Introduction There is an ongoing discussion about the role of anaesthesiologists in opioid epidemic during the last few years that had caused a large number of deaths and an even larger number of addicted patients. the pivotal role of multimodal anaesthesia in opioid-sparing strategy is well understood. a combination of simple analgesics such as paracetamol and NSAIDs with other agents like magnesium sulphate, lidocaine, ketamine, clonidine, dexmedetomidine, esmolol, gabapentinoids and dexamethasone has been described by an increasing number of enthusiasts. Regional anaesthesia is a prominent component of multimodal anaesthesia as it can provide satisfactory opioid free analgesia in the postoperative period where the administration of the majority of intravenous agents cannot be extended.

Opioid epidemic and problems arising from the use of opioids The opioid epidemic is a devastating problem, declared by the US government as a public health emergency ¹ and is reasonably questioning the involvement of physicians. ^2–4 a combination of enormous efforts to manage acute and chronic pain (that is considered as the fifth vital sign) and an aggressive pharmaceutical marketing led to prolonged opioid intake by a large number of patients for chronic pain or post-surgery and surprisingly to addiction more commonly than it was believed. ⁴ It is now recognised that the risk of dependence or addiction increases if a large amount of opioid is prescribed for a long time ^{4 5} and that postoperative poor pain control is a significant risk factor for prolonged opioid use. ^{4 6} the role of secondary hyperalgesia in the development of chronic or persisting pain is also underestimated.⁷

Apart from the common and well described side effects of opioids, such as postoperative ileus, nausea and vomiting, urinary retention, respiratory depression and sleep-disordered breathing, a lot of questions have been arisen about the immune effect of these agents and their role in cancer recurrence as well as opioid induced hyperalgesia and tolerance. ⁸ All opioids can induce hyperalgesia, especially remifentanil, infused in high doses although this phenomenon can be attenuated by the simultaneous use of ketamine ^{4 8 9} and by gradual decrease of the dose infused. Opioid induced hyperalgesia is associated with increased postoperative pain scores and opioid requirements and may lead to the development of persistent pain. ^{3 8 10–12} Furthermore, opioids cause tolerance making satisfactory pain management progressively more difficult.^{4 11} Although opioids have been implicated in cancer recurrence and metastasis, results from experimental and human studies are conflicting.^{4 8 13–15} To date, there is no undisputable contemporary evidence suggesting that opioid intake plays a crucial role in cancer recurrence and patient survival. ^{4 16}

Therefore, the solution may be a satisfactory pain management strategy with the smallest dose of opioids for the shortest period of time with the implementation of multimodal analgesia. ⁴

Multimodal analgesia The variety of types of pain as well as the sites and the way that agents can potentially act along pathways make pain management extremely complicated. the rationale of multimodal analgesia is pain modulation at different sites and analgesia enhancement resulting in a reduction of opioid requirements. ^{17 18} Although the definition of pain seems to describe pain as a subjective phenomenon ¹⁹ in the unconscious patient the term nociception has been used in order to describe the neural processes of encoding and processing noxious stimuli. ²⁰ Nociceptive inputs to CNS trigger central sensitisation that plays a significant role in acute and long-lasting pain after surgery. ^{8 20–22} Nociceptive pathways involve many neurotransmitters so the role of opioids interfering with enkephalins is restricted. the question that arises is whether opioids are the best agent to control nociception. Another major problem is the lack of accurate monitoring of intraoperative nociception. ²⁰ It is recognised that intraoperative use of opioids is a way to achieve haemodynamic stability by sympathetic system suppression. Other agents also can be used to blunt sympathetic response to painful stimuli, such as a2 agonists (clonidine, dexmedetomidine) that provide postoperative opioid-sparing analgesia. the unique beneficial role of these agents includes haemodynamic stability, prevention of shivering without prolongation of awakening. ⁸ Dexmedetomidine seems to decrease opioid consumption in the first 24 hours ²³ while clonidine provides a less pronounced effect. ^{18 24} Especially in morbidly obese patients, dexmedetomidine showed reduced morphine requirements in PACU without episodes of desaturation or airway obstruction. ^{7 25 26} B-blockers (esmolol) have also been used to blunt sympathetic reaction to surgical stress.^{7 27} a meta-analysis ²⁷ about the role of esmolol on early postoperative pain showed that perioperative esmolol infusion lead in reduced opioid consumption. Ketamine also plays a crucial role as it prevents hyperalgesia and maintains haemodynamic stability. Ketamine possesses different mechanisms of action including NMDA receptor blockade, potentiation of GABA inhibition, sodium channel blockade as well as interaction with norepinephrine, dopamine and serotonin levels. ²⁸ Based on the latest guidelines, ²⁹ subanaesthetic ketamine should be considered for painful surgery and may be considered for opioid dependent or tolerant patients and as an adjuvant in patients with sleep apnoea. Magnesium sulphate can decrease heart rate variability. ⁸ Its antinociceptive targets are most likely those of ketamine as well as other non-specific targets.^{7 17} In a meta-analysis of 25 studies,³⁰ magnesium reduced morphine consumption in the first 24 hours postoperatively. Though lidocaine analgesic properties have been described when used intravenously and a 2015 Cochrane Systematic Review ³¹ showed reduced opioid consumption, in its 2018 update ³² uncertainty about its efficacy has been expressed. Usually a bolus dose (1–3 mg/kg) of lidocaine followed by a continuous infusion (1–5 mg/kg/h) has been used. ⁷ Large evidence supports gabapentinoids’ use in the perioperative setting.^33–36

Opioid free anaesthesia (OFA) in the extremes of multimodal analgesia Opioid free anaesthesia may improve patient’s early and later outcome in a variety of ways. OFA decreases the risk of common opioid adverse effects like nausea and vomiting, prevents the appearance of acute tolerance phenomenon and hyperalgesia and contributes to enhanced recovery ²⁰ in specific populations like bariatric patients, chronic pain and opioid dependent patients. ²⁶ Despite the increasing number of OFA enthusiasts, little data is found in the literature mostly expressing authors’ personal opinion, clinical practice and regimen. ^{7 26} ‘Mullimix’ a combination of a low dose of dexmedetomidine and ketamine with lidocaine has been proposed and extensively used by Mulier ^{37 38} both as bolus and continuous infusion. the main issue about opioid free strategies is that even if intraoperative omission of opioids is achieved, a poor postoperative analgesic plan will result in opioid rescue. An analgesic strategy that will extend beyond PACU, hospital ward and patient discharge is therefore mandatory. as Lirk ⁴ has noticed, we have to change the way other clinicians think about opioids and pain, otherwise our OFA strategy will have little impact. as so far OFA did not achieve the reduction of the opioids prescribed on discharge, an educational problem among physicians was arisen.

Regional anaesthesia In order to enhance patient recovery, non-opioid adjuvant medication and regional anaesthesia including peripheral and neuraxial blocks have extensively been proposed and incorporated into Enhanced Recovery Pathways. ³⁹ There is a large body of publications showing that regional anaesthesia (neuraxial or peripheral blocks) used in different types of surgery reduces the opioids consumed in early postoperative period. ¹⁸ Continuous blocks used for shoulder surgery ^{18 40} reduced opioids up to 48 hours, for forearm or hand surgery up to 24 hours. ^{18 41} Similarly, lower limb blocks reduced opioid consumption in different operations.^{18 42–45} the universal implementation of ultrasound guidance resulted in new blocks not only of the limbs but mostly new sensory blocks of the trunk with higher success rates when compared with blind techniques. TAP block^{18 49–51} was rediscovered and although, in the beginning, it was considered as the holy grail for abdominal procedures, nowadays modern blocks as quadratus lumborum, erectus spinae or pectoral nerve blocks and serratus block for mastectomies ^{18 39 52–56} became more popular. Furthermore, paravertebral blocks gained special interest for their use in breast cancer surgery. ¹⁶ Dexamethasone perineurally or intravenously, clonidine and dexmedetomidine have increasingly been used, off-label, as adjuvants to extend sensory block and analgesia. Epidural analgesia as, a component of ERAS pathways, may decrease perioperative opioid consumption^{18 57} and is proposed to prevent hyperalgesia. ^{8 58} In addition, epidural analgesia is proposed to cancer surgery as a way to reduce opioid-correlated cancer recurrence. ^{16 59} Mulier underlines that even major thoracic or abdominal surgery can remain opioid-free if combined with locoregional techniques. ³⁸ What is disappointing though is the fact that locoregional techniques are underused against the vast evidence of their efficiency. ⁷ Finally, although there is enormous data about the efficacy of regional anaesthesia in the early postoperative period, long term results concerning pain and opioid consumption are unknown.

Summary In summary, although opioid free anaesthesia is not always feasible, the implementation of locoregional techniques in opioid sparing anaesthesia should always be in mind, in order to reduce opioid consumption and their side effects especially in specific groups of patients such as morbidly obese or addicted. the desirable goal is the expansion of opioid-free strategies but mainly, the education towards a postoperative pain management strategy with a restriction of opioid prescription.

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