Opioid-free anaesthesia

This Editorial is part of a Pro and Con debate and is accompanied by the following articles: Veyckemans F. Opioid-free anaesthesia. Still a debate? Eur J Anaesthesiol 2019; 36:245–246. Lavand’homme P. Opioid-free anaesthesia. Pro: damned if you don’t use opioids during surgery. Eur J Anaesthesiol 2019; 36:247–249. As this Editorial is being written, an unprecedented opioid crisis deeply affects a number of Western societies, including the United States of America,1 Canada2 and Australia.3 This crisis has its roots in the well intentioned introduction of Pain as the ‘fifth vital sign’, and efforts to improve pain treatment for both acute and chronic pain. At the same time, aggressive pharmaceutical marketing programmes grew, some going so far as to offer incentives to healthcare providers and hospitals to favour opioid-based analgesia.4 Over the span of just a few years, opioids were being prescribed to enormous numbers of patients, many with longstanding chronic pain conditions and all too often for prolonged periods after surgery. Per capita, the United States now consumes more than 10-fold the global mean quantity of strong opioids (Fig. 1). Most individuals on long-term opioid therapy become opioid-dependent, with uncomfortable signs and symptoms appearing when the opioids are abruptly discontinued. Overt addiction, with uncontrollable cravings, inability to control drug use, compulsive drug use and continued use despite doing harm to oneself or others is more common than once believed in those on chronic opioid therapy. Stories of patients initially prescribed opioids to treat pain transitioning to acquire their substance of abuse on the black market have become common, some subsequently moving on to use more affordable and available (but also more deadly) related street drugs, such as fentanyl, acetyl-fentanyl, carfentanil and mixtures of heroin and fentanyl.5,6 The results have been devastating. A spiralling increase in the number of neonates suffering from neonatal abstinence syndrome has been observed,7 and more than 60 000 US adults died from drug overdose in 2017 alone, surpassing the number of US soldiers killed during the entire Vietnam war.8 This is, however, just a small glimpse at the devastating impact of the opioid epidemic, the proverbial tip of the iceberg; the broader societal impact of this epidemic cannot be overstated.1 Despite prominent political and healthcare initiatives, this crisis has yet to reach its peak. Estimates are that three quarters of heroin users in the United States today have transitioned to illicit drug use from initial exposure to prescription opioids.9,10 Often, opiate therapy is initiated to treat pain associated with illness or injury. However, the longer patients are on opioids, the higher their likelihood to go on to persistent use, dependence and addiction.11 So, why not get rid of opioids altogether? Why not replace opioid-based anaesthesia by opioid-free anaesthesia (OFA) for the patients whose care has been entrusted to us? Are they not addictive, make pain worse rather than better, promote cancer recurrence and metastasis, and is there not enough evidence for opioid-sparing techniques that we might as well abandon opioids altogether? It is our role to be the advocatus diaboli against OFA. Despite our own deeply held bias against the pervasive use of opioids, in the following paragraphs we will provocatively argue against some of the commonly held misconceptions about opioids. Indeed, the ideal of OFA for all surgeries seems unrealistic today without alternative analgesics that are effective for treating the most severe pain, so finding a reasonable balance that minimises the risks associated with opioid use is critical for all prescribers.Fig. 1: Total opioid consumption per capita for selected countries, and mean global consumption, over time. Sources: International Narcotics Control Board; World Health Organization population data. By: Pain & Policy Studies Group, University of Wisconsin / WHO Collaborating Center, 2018.Are opioids addictive? The answer is clearly yes, opioids do lead to addiction in a subset of people once they are exposed. So, how can we limit the number of people who are exposed and minimise the risk of addiction in those who do require some opioid exposure to adequately control pain after surgery? We now understand some of the risk factors that are associated with persistent opioid use after surgery.12 Poorly controlled pain, higher opioid doses and use for longer periods of time after surgery are all associated with persistent opioid use months to years after surgery. Ensuring adequate pain control using the smallest doses of opioids for the shortest periods of time may well help reduce long-term opioid use. This implies that patients should be treated in the context of multimodal regimens, using as many nonopioids (including regional anaesthesia) as feasible to minimise the number of opioids given, and the time patients spend on opioids. It is high time to reshape how patients have been prescribed opioids in the past. As illustrated in Fig. 1, Scandinavian countries, for example Denmark, use about half of the opioids per capita as used in the United States, and The Netherlands consume less than a quarter. Changing the pervasive use of opioids in the United States will require nothing short of a cultural reorientation which involves patients, caregivers, hospitals and insurers, with an emphasis on using as little opioids for as brief a time possible. Countries in which opioids are prescribed liberally have a huge dependency, diversion and epidemic addiction problem, countries which limit and strictly oversee prescription and access (e.g. The Netherlands) do not (Fig. 1). This would suggest that it is not opioids that are the problem but the way in which many of us use them. The challenge for the coming decade is to develop sensible opioid prescribing guidelines, tailored to meet the (time-dependent) analgesic needs of each specific procedure and patient, and incorporating effective nonopioid comedications. Implementation of multimodal strategies is, on the contrary, very inconsistent.13 Lastly, a word of caution is in order: opioids are by no means the only addictive substances to which patients and caregivers may be exposed. We find that many agents used in OFA protocols such as propofol, ketamine, benzodiazepines and gabapentin also have substantial addictive potential,14–17 and may also lead to long-term difficulties for our colleagues and our patients. Do opioids actually make pain worse? Opioids are admittedly suboptimal analgesics in that they lead to hyperalgesia and tolerance, making management progressively more difficult over time. Opioid-induced hyperalgesia, most potently induced by remifentanil, is dose-dependent,18 and the clinical relevance is most apparent in very painful procedures or over long periods of treatment in patients with chronic pain. But it appears that this hyperalgesia can be easily attenuated by simultaneous infusion of low-dose ketamine.19 So, while hyperalgesia is a real problem, it can be easily overcome, at least in the acute postoperative setting. Do opioids increase the likelihood of cancer recurrence? Opioids have been implicated in cancer recurrence and metastasis, and a reduction in opioid exposure has been proposed as one of the mechanisms by which regional anaesthesia may improve patient outcomes after some types of cancer surgery.20 There is experimental evidence both supporting21 and refuting22 the tumour-promoting activity of opioids. A recent meta-analysis of animal experiments concluded that there is no effect of opioids on tumour progression.23 The human data are difficult to interpret. For example, Wang et al. retrospectively observed that patients treated with opioids after tumour surgery had a poorer prognosis. However, looking more closely at the data, the opioid-treated patients, on average, had larger or more advanced tumours, larger surgeries, and more pain, and this could explain the poorer survival.24 Population-based and propensity-matched data such as those reported in Danish population studies suggest that intake of opioids has no effect on patient survival.25,26 The available data thus do not suggest a clinically important effect on tumour recurrence. There are many good reasons to reduce peri-operative and postoperative opioids, but from what we know in 2019, cancer recurrence is not one of them. Can (/should) we eliminate opioids altogether? Multimodal analgesia has been shown again and again to be superior to opioid-only regimens.27 Should we take this to the extreme and simply give drugs such as beta-blockers to attenuate the surgical stress response, eliminating opioids altogether? There is ample evidence that reducing opioids and resting postoperative analgesia on a broader base is a noble undertaking. Whether it is necessary to eliminate opioids completely for all surgeries is another question. Even if we succeed in introducing an entirely opioid-free anaesthetic, we would need to weave this together with an analgesic plan that will extend well beyond the operating room and hospital discharge. Brandal et al.28 summarised their institution's findings upon introducing enhanced recovery and opioid-free anesthesia. Although intra-operative opioids could be reduced dramatically, opioids prescribed at the time of discharge remained the same, indicating that reducing opioids is an institutional effort, and the culture and protocols across a variety of services need to be modified. If we cannot change the way the recovery room, the patient wards, and patients themselves think about opioids and pain, our intra-operative efforts to reduce opioids will have little impact. From what we know today, a difference of a few micrograms of fentanyl or sufentanil in the operating room is unlikely to make a huge difference in patients’ lives. In contrast, keeping patients on postoperative opioids for longer periods than needed, and discharging patients with large prescriptions of strong opioids may be what sets these patients up for problems.11 Rather than painstakingly trying to get rid of all the opioids in the operating room, we should adopt sensible opioid-sparing strategies, weaning patients from opioids as quickly as possible. For those patients who cannot be weaned off opioids immediately, close follow-up in a transitional or chronic pain clinic should ensure that their trajectory does not progress towards long-term dependence.29 Is there no evidence to support the routine use of OFA? While reducing opioids by administering coanalgesics and/or regional anaesthesia is logical and has been proven effective in many surgical settings,27 the concept of ‘pure’ OFA is, today, without sufficient evidence to become routine practice. Many institutions and individuals have devised their own ‘cocktail’ of drugs and analgesic techniques to achieve OFA. Despite the growing number of providers practicing OFA, there is surprisingly little data in the literature, few clinical trials, and no prospectively collected high-quality evidence that switching from a contemporary multimodal analgesic regimen to OFA offers any real benefit to the patient which would justify these often complicated and expensive regimens. We do not know enough about how patients recover and how their postoperative trajectory differs from that of patients receiving opioids in the framework of good multimodal analgesia. We do not know which surgeries and procedures can be done well with OFA and which cannot. It seems almost too much to suggest that all patients for all surgeries, from knee arthroscopy to craniotomy, should henceforth receive OFA. Intuitively, the more painful and the longer the surgery, the bigger the impact of opioid-sparing strategies would be.30 However, most OFA articles available today offer only the authors’ opinions from their own clinical practices rather than rigorous clinical evidence. The question of implementation also remains. Our specialty has been notoriously slow to adopt new analgesic techniques. Even the implementation of something as simple as multimodal analgesia has been slow and still incomplete.13,31 After decades of pain research and broad efforts to implement modern strategies, pain scores (with all their limitations) reported in the literature remain high, even after minor surgeries.32–34 We propose that our first strategy should be to put all of our energy behind widespread introduction of multimodal analgesia, and then look whether there is sufficient evidence to go the extra mile to OFA. Opioids have many limitations and dangers as analgesic agents, but many of them may have more to do with the way that providers use these drugs today and the expectations we have built in our patients. Opioids are addictive, but so too are many other drugs used for OFA (propofol, ketamine, benzodiazepines, gabapentinoids), raising the question about comparative safety. Opioids cause hyperalgesia, but addition of a low-dose ketamine infusion seems to be a simple solution to this problem in the setting of acute pain treatment. In the past, opioids have been linked with tumour progression but the most current evidence refutes this association. We agree that minimising opioids in the peri-operative period is always a good idea, but implementation of multimodal analgesia should be our primary focus today, as this approach is already supported by scientific evidence. OFA is already widely practiced in many centres, but there is no evidence that patient outcomes are as good or better than modern multimodal analgesic regimens, including targeted use of regional anaesthesia. We would like to appeal to those practitioners who use OFA regularly to conduct the well controlled clinical trials that are desperately needed to understand the risks and benefits of this new approach. Over the past 20 years, we have seen a sharp rise in the use of opioids in many Western countries. In those countries with the highest rise in opioid consumption, opioid abuse has also risen dramatically. This suggests that it is not the opioids themselves that are to blame, but the way in which many have grown accustomed to using them. Opioids continue to hold an indispensable role as potent analgesics in contemporary medicine. More sensible use of opioids in the years ahead is a far better alternative than a regression to a fear of opioids and the danger of returning to a prior era of reluctant and often inadequate pain management. When used in the context of multimodal analgesia, in modest doses, and for limited periods of time, opioids remain safe and effective for the treatment of pain in countless patients worldwide. Acknowledgements relating to this article Assistance with the Editorial: none. Financial support and sponsorship: none. Conflicts of interest: none. Comment from the Editor: this article is based on the lecture ‘Opioid-Free Anaesthesia: CON’, delivered by PL at the 2018 Euroanaesthesia Congress, Copenhagen, Denmark. PL is an Associate Editor of the European Journal of Anaesthesiology. This Editorial was checked by the editors but was not sent for external peer review.

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