate) by a one-pot method (see Table 1 in Ref. [44]). To the best of our knowledge, only Au/Pt, Au/Ag, and Au/Pd have been synthesized in a different intrastructure by different authors. Thus, when a rigid film (such as provided by AOT) is used, Au-Pt nanoparticles are arranged in a core-shell distribution [39]. On the contrary, more flexible surfactants such as Brij30 [49], tergitol [17], or TritonX-100 [48] give rise to alloyed nanoparticles. In relation to Au/Ag, alloys were obtained with TritonX-100 [51] and C11E3 and C11E5 [52], but an enriched in Ag surface was observed when microemulsion contains AOT [53]. Finally, AOT was also used to obtain core-shell Au-Pd nanoparticles [54] and alloys with Pd-rich surface [55]. In contrast, true Au-Pd alloys [4] have been obtained with Brij30 and TritonX-100. With that in mind, it could be suggested that metal segregation in the nanoparticle can be modified by a change in the microemulsion composition only when one of the metals is Au or another very fast reduction rate metal. Nevertheless, in spite of the agreement between theoretical and experimental data, this assumption is based on the kinetic constants, which were calculated from the linear plot shown in Figure 4. It must be emphasized that the linear regime is not fulfilled at initial stages of the reaction, when the core is been building up. With the aim of studying the relevance of the non-linear behavior at the beginning of the synthesis, the half-life, defined as the time that it takes for the reactant concentration to decay to half of its initial value, was calculated for each case. Stars in Figure 4 show half-life under different synthesis conditions (Au, Pt, and Rh are represented by red, blue, and green stars, respectively). With the exception of Rh and Pt at very low concentration, half-life is usually smaller than the time needed to achieve the linear regime. As observed in Figure 4C and D, Au and Pt reductions in a rigid microemulsion and at high concentration have a half-life much earlier than linear plot. This means that not only the initial layers but also the middle ones are formed under a nonlinear regime. So, chemical reductions are still not a first-order process during the formation of a large part of the particle (for a deeper discussion on life time, see Ref. [38]).
\nThe generalized belief according to which the difference in the reduction potentials determines the intrastructure in a bimetallic nanoparticle should be improved. We propose that there are three potentially limiting factors which restrict chemical kinetics of bimetallic nanoparticles prepared from microemulsions: chemical reduction rate itself, exchange rate of reactants between micelles, and reactants concentration. The specific combination of these three factors determines the reaction rate of each metal, which in turn determines the sequence of metals deposition and the resulting bimetallic arrangement.
\nThe kinetic study of Pt/M nanoparticles prepared via microemulsions under isolation conditions shows that chemical reductions are pseudo-first-order reactions, but not from the initial stages. At the beginning of the synthesis, the reactants encounter is dictated by the redistribution of reactants between micelles, which is controlled by the intermicellar exchange rate. As a result, the limiting step of faster reduction metals, such as Au, is the intermicellar exchange. On the contrary, microemulsion dynamics has a little effect if reduction rates are very slow (i.e., Rh). This means that compartmentalization of the reaction media has a different impact depending on the reduction rate of the particular metal. We are not referring only to the reduction rate of a metal in relation to the another metal in the pair but also how fast the reduction takes place in relation to the intermicellar exchange rate. Specifically, for a given reduction rates ratio and keeping fixed microemulsion composition and concentration, the fact that the two reactions were slow (as in Pt/Rh) leads to a better metal segregation than if both reactions are faster (as in Au/Pt). Therefore, with the exception of very slow metal reduction as Rh, intermicellar exchange rate drastically impacts on chemical kinetics, particularly at the beginning of the synthesis. This is not a minor matter, because it will be reflected in the composition of the core and middle layers of the resulting nanoparticle. So, the ability of microemulsion to manipulate the sequence of metal deposition, when the metal reductions are quite fast in relation to the intermicellar exchange rate, can be used to design the experiments to synthesize bimetallic particles with ad hoc nanoarrangements. This ability disappears when the two chemical reductions are slow, because of chemically controlled kinetics.
\nIn this paper, computer simulation has proved to be very useful tool to identify suitable synthesis parameters, which control metal segregation in a bimetallic nanoparticle. Further insights into the interplay between metal nature, exchange rate, and final bimetallic structure can be gained from kinetics studies.
\nThis work was supported by MINECO, Spain (MAT2015-67458-P, co-financed with FERDER Funds), from the European Union’s H2020 research and innovation programme under grant agreement No. 646155 (INSPIRED) and from Xunta de Galicia (Programa REDES ED431D-2017/18). D.B. thanks for the postdoc grant from Xunta de Galicia, Spain (POS-A/2013/018).
\nThe authors declare no conflict of interest.
This research is dedicated to Prof. Julio Casado Linarejos, who teached us the fundamentals of chemical kinetics.
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Today his focus is on defining the growth and development strategy for the company.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"19816",title:"Prof.",name:"Alexander",middleName:null,surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/19816/images/1607_n.jpg",biography:"Alexander I. Kokorin: born: 1947, Moscow; DSc., PhD; Principal Research Fellow (Research Professor) of Department of Kinetics and Catalysis, N. Semenov Institute of Chemical Physics, Russian Academy of Sciences, Moscow.\r\nArea of research interests: physical chemistry of complex-organized molecular and nanosized systems, including polymer-metal complexes; the surface of doped oxide semiconductors. 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I received a B.Eng. degree in Computer Engineering with First Class Honors in 2008 from Prince of Songkla University, Songkhla, Thailand, where I received a Ph.D. degree in Electrical Engineering. My research interests are primarily in the area of biomedical signal processing and classification notably EMG (electromyography signal), EOG (electrooculography signal), and EEG (electroencephalography signal), image analysis notably breast cancer analysis and optical coherence tomography, and rehabilitation engineering. I became a student member of IEEE in 2008. During October 2011-March 2012, I had worked at School of Computer Science and Electronic Engineering, University of Essex, Colchester, Essex, United Kingdom. In addition, during a B.Eng. 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I am a Reviewer for several refereed journals and international conferences, such as IEEE Transactions on Biomedical Engineering, IEEE Transactions on Industrial Electronics, Optic Letters, Measurement Science Review, and also a member of the International Advisory Committee for 2012 IEEE Business Engineering and Industrial Applications and 2012 IEEE Symposium on Business, Engineering and Industrial Applications.",institutionString:null,institution:{name:"Joseph Fourier University",country:{name:"France"}}},{id:"55578",title:"Dr.",name:"Antonio",middleName:null,surname:"Jurado-Navas",slug:"antonio-jurado-navas",fullName:"Antonio Jurado-Navas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/55578/images/4574_n.png",biography:"Antonio Jurado-Navas received the M.S. degree (2002) and the Ph.D. degree (2009) in Telecommunication Engineering, both from the University of Málaga (Spain). He first worked as a consultant at Vodafone-Spain. 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