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Pharmacological advances in the multimodal management of perioperative analgesia
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Rev Esp Anestesiol Reanim. 2017;xxx(xx):xxx---xxx
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Pharmacological advances in the multimodal management of perioperative analgesia夽 M. Matute Crespo, A. Montero Matamala ∗ Servicio de Anestesiología, Reanimación y clínica del Dolor, Hospital Universitario Arnau de Vilanova, Lleida, Spain Received 17 February 2017; accepted 9 March 2017
KEYWORDS Perioperative analgesia; Multimodal analgesia; Analgesic advances
PALABRAS CLAVE Analgesia perioperatoria; Analgesia multimodal; Avances analgésicos
Abstract The concept of multimodal analgesia is currently widespread in our clinical practice. The aim of multimodal analgesia is to reduce the side effects derived from the drugs or techniques used for the control of pain together with greater effectiveness (combination of multiple mechanisms of action) with the maximum efficiency, that is, to combine different pharmacodynamics (synergistic or additive effects) and pharmacokinetics, in the context of a predictable acute pain model, thus allowing a prior strategy such as the model of acute postoperative pain. Pain is a complex physiological phenomenon. Postoperative pain involves multiple pathways including nociceptive, inflammatory, and neuropathic sources. In the transmission of pain therefore, different molecules participate, which means that there are multiple pharmacological targets on which to act, and therefore a wide range of drugs to be used following the physiology of pain. © 2017 Sociedad Espa˜ nola de Anestesiolog´ıa, Reanimaci´ on y Terap´ eutica del Dolor. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
Avances farmacológicos en el manejo multimodal de la analgesia perioperatoria Resumen El concepto de analgesia multimodal está actualmente muy extendido en nuestra práctica clínica. El objetivo de la analgesia multimodal es la disminución de efectos secundarios derivados de los fármacos o técnicas utilizados para el control del dolor junto a una mayor efectividad (combinación de múltiples mecanismos de acción) con la máxima eficiencia, es decir, combinar diferentes farmacodinamias (efectos sinérgicos o aditivos) y farmacocinéticas en el contexto de un modelo de dolor agudo previsible y por lo tanto que nos permite una estrategia previa como es el modelo del dolor agudo postoperatorio.
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Please cite this article as: Matute Crespo M, Montero Matamala A. Avances farmacológicos en el manejo multimodal de la analgesia perioperatoria. Rev Esp Anestesiol Reanim. 2017. http://dx.doi.org/10.1016/j.redar.2017.03.006 ∗ Corresponding author. E-mail addresses: [email protected], [email protected] (A. Montero Matamala). 2341-1929/© 2017 Sociedad Espa˜ nola de Anestesiolog´ıa, Reanimaci´ on y Terap´ eutica del Dolor. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
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M. Matute Crespo, A. Montero Matamala El dolor es un fenómeno fisiológico complejo. En el dolor postoperatorio intervienen múltiples vías incluyendo fuentes nociceptivas, inflamatorias y neuropáticas. En la transmisión del dolor por lo tanto, participan distintas moléculas; este hecho supone que existen múltiples dianas farmacológicas sobre las que actuar y por lo tanto una amplio abanico de fármacos a utilizar siguiendo la fisiología del dolor. © 2017 Sociedad Espa˜ nola de Anestesiolog´ıa, Reanimaci´ on y Terap´ eutica del Dolor. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction There is ample evidence to support the use of different drug combinations in multimodal analgesia.1,2 However, each drug has its advantages and disadvantages and specific safety profile, and it is imperative to select the right analgesic for each patient. Multimodal analgesia, therefore, must be planned according to the patient and the type of intervention performed at a given time, and this calls for the creation of a personalised multimodal analgesia strategy that takes advantage of the growing array of analgesics available. New approaches are currently available that will probably allow us to maximise the benefits of perioperative analgesia and provide us with new analgesics that can be adapted to each type of intervention and patient.3 These include traditional analgesics with novel routes of administration (intravenous ibuprofen, sulfentanil and intrathecal butorphanol), adjuvants (ketamine, magnesium, lidocaine, neostigmine, gabapentinides, dexmedetomidine, ondansetron) and combinations of opioids with different onsets of action. The following is a review of the different pharmacological options used in perioperative multimodal analgesia.
Ketamine Ketamine is pharmacologically classified as an N-methyl-daspartate (NMDA) receptor antagonist, although its action on different receptors is dose-dependent. Most ketamine preparations are racemic. The most active enantiomer, Sketamine, has been available in Europe since 1994.4 The affinity of ketamine for opiate receptors has also been linked to its ability to produce analgesia at the level of the CNS and the spinal cord. Subanaesthetic doses of ketamine (≤0.3 mg/kg) are analgesic due to the drug’s capacity to inhibit NMDA receptors. It also has an anti-inflammatory action by reducing IL-6 levels, and may prevent hyperalgesia in patients receiving remifentanil. Because of this broad spectrum of action, ketamine has been used in multiple studies on multimodal analgesia for perioperative pain management. Many anaesthesiologists are wary of using this drug due to its potent psychotogenic side effects. Most of these,
however, appear after higher doses than those used in multimodal analgesia strategies. Ketamine has been suggested as a concomitant drug in patients undergoing both general and regional anaesthesia.5 There is little consensus on the ideal route of administration of the drug in perioperative analgesia, but intravenous administration is generally thought to be better than epidural due to the risk of toxicity associated with the latter, and because other drugs (such as fentanyl or sulfentanil) can be administered via the epidural route. The correct dose, timing and duration of administration of intravenous ketamine is also unclear. Although many studies have explored this issue, we will focus on the conclusions published in the review by Gorlin et al.6 in 2016: - The ideal dose of sub-anaesthetic ketamine is <0.3 mg/kg (ideal weight). - In interventions lasting <60 min, an induction dose of 0.1---0.3 mg/kg should be given. - In longer surgeries, a dose of 0.1---0.3 mg/kg can be used for induction, repeating the bolus every 30---60 min. - If ketamine will be administered in the immediate postoperative period, similar dosage as that given during induction should be used, followed by continuous infusion of 0.1---0.2 mg/kg, which can be maintained for 72 h. After the first 24 h, consider reducing infusion to a maximum of 10 mg/h. Following the review published by Gorlin et al., Ramachandran and Rewari7 called for more clinical guidelines to standardise administration of ketamine. All the evidence to date, however, shows that it is an effective analgesic and a useful additive in multimodal analgesia.
Magnesium Magnesium is needed to maintain normal bodily functions. At the pharmacological level, it acts as a non-competitive NMDA receptor antagonist and inhibits voltage-dependent calcium channels. Addition of magnesium reduces C-fibre activation by inhibiting the slow excitatory post-synaptic currents produced by NMDA receptor activation. NMDA receptor antagonists interfere with the influx of calcium and sodium into the cells that causes central sensitisation.8 It also has a vasodilatory effect mediated by endotheliumnitric oxide.
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Pharmacological advances in the multimodal management of perioperative analgesia Magnesium can be administered both intravenously and epidurally. Several studies have suggested the use of intravenous magnesium as an analgesic adjuvant, and it is included in the enhanced recovery after abdominal surgery programme. The authors of a review published in 2013 concluded that the use of intravenous magnesium effectively reduced opioid use and, to a lesser extent, pain scores in the first 24 postoperative hours, with no serious adverse effects.9 It can be administered as a single (30---40 mg/kg) or combined bolus, or in continuous infusion (10 mg/kg/h), both of which are equally effective. Regarding the route of administration of magnesium, some authors suggest supplementing epidural anaesthesia with intrathecal or epidural MgSO. In some studies, this has significantly reduced postoperative analgesic requirements and increased the duration of blockade. The addition of magnesium to epidural fentanyl and bupivacaine in women undergoing elective caesarean section with combined spinal---epidural anaesthesia improved intraoperative conditions and the quality of postoperative analgesia. Addition of magnesium reduces C-fibre activation by inhibiting the slow excitatory post-synaptic currents produced by NMDA receptor activation. Both ketamine and magnesium sulphate have been tentatively associated with cerebral neuroprotection. In a recently published study10 in patients undergoing laminectomy, intravenous magnesium did not reduce consumption of opioids, although a previous metaanalysis11 evaluating 25 studies comparing magnesium with placebo concluded that perioperative intravenous magnesium reduces opioid use and, to a lesser extent, pain scores in the first 24 postoperative hours. Therefore, although the evidence is inconsistent, most authors consider magnesium to be an effective component of multimodal analgesia strategies.
Lidocaine Like ketamine and magnesium, intravenous lidocaine is increasingly indicated in acute and chronic neuropathic and nociceptive pain.11 Several studies have been published on the use of lidocaine in perioperative analgesia strategies. It has been suggested that lidocaine has an indirect antiinflammatory action produced by blocking the stimulus that triggers the inflammatory response.12 A Cochrane review13 published in 2015 concluded that there is low to moderate evidence of this, and that the optimal dose and duration of administration remain unclear. However, the review concluded that it may be a useful adjuvant during general anaesthesia because of its beneficial effect after surgery, although evidence is weak. Lidocaine, therefore, is considered an option to be considered in a multimodal analgesia strategy. As far as dose and timing is concerned, although no firm evidence or guidelines are available, the doses most frequently evaluated in studies are boluses of 1---1.5 mg/kg during or after induction, which can be followed by continuous infusion of 1---1.5 mg/kg/h. The optimal treatment regimen remains unclear, but lidocaine appears to have a good safety profile.
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Intravenous ibuprofen Intravenous ibuprofen, which has the same pharmacological effect as the oral formulation, has recently been approved in Spain, thus adding a new alternative to the existing range of intravenous NSAIDs. The antipyretic and anti-inflammatory effect of the drug is a result of its inhibition of prostaglandin E2 and I2 production by reversible competitive blockade of constitutive and inducible COX isoforms (COX-1 and COX-2, respectively), which prevents the activation of proinflammatory processes and leucocyte infiltration. Prostaglandins are responsible for many physiological processes and also for most side effects. This is why the precautions and limitations associated with their use are derived from their interference with these physiological processes. Intravenous ibuprofen14 can only be used for short-term pain management, although this is not a disadvantage in perioperative multimodal analgesia strategies. The effect of ibuprofen on the gastrointestinal and cardiovascular systems is time-dependent, so short-term administration reduces the risk of drug-induced side effects. Several studies have shown its efficacy as a perioperative analgesic, both alone or in combination with paracetamol, and even as a preoperative preventive analgesic. A recent meta-analysis15 concluded that intravenous ibuprofen did not increase incidence of perioperative infection or ischaemia, although the risk of bleeding and the increased risk of gastrointestinal lesions should be taken into account.
Opiate combinations Opiates as adjuvants in regional anaesthesia Opioids are widely used in conjunction with local anaesthesia, as they permit the use of lower doses of local anaesthetics without compromising anaesthesia and analgesia quality. They provide both adequate anaesthesia as well as less drug toxicity. In this article we will focus on the latest opioids used in multimodal strategies. Butorphanol Butorphanol is a lipophilic opioid that has been used both for epidural and intrathecal administration. A recent study16 showed that low-dose bupivacaine combined with butorphanol had no side effects, although bupivacaine combined with fentanyl is superior in terms of early postoperative recovery resulting in early discharge. The authors concluded that it could be an option to consider in elderly patients with comorbidity. Intradural sulfentanil The administration of either intradural and epidural sulfentanil (in labour) has been studied in different interventions, particularly caesarean section,17 at doses of between 2.5 and 5 g (the latter being the most frequently used). Efficacy outcomes vary, and not all studies have shown sulfentanil to be superior to intradural fentanyl. In terms of side effects, haemodynamic stability was similar to
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4 fentanyl administered by the same route, and sulfentanil does not seem to reduce tremors, but does increase incidence of pruritus. There is clear evidence that intradural fentanyl in chronic opioid users prolongs the sensory and motor blockade to achieve a duration similar to that achieved in non-opioid users, suggesting that it could be the opioid of choice in this subpopulation of patients. Further studies are needed to conclusively demonstrate the superiority of sulfentanil over intradural fentanyl as an adjunct to analgesia in multimodal management. Sublingual sulfentanil (a recent formulation) also opens up new possibilities in the management of pain in the immediate postoperative period.
Combination with intravenous remifentanil The duration and dosage of remifentanil infusion when used in combination with other opioids varies considerably. Short-acting opioids such as remifentanil have been associated with acute tolerance to opioids and/or opioidinduced hyperalgesia. These side effects appear to be dose- or infusion time-dependent; doses in excess of 0.25 g/kg−1 /min−1 are associated with tolerance (increased consumption of postoperative opioids) and hyperalgesia (lower pressure, cold or pain thresholds). The use of multimodal concomitant analgesia, especially NMDA receptor antagonists, may prevent these side effects. Remifentanil is administered at lower doses when used in multimodal analgesia, a factor that reduces the risk of side effects.18
Ondansetron Ondansetron is a specific 5-hydroxytryptamine-3 (5-HT3 or serotonin) antagonist commonly used as an antiemetic for the prevention or treatment of postoperative nausea and vomiting. Side effects are minimal, the most common being constipation, dizziness and headache. The anti-inflammatory and analgesic properties of 5-HT antagonists are derived from their affinity to -opioid receptors and capacity to block sodium channels. A study by Farouk19 reported that the addition of ondansetron to lidocaine may improve the quality of intravenous regional anaesthesia and prolong postoperative analgesia in patients undergoing hand surgery. However, no systematic reviews have been published on the use of ondansetron as an adjuvant of intravenous regional anaesthesia with lidocaine.20 A study in paediatric patients21 found an interaction between acetaminophen and ondansetron and increased consumption of opioids in the immediate postoperative period, suggesting that ondansetron should not be used within a multimodal analgesia strategy that includes intravenous paracetamol. More studies are needed to evaluate whether this finding has sufficient clinical relevance to disadvise simultaneous perioperative administration of both drugs.
M. Matute Crespo, A. Montero Matamala
Dexmedetomidine Dexmedetomidine is an alpha 2 adrenergic agonist that can be used in both intravenous and spinal administration. The mechanism of analgesic action is unclear, although it seems to produce endogenous modulation, due to its effect on receptors located at the level of the dorsal horn of the spinal cord and brain, and also acts on substance P. Pre-anaesthesia single-shot administration of 1 g/kg dexmedetomidine decreases anaesthesia requirements.22 The addition of a small (0.05 g/kg) single shot of dexmedetomidine to bupivacaine and fentanyl in women undergoing elective caesarean section with combined spinal---epidural anaesthesia improved intraoperative conditions and the quality of postoperative analgesia. In another study,22 the authors found that dexmedetomidine may be a better additive to levobupivacaine than fentanyl for caudal postoperative analgesia in children. Dexmedetomidine could be used in multimodal analgesia, but further studies are required before definitive conclusions can be drawn.
Pregabalin The use of preoperative pregabalin has been highly controversial after studies showing its efficacy had to be withdrawn due to methodological defects. A clinical trial performed after the withdrawal of these studies found no clear benefit for this drug.23 It has been suggested that pregabalin may be effective in reducing neuropathic pain, albeit at the expense of increased sedation. Therefore, although this option exists, it cannot be clearly recommended.
Conclusions As this review shows, the term ‘‘personalised multimodal analgesia’’ has arisen due to the many different drugs available in this setting. However, choosing the right combination from the wide range of alternatives is a challenge for the anaesthesiologists. We must not lose sight of the main objective of multimodal analgesia, which is to increase efficiency by minimising side effects. To achieve this, we must fully understand the effects of the drugs added to multimodal strategies as analgesics or co-analgesics in order to improve efficacy and safety and avoid iatrogenic damage.
Ethical disclosures Protection of human and animal subjects. The authors declare that no experiments were performed on humans or animals for this study. Confidentiality of data. The authors declare that they have followed the protocols implemented in their place of work regarding the use of patient data in publications. Right to privacy and informed consent. The authors declare that no patient data appears in this article.
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Pharmacological advances in the multimodal management of perioperative analgesia
Conflict of interest The authors declare they have no conflict of interest.
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References 1. Hebl JR, Dilger JA, Byer DE, Kopp SL, Stevens SR, Pagnano MW, et al. A pre-emptive multimodal pathway featuring peripheral nerve block improves perioperative outcomes after major orthopedic surgery. Reg Anesth Pain Med. 2008;33:510---7. 2. Dunn LK, Durieux ME, Nemergut EC. Nemergut EC2 nonopioid analgesics: novel approaches to perioperative analgesia for major spine surgery. Best Pract Res Clin Anaesthesiol. 2016;30:79---89. 3. Tan M, Law LS, Gan TJ. Optimizing pain management to facilitate enhanced recovery after surgery pathways. Can J Anaesth. 2015;62:203---18. 4. Himmelseher S, Durieux M. Ketamine for perioperative pain management. Anesthesiology. 2005;102:211---20. 5. Elia N, Tramèr M. Ketamine and postoperative pain --- a quantitative systematic review of randomized trials. Pain. 2005;113:61---70. 6. Gorlin AW, Rosenfeld DM, Ramakrishna H. Intravenous subanesthetic ketamine for perioperative analgesia. J Anaesthesiol Clin Pharmacol. 2016;32:160---7. 7. Ramachandran R, Rewari V. Resurfacing of ketamine: the subanesthetic paradigm. J Anaesthesiol Clin Pharmacol. 2016;32:286---7. 8. Usmani H, Quadir A, Alam M, Rohtagi A, Ahmed G. Evaluation of perioperative magnesium sulphate infusion on postoperative pain and analgesic requirements in patients under going upper abdominal surgery? J Anaesthesiol Clin Pharmacol. 2007;23:255---8302. 9. Murphy JD, Paskaradevan J, Eisler LL, Ouanes JP, Tomas VA, Freck EA, et al. Analgesic efficacy of continuous intravenous magnesium infusion as an adjuvant to morphine for postoperative analgesia a systematic review and meta-analysis. Middle East J Anaesthesiol. 2013;22:11---20. 10. Ghaffaripour S, Mahmoudi H, Eghbal H, Rahimi A. The effect of intravenous magnesium sulfate on post-operative analgesia during laminectomy. Cureus. 2016;8:e626. 11. Albrecht E, Kirkham KR, Liu SS, Brull R. Peri-operative intravenous administration of magnesium sulphate and postoperative pain: a meta-analysis. Anaesthesia. 2013;68:79---90. 12. Bakan M, Umutoglu T, Topuz U, Uysal H, Bayram M, Kadioglu H, et al. Opioid-free total intravenous anesthesia with propofol
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dexmedetomidine and lidocaine infusions for laparoscopic cholecystectomy: a prospective randomized double-blinded study. Rev Bras Anestesiol. 2015;65:191---9. Kranke P, Jokinen J, Pace NL, Schnabel A, Hollmann MW, Hahnenkamp K, et al. Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery. Cochrane Database Syst Rev. 2015;16:CD009642. Koh W, Nguyen KP, Jahr JS. Intravenous non-opioid analgesia for peri and postoperative pain management: a scientific review of intravenous acetaminophen and ibuprofen. Korean J Anesthesiol. 2015;68:3---12. Kroll PB, Meadows L, Rock A, Pavliv L. A multicenter randomized double-blind placebo-controlled trial of intravenous ibuprofen (i.v.-ibuprofen) in the management of postoperative pain following abdominal hysterectomy. Pain Pract. 2011;11:23---32. Kumar G, Singh N, Kumari R. A randomized controlled study between fentanyl and butorphanol with low dose intrathecal bupivacaine to facilitate early postoperative ambulation in urological procedures. Anesth Essays Res. 2016;10:508---11. Dourado AD, Filho RL, Fernandes RA, Gondim MC, Nogueira EV. Sufentanil in combination with low-dose hyperbaric bupivacaine in spinal anesthesia for cesarean section a randomized clinical trial. Braz J Anesthesiol. 2016;66:622---7. Yu EH, Tran DH, Lam SW, Irwin MG. Remifentanil tolerance and hyperalgesia short-term gain long-term pain? Anaesthesia. 2016;71:1347---62. Farouk S. Ondansetron added to lidocaine for intravenous regional anaesthesia. Eur J Anaesthesiol. 2009;26:1032---6. Badeaux J, Bonanno L, Au H. Effectiveness of ondansetron as an adjunct to lidocaine intravenous regional anesthesia on tourniquet pain and postoperative pain in patients undergoing elective hand surgery: a systematic review protocol. JBI Database System Rev Implement Rep. 2015;13:27---38. Ramirez L, Cros J, Marin B, Boulogne A, Bergeron A, de Lafont GE, et al. Analgesic interaction between ondansetron and acetaminophen after tonsillectomy in children: the Paratron randomized controlled trial. Eur J Pain. 2016;65:516---21. Elfawal SM, Abdelaal WA, Hosny MR. A comparative study of dexmedetomidine and fentanyl as adjuvants to levobupivacaine for caudal analgesia in children undergoing lower limb orthopedic surgery. Saudi J Anaesth. 2016;10:423---7. Demirhan A, Tekelioglu UY, Akkaya A, Bilgi M, Apuhan T, Karabekmez FE, et al. Effect of pregabalin and dexamethasone addition to multimodal analgesia on postoperative analgesia following rhinoplasty surgery. Aesthetic Plast Surg. 2013;37:1100---6.
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Rev Esp Anestesiol Reanim. 2017;xxx(xx):xxx---xxx
Revista Española de Anestesiología y Reanimación www.elsevier.es/redar
CONTINUING EDUCATION
Pharmacological advances in the multimodal management of perioperative analgesia夽 M. Matute Crespo, A. Montero Matamala ∗ Servicio de Anestesiología, Reanimación y clínica del Dolor, Hospital Universitario Arnau de Vilanova, Lleida, Spain Received 17 February 2017; accepted 9 March 2017
KEYWORDS Perioperative analgesia; Multimodal analgesia; Analgesic advances
PALABRAS CLAVE Analgesia perioperatoria; Analgesia multimodal; Avances analgésicos
Abstract The concept of multimodal analgesia is currently widespread in our clinical practice. The aim of multimodal analgesia is to reduce the side effects derived from the drugs or techniques used for the control of pain together with greater effectiveness (combination of multiple mechanisms of action) with the maximum efficiency, that is, to combine different pharmacodynamics (synergistic or additive effects) and pharmacokinetics, in the context of a predictable acute pain model, thus allowing a prior strategy such as the model of acute postoperative pain. Pain is a complex physiological phenomenon. Postoperative pain involves multiple pathways including nociceptive, inflammatory, and neuropathic sources. In the transmission of pain therefore, different molecules participate, which means that there are multiple pharmacological targets on which to act, and therefore a wide range of drugs to be used following the physiology of pain. © 2017 Sociedad Espa˜ nola de Anestesiolog´ıa, Reanimaci´ on y Terap´ eutica del Dolor. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
Avances farmacológicos en el manejo multimodal de la analgesia perioperatoria Resumen El concepto de analgesia multimodal está actualmente muy extendido en nuestra práctica clínica. El objetivo de la analgesia multimodal es la disminución de efectos secundarios derivados de los fármacos o técnicas utilizados para el control del dolor junto a una mayor efectividad (combinación de múltiples mecanismos de acción) con la máxima eficiencia, es decir, combinar diferentes farmacodinamias (efectos sinérgicos o aditivos) y farmacocinéticas en el contexto de un modelo de dolor agudo previsible y por lo tanto que nos permite una estrategia previa como es el modelo del dolor agudo postoperatorio.
夽
Please cite this article as: Matute Crespo M, Montero Matamala A. Avances farmacológicos en el manejo multimodal de la analgesia perioperatoria. Rev Esp Anestesiol Reanim. 2017. http://dx.doi.org/10.1016/j.redar.2017.03.006 ∗ Corresponding author. E-mail addresses: [email protected], [email protected] (A. Montero Matamala). 2341-1929/© 2017 Sociedad Espa˜ nola de Anestesiolog´ıa, Reanimaci´ on y Terap´ eutica del Dolor. Published by Elsevier Espa˜ na, S.L.U. All rights reserved.
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M. Matute Crespo, A. Montero Matamala El dolor es un fenómeno fisiológico complejo. En el dolor postoperatorio intervienen múltiples vías incluyendo fuentes nociceptivas, inflamatorias y neuropáticas. En la transmisión del dolor por lo tanto, participan distintas moléculas; este hecho supone que existen múltiples dianas farmacológicas sobre las que actuar y por lo tanto una amplio abanico de fármacos a utilizar siguiendo la fisiología del dolor. © 2017 Sociedad Espa˜ nola de Anestesiolog´ıa, Reanimaci´ on y Terap´ eutica del Dolor. Publicado por Elsevier Espa˜ na, S.L.U. Todos los derechos reservados.
Introduction There is ample evidence to support the use of different drug combinations in multimodal analgesia.1,2 However, each drug has its advantages and disadvantages and specific safety profile, and it is imperative to select the right analgesic for each patient. Multimodal analgesia, therefore, must be planned according to the patient and the type of intervention performed at a given time, and this calls for the creation of a personalised multimodal analgesia strategy that takes advantage of the growing array of analgesics available. New approaches are currently available that will probably allow us to maximise the benefits of perioperative analgesia and provide us with new analgesics that can be adapted to each type of intervention and patient.3 These include traditional analgesics with novel routes of administration (intravenous ibuprofen, sulfentanil and intrathecal butorphanol), adjuvants (ketamine, magnesium, lidocaine, neostigmine, gabapentinides, dexmedetomidine, ondansetron) and combinations of opioids with different onsets of action. The following is a review of the different pharmacological options used in perioperative multimodal analgesia.
Ketamine Ketamine is pharmacologically classified as an N-methyl-daspartate (NMDA) receptor antagonist, although its action on different receptors is dose-dependent. Most ketamine preparations are racemic. The most active enantiomer, Sketamine, has been available in Europe since 1994.4 The affinity of ketamine for opiate receptors has also been linked to its ability to produce analgesia at the level of the CNS and the spinal cord. Subanaesthetic doses of ketamine (≤0.3 mg/kg) are analgesic due to the drug’s capacity to inhibit NMDA receptors. It also has an anti-inflammatory action by reducing IL-6 levels, and may prevent hyperalgesia in patients receiving remifentanil. Because of this broad spectrum of action, ketamine has been used in multiple studies on multimodal analgesia for perioperative pain management. Many anaesthesiologists are wary of using this drug due to its potent psychotogenic side effects. Most of these,
however, appear after higher doses than those used in multimodal analgesia strategies. Ketamine has been suggested as a concomitant drug in patients undergoing both general and regional anaesthesia.5 There is little consensus on the ideal route of administration of the drug in perioperative analgesia, but intravenous administration is generally thought to be better than epidural due to the risk of toxicity associated with the latter, and because other drugs (such as fentanyl or sulfentanil) can be administered via the epidural route. The correct dose, timing and duration of administration of intravenous ketamine is also unclear. Although many studies have explored this issue, we will focus on the conclusions published in the review by Gorlin et al.6 in 2016: - The ideal dose of sub-anaesthetic ketamine is <0.3 mg/kg (ideal weight). - In interventions lasting <60 min, an induction dose of 0.1---0.3 mg/kg should be given. - In longer surgeries, a dose of 0.1---0.3 mg/kg can be used for induction, repeating the bolus every 30---60 min. - If ketamine will be administered in the immediate postoperative period, similar dosage as that given during induction should be used, followed by continuous infusion of 0.1---0.2 mg/kg, which can be maintained for 72 h. After the first 24 h, consider reducing infusion to a maximum of 10 mg/h. Following the review published by Gorlin et al., Ramachandran and Rewari7 called for more clinical guidelines to standardise administration of ketamine. All the evidence to date, however, shows that it is an effective analgesic and a useful additive in multimodal analgesia.
Magnesium Magnesium is needed to maintain normal bodily functions. At the pharmacological level, it acts as a non-competitive NMDA receptor antagonist and inhibits voltage-dependent calcium channels. Addition of magnesium reduces C-fibre activation by inhibiting the slow excitatory post-synaptic currents produced by NMDA receptor activation. NMDA receptor antagonists interfere with the influx of calcium and sodium into the cells that causes central sensitisation.8 It also has a vasodilatory effect mediated by endotheliumnitric oxide.
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Pharmacological advances in the multimodal management of perioperative analgesia Magnesium can be administered both intravenously and epidurally. Several studies have suggested the use of intravenous magnesium as an analgesic adjuvant, and it is included in the enhanced recovery after abdominal surgery programme. The authors of a review published in 2013 concluded that the use of intravenous magnesium effectively reduced opioid use and, to a lesser extent, pain scores in the first 24 postoperative hours, with no serious adverse effects.9 It can be administered as a single (30---40 mg/kg) or combined bolus, or in continuous infusion (10 mg/kg/h), both of which are equally effective. Regarding the route of administration of magnesium, some authors suggest supplementing epidural anaesthesia with intrathecal or epidural MgSO. In some studies, this has significantly reduced postoperative analgesic requirements and increased the duration of blockade. The addition of magnesium to epidural fentanyl and bupivacaine in women undergoing elective caesarean section with combined spinal---epidural anaesthesia improved intraoperative conditions and the quality of postoperative analgesia. Addition of magnesium reduces C-fibre activation by inhibiting the slow excitatory post-synaptic currents produced by NMDA receptor activation. Both ketamine and magnesium sulphate have been tentatively associated with cerebral neuroprotection. In a recently published study10 in patients undergoing laminectomy, intravenous magnesium did not reduce consumption of opioids, although a previous metaanalysis11 evaluating 25 studies comparing magnesium with placebo concluded that perioperative intravenous magnesium reduces opioid use and, to a lesser extent, pain scores in the first 24 postoperative hours. Therefore, although the evidence is inconsistent, most authors consider magnesium to be an effective component of multimodal analgesia strategies.
Lidocaine Like ketamine and magnesium, intravenous lidocaine is increasingly indicated in acute and chronic neuropathic and nociceptive pain.11 Several studies have been published on the use of lidocaine in perioperative analgesia strategies. It has been suggested that lidocaine has an indirect antiinflammatory action produced by blocking the stimulus that triggers the inflammatory response.12 A Cochrane review13 published in 2015 concluded that there is low to moderate evidence of this, and that the optimal dose and duration of administration remain unclear. However, the review concluded that it may be a useful adjuvant during general anaesthesia because of its beneficial effect after surgery, although evidence is weak. Lidocaine, therefore, is considered an option to be considered in a multimodal analgesia strategy. As far as dose and timing is concerned, although no firm evidence or guidelines are available, the doses most frequently evaluated in studies are boluses of 1---1.5 mg/kg during or after induction, which can be followed by continuous infusion of 1---1.5 mg/kg/h. The optimal treatment regimen remains unclear, but lidocaine appears to have a good safety profile.
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Intravenous ibuprofen Intravenous ibuprofen, which has the same pharmacological effect as the oral formulation, has recently been approved in Spain, thus adding a new alternative to the existing range of intravenous NSAIDs. The antipyretic and anti-inflammatory effect of the drug is a result of its inhibition of prostaglandin E2 and I2 production by reversible competitive blockade of constitutive and inducible COX isoforms (COX-1 and COX-2, respectively), which prevents the activation of proinflammatory processes and leucocyte infiltration. Prostaglandins are responsible for many physiological processes and also for most side effects. This is why the precautions and limitations associated with their use are derived from their interference with these physiological processes. Intravenous ibuprofen14 can only be used for short-term pain management, although this is not a disadvantage in perioperative multimodal analgesia strategies. The effect of ibuprofen on the gastrointestinal and cardiovascular systems is time-dependent, so short-term administration reduces the risk of drug-induced side effects. Several studies have shown its efficacy as a perioperative analgesic, both alone or in combination with paracetamol, and even as a preoperative preventive analgesic. A recent meta-analysis15 concluded that intravenous ibuprofen did not increase incidence of perioperative infection or ischaemia, although the risk of bleeding and the increased risk of gastrointestinal lesions should be taken into account.
Opiate combinations Opiates as adjuvants in regional anaesthesia Opioids are widely used in conjunction with local anaesthesia, as they permit the use of lower doses of local anaesthetics without compromising anaesthesia and analgesia quality. They provide both adequate anaesthesia as well as less drug toxicity. In this article we will focus on the latest opioids used in multimodal strategies. Butorphanol Butorphanol is a lipophilic opioid that has been used both for epidural and intrathecal administration. A recent study16 showed that low-dose bupivacaine combined with butorphanol had no side effects, although bupivacaine combined with fentanyl is superior in terms of early postoperative recovery resulting in early discharge. The authors concluded that it could be an option to consider in elderly patients with comorbidity. Intradural sulfentanil The administration of either intradural and epidural sulfentanil (in labour) has been studied in different interventions, particularly caesarean section,17 at doses of between 2.5 and 5 g (the latter being the most frequently used). Efficacy outcomes vary, and not all studies have shown sulfentanil to be superior to intradural fentanyl. In terms of side effects, haemodynamic stability was similar to
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4 fentanyl administered by the same route, and sulfentanil does not seem to reduce tremors, but does increase incidence of pruritus. There is clear evidence that intradural fentanyl in chronic opioid users prolongs the sensory and motor blockade to achieve a duration similar to that achieved in non-opioid users, suggesting that it could be the opioid of choice in this subpopulation of patients. Further studies are needed to conclusively demonstrate the superiority of sulfentanil over intradural fentanyl as an adjunct to analgesia in multimodal management. Sublingual sulfentanil (a recent formulation) also opens up new possibilities in the management of pain in the immediate postoperative period.
Combination with intravenous remifentanil The duration and dosage of remifentanil infusion when used in combination with other opioids varies considerably. Short-acting opioids such as remifentanil have been associated with acute tolerance to opioids and/or opioidinduced hyperalgesia. These side effects appear to be dose- or infusion time-dependent; doses in excess of 0.25 g/kg−1 /min−1 are associated with tolerance (increased consumption of postoperative opioids) and hyperalgesia (lower pressure, cold or pain thresholds). The use of multimodal concomitant analgesia, especially NMDA receptor antagonists, may prevent these side effects. Remifentanil is administered at lower doses when used in multimodal analgesia, a factor that reduces the risk of side effects.18
Ondansetron Ondansetron is a specific 5-hydroxytryptamine-3 (5-HT3 or serotonin) antagonist commonly used as an antiemetic for the prevention or treatment of postoperative nausea and vomiting. Side effects are minimal, the most common being constipation, dizziness and headache. The anti-inflammatory and analgesic properties of 5-HT antagonists are derived from their affinity to -opioid receptors and capacity to block sodium channels. A study by Farouk19 reported that the addition of ondansetron to lidocaine may improve the quality of intravenous regional anaesthesia and prolong postoperative analgesia in patients undergoing hand surgery. However, no systematic reviews have been published on the use of ondansetron as an adjuvant of intravenous regional anaesthesia with lidocaine.20 A study in paediatric patients21 found an interaction between acetaminophen and ondansetron and increased consumption of opioids in the immediate postoperative period, suggesting that ondansetron should not be used within a multimodal analgesia strategy that includes intravenous paracetamol. More studies are needed to evaluate whether this finding has sufficient clinical relevance to disadvise simultaneous perioperative administration of both drugs.
M. Matute Crespo, A. Montero Matamala
Dexmedetomidine Dexmedetomidine is an alpha 2 adrenergic agonist that can be used in both intravenous and spinal administration. The mechanism of analgesic action is unclear, although it seems to produce endogenous modulation, due to its effect on receptors located at the level of the dorsal horn of the spinal cord and brain, and also acts on substance P. Pre-anaesthesia single-shot administration of 1 g/kg dexmedetomidine decreases anaesthesia requirements.22 The addition of a small (0.05 g/kg) single shot of dexmedetomidine to bupivacaine and fentanyl in women undergoing elective caesarean section with combined spinal---epidural anaesthesia improved intraoperative conditions and the quality of postoperative analgesia. In another study,22 the authors found that dexmedetomidine may be a better additive to levobupivacaine than fentanyl for caudal postoperative analgesia in children. Dexmedetomidine could be used in multimodal analgesia, but further studies are required before definitive conclusions can be drawn.
Pregabalin The use of preoperative pregabalin has been highly controversial after studies showing its efficacy had to be withdrawn due to methodological defects. A clinical trial performed after the withdrawal of these studies found no clear benefit for this drug.23 It has been suggested that pregabalin may be effective in reducing neuropathic pain, albeit at the expense of increased sedation. Therefore, although this option exists, it cannot be clearly recommended.
Conclusions As this review shows, the term ‘‘personalised multimodal analgesia’’ has arisen due to the many different drugs available in this setting. However, choosing the right combination from the wide range of alternatives is a challenge for the anaesthesiologists. We must not lose sight of the main objective of multimodal analgesia, which is to increase efficiency by minimising side effects. To achieve this, we must fully understand the effects of the drugs added to multimodal strategies as analgesics or co-analgesics in order to improve efficacy and safety and avoid iatrogenic damage.
Ethical disclosures Protection of human and animal subjects. The authors declare that no experiments were performed on humans or animals for this study. Confidentiality of data. The authors declare that they have followed the protocols implemented in their place of work regarding the use of patient data in publications. Right to privacy and informed consent. The authors declare that no patient data appears in this article.
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Pharmacological advances in the multimodal management of perioperative analgesia
Conflict of interest The authors declare they have no conflict of interest.
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