Perioperative Opioid Administration: A Critical Review of Opioid-free Versus Opioid-sparing Approaches

Harsha Shanthanna, M.D., Ph.D., F.R.C.P.C.; Karim S. Ladha, M.D., M.Sc., F.R.C.P.C.; Henrik Kehlet, M.D., Ph.D.; Girish P. Joshi, M.B.B.S., M.D., F.F.A.R.C.S.I.


Anesthesiology. 2021;134(4):645-659. 

In This Article

Perioperative Opioid use

Traditionally, the perioperative phases in which analgesics are used include the intraoperative period, the postoperative in-hospital period, and the postdischarge period. However, the preoperative period also constitutes an important phase in which analgesics are to be managed within the context of enhanced recovery after surgery pathways.[25,26] It is necessary to categorize into these phases because factors involved in the analgesic choices and available options differ. For example, the in-hospital period allows more analgesic options and modalities of administration as compared with the postdischarge period, in which the options are restricted to oral analgesics,[4] unless there is a specific pathway to address such needs in the form of a transitional pain care or perioperative surgical home.[27]

Intraoperative Considerations and Challenges

Balanced Anesthesia and Opioids. The concept of balanced general anesthesia includes unconsciousness, amnesia, immobility, and antinociception.[28,29] Under general anesthesia, although the patient does not suffer from pain (subjective experience), nociceptive signals are continuously generated and carry negative physiologic consequences,[30] as well as a higher risk of awareness. The nociceptive pathways have strong connections with arousal pathways and administering anti-nociceptive agents decreases arousal.[28,31] Cividjian et al.[29] note that it would be wrong to assume that there is no interaction between the adequacy of hypnosis and the adequacy of antinociception under general anesthesia. Fleischer and Glass[32] note the following regarding the link between nociceptive signals and awareness: "One of the most common pitfalls in the use of state-of-consciousness monitoring in preventing awareness has been the failure to anticipate changing levels of noxious stimulus and their likely effect on the hypnotic state. During sleep, depending on how 'light' or 'deep,' one may be awakened by noise of a lesser or greater degree, so during general anesthesia, the hypnotic state will be affected by stronger or weaker stimuli, depending on the adequacy of the analgesic component of the anesthetic. It is this component that is not measured by the Bispectral Index or any other monitor currently available and that is most likely responsible for case reports of awareness at Bispectral Index levels generally accepted as synonymous with unconsciousness." Within an analysis of the American Society of Anesthesiologists Closed Claims Project, intraoperative pain was the third most common event recalled by patients.[33] The adequacy of antinociception is assessed by autonomic changes such as blood pressure and heart rate, as well as patient movements in an unparalyzed patient.[1,28,32] Opioids act as the primary agents of antinociception and decrease arousal by acting on receptors at several levels.[1,28,34–36] As an adjuvant to other components of general anesthesia, they decrease the need for sedative-hypnotics during induction and maintenance[31,37] and contribute to a significant decrease in the minimum alveolar concentration.[1] They mitigate hyperdynamic responses for laryngoscopy and intubation, and blunt cough and gag reflexes during airway manipulation.[38]

Despite these benefits, it is clear that opioids should be used sparingly because they have recognized short-term adverse effects that can influence patient-important outcomes and cost.[3] This can be achieved by using nonopioid analgesics. Although the initial advocation of multimodal analgesia was toward the adequate control of postoperative pain and minimizing adverse effects from individual agents,[39] it has now been extended to the entire perioperative phases, including the intraoperative part, wherein the objective is to reduce opioid requirements (i.e., opioid sparing).[3,40,41] However, the amount of intraoperative opioid sparing could differ between surgical procedures, and not all analgesics may be safe in all procedures or patients.[4,42,43]

Opioid-free Anesthesia and its Challenges. Opioid-free anesthesia is a claim toward "no opioid use," specifically to separate it from opioid sparing. Despite the claim, people differ in their interpretation regarding the need for opioids even within opioid-free anesthesia. For example, one definition suggests opioid-free anesthesia as a technique in which no intraoperative opioid is administered via any route, including systemic, neuraxial, or tissue infiltration.[44] Forget[45] defines it as "the combination of various opioids sparing techniques leading to the disappearance of the intraoperative opioids."

The known nonopioid analgesic strategies include the use of acetaminophen, nonsteroidal anti-inflammatory drugs or cyclooxygenase-2–specific inhibitors, local/regional analgesic techniques and nonpharmacologic adjuncts.[4] Medications commonly considered as analgesic adjuncts include steroids, gabapentinoids, intravenous lidocaine infusion, and ketamine infusion.[28,46,47] More recently, dexmedetomidine, magnesium, and β-blocker infusions were added.[20,41,48] Paradigms of opioid-free anesthesia proposed include administration of several nonopioid analgesics, plus some or all of the above noted analgesic adjuncts, along with infusions of dexmedetomidine, magnesium, and β-blockers, in various combinations.[2,19,20,41,48,49] There are some important considerations and limitations of these approaches (Figure 1).

Figure 1.

A representation of intra- and postoperative care considerations and limitations in the context of opioid-sparing versus opioid-free strategies. Opioid-free paradigms include multimodal analgesia options indicated in the top part along with other infusion options in the bottom part. NSAID, nonsteroidal anti-inflammatory drug.

All agents considered, excepting opioids, are limited by a ceiling effect and, with most agents, a small therapeutic index for safety. Most adjuncts are to be administered as a combination of fixed-dose infusions, and one cannot titrate them to an effect, which is a necessity during the intraoperative period. With an attempt to take out the reliance on opioids for anti-nociception, an objective and effective way to discern the level of nociception in a patient under general anesthesia becomes essential.[3,28] Nociceptive monitoring relies on indirect measures of peripheral and central responses and depends either on single responses such as skin conductance or on indices combining multiple measures such as the surgical stress index or nociception level index.[50,51] However, because of technological limitations and potential inaccuracies, their present use is precluded.[52] A recent systematic review looked at nociception monitor–guided anesthesia effects on opioid consumption and noted that no consistent effect of such monitoring on anesthesia could be established.[53] Optimal combination of these agents or their dosing remains unclear.[54] Frauenknecht et al.[55] recently published a systematic review and meta-analysis looking for analgesic impact of intraoperative opioids versus opioid-free anesthesia. They looked within PubMed and Google Scholar for trials that compared any type of intraoperative opioid administration with placebo injection or absence of opioids and included 23 trials for analysis. However, many included trials were not clearly opioid-free anesthesia as the name implied; Inoue et al.[56] used fentanyl for induction in all three groups, and Song and White[57] used remifentanil in both groups. Other studies, some of which were not included in this review, involve the use of three or more adjuncts at varying doses,[23,58] which makes it extremely difficult to tease out the incremental clinical value and cost considerations for individual agents.[59,60] As an example, let us look at two recent randomized controlled trials proposing opioid-free anesthesia for laparoscopic cholecystectomies. Toleska and Dimitrovski[61] report a trial of 30 patients having fentanyl-based anesthesia compared with 30 patients having infusions of lidocaine and magnesium. There were methodologic limitations affecting internal validity with no prespecified primary outcome, and the fentanyl group did not have any multimodal analgesia compared with the opioid-free anesthesia group, who had dexamethasone, paracetamol, and an anti-inflammatory medication. Toleska and Dimitrovski[61] only report pain scores for each hour throughout the recovery and do not report any outcome on opioid usage or adverse effects. In another trial, Bakan et al.[62] report an 80-patient trial in which all patients had multimodal analgesia, with the opioid-free anesthesia group having a combination of lidocaine plus dexmedetomidine and propofol infusion during surgery compared with remifentanil and fentanyl in the standard group. The primary outcome of opioid consumption within 6 h after extubation was not significantly different between the two groups. There was actually a significant increase in the discharge time from recovery in the opioid-free anesthesia group. If other studies propose adding other nonopioid adjuncts, such as calcium channel blocker[63] or β-blocker with potential analgesic properties, how do we determine whether it should be included in the opioid-free anesthesia combination?

Suggested clinical approaches to opioid-free anesthesia seem to ignore the concerns about safety and drug interactions and do not appreciate the practical resource limitations.[21,64] Even a single dose of intraoperative ketamine can cause hallucinations and nightmares;[65] dexmedetomidine can cause clinically important hypotension and prolong readiness to discharge, as well as an increased risk of airway collapse and prolonged hypoxia;[62,66–70] β-blockers can increase the risk of death, stroke, and hypotension;[71,72] and magnesium can cause arrhythmias and potentiate neuromuscular blockade and increase the risk of residual paralysis.[73] Although gabapentinoids have been used in many multimodal analgesia regimens,[54] their safety has been recently questioned.[74–78] A recent French survey found a clear mismatch between existing evidence and clinical use of perioperative gabapentinoids.[79] This is an example of how widespread adoption of an analgesic adjunct in a fixed combination seeps into clinical practice without appropriate consideration of its individual risk–benefit ratio. Multiple intravenous medications necessitate equipment for infusions. This can be burdensome, apart from increased costs of using such equipment for every case.[80] It is unclear which of the adjuncts in the combination should be stopped for an observed adverse effect, and how will it impact on the subsequent delivery of opioid-free anesthesia? Similarly, which of these adjuncts would continue to provide analgesia that will extend beyond the operating room and discharge?

Two other considerations are pertinent to discuss: opioid-induced hyperalgesia and cancer recurrence. Opioid-induced hyperalgesia has bigger implications in chronic pain practice, and it is very likely to be a real phenomenon even in acute care settings.[81] Studies suggest that opioid-induced hyperalgesia is more pronounced, with short-acting or ultrashort-acting agents such as fentanyl and remifentanil.[82] In a systematic review and meta-analysis, Fletcher and Martinez[83] showed that patients with higher intraoperative opioid doses had higher pain scores than controls. The difference was less than 10 mm on a 100-mm scale at 1 h after surgery and decreased further over time. Whether the differences from opioid-induced hyperalgesia are big enough to make clinical relevance and offset limitations of not using them are important questions. Preclinical evidence and uncontrolled studies suggested that opioids can increase cancer recurrence by inhibiting the function of natural killer cells and by their effect on angiogenesis and tumor cell signaling pathways.[84] However, a recent review,[85] as well as a large (n = 2,108) multicenter randomized controlled trial, concluded that there was insufficient evidence to recommend any particular analgesic technique for patients undergoing cancer surgery.[86]

Postoperative In-hospital Analgesia Considerations and Challenges

Patient-centered Pain Relief in the Context of Multimodal Analgesia. Although the nature of pain after surgery is to a large extent determined by the surgical procedure,[87,88] the intensity of pain and the need for analgesics can vary even among patients having the same surgery.[4,87,89] There is also individual variability in the amount of opioid sparing with known analgesics used for multimodal analgesia.[90,91] The incidence of moderate to severe pain in-hospital and on the first postoperative day is reported in around 30 to 80% of patients.[92–94] There is consistent evidence to suggest that a substantial proportion of patients continue to have inadequately managed postoperative pain with deleterious consequences, including persistent postsurgical pain.[88,95,96] In summary, it is vital to recognize that a one-size-fits-all approach cannot be appropriate and runs against the tenet of personalized medicine, so allowance for analgesic titration is a much-needed necessity.

Opioid-free Analgesia and its Challenges. Many protocols that have been suggested as opioid-free analgesia do not clarify their method of analgesia in the recovery unit.[4,96] There is no literature on how these patients recover or about their postoperative trajectory in comparison with patients who receive opioids within a framework of good multimodal analgesia.[23] In the review by Frauenknecht et al.,[55] 15 of 23 trials used parenteral opioids in the postoperative period. With the absolute avoidance of opioids in opioid-free analgesia, there is no allowance for any measures or analgesic to be titrated to individual patient requirements, other than the local/regional analgesic options. Nonsteroidal anti-inflammatory drugs have a maximum daily safe dose;[97] acetaminophen also has a daily maximum dose and cannot provide meaningful rescue analgesia in moderate to severe pain;[98] and gabapentinoids or other adjuvants are not pure analgesics and cannot be used as rescue analgesia by titration.[76] Within the context of treating postoperative pain in-hospital, we do not overtreat pain;[7,99,100] more relevantly, do we overdepend on opioids? If so, why? Do we have realistic options to forego opioid use completely?

The components of multimodal analgesia are chosen considering their (1) intrinsic analgesic potency, (2) opioid-sparing potential, and (3) potential side effects. The first two characteristics go in parallel: larger analgesic potency leads to higher opioid sparing. As highlighted within the PROcedure-SPECific Postoperative Pain ManagemenT (PROSPECT) recommendations, not all medications carry the same potential in different surgeries,[88] such as the variation in the opioid-sparing effect of acetaminophen[98,101,102] or the benefit of local infiltration analgesia observed in knee arthroplasties but not hip.[103] Despite broader acceptance of the concept of multimodal analgesia, there have been disappointing results, as observed by the proportion of surgical patients who continue to have inadequate pain relief.[4,104] This is likely as a result of nonutilization or inconsistent application of available modalities rather than the nonavailability of newer modalities.[23,46,90,104] Locoregional analgesia, whether delivered by surgeons or anesthesiologists, has been shown to have important effects for analgesia and opioid sparing.[105,106] Despite this knowledge, in a recent study of nearly 13 million patients, only 3.3% among 25% patients considered eligible had nerve blocks.[107] In another study, only 29.8% of colectomy patients and 76.5% of knee arthroplasty patients received any nonopioid analgesic on the day of surgery.[46]

There are several potential nonpharmacologic approaches to pain management that may reduce the use of medications and improve outcomes in the postoperative period. In clinical practice they are used as adjuncts rather than a primary analgesic and can be broadly categorized as physical and psychologic modalities. Physical modalities include transcutaneous electrical nerve stimulation, acupuncture, massage, yoga, continuous passive movement, and cryotherapy. Among these treatment options, systematic reviews and guidelines have determined that transcutaneous electrical nerve stimulation and acupuncture have demonstrated evidence to support their consideration.[108] However, the level of evidence and certainty is low, and the amount of analgesia provided is unclear. Other physical modalities are considered safe but are not supported by rigorous scientific studies. Psychologic modalities can be grouped into four categories: information provision, stress reduction, attentional strategies, and cognitive–behavioral interventions.[108] These categories overlap and can be used in combination within a comprehensive intervention. Although initial evidence demonstrates significant potential of psychologic therapies for reducing postoperative pain, there is insufficient data to recommend a particular method or technique.[109] Given the relative safety of both physical and psychologic modalities, further investigations addressing their efficacy and cost effectiveness is warranted to justify wider adoption.

When we look at suggested regimens for opioid-free analgesia, many include continued infusions of lidocaine, magnesium, ketamine, and dexmedetomidine in various combinations,[19,41] although some even include using fentanyl patient-controlled analgesia in postoperative wards.[19] Apart from the limitations highlighted during the intraoperative phase, these infusion regimens necessitate monitoring, additional resources and equipment, and cost. For example, even for adjuncts with relatively better evidence such as ketamine and lidocaine infusions, more frequent and high-dependency monitoring, including continuous electrocardiogram, blood pressure, sedation level, and oxygen saturation, are required in most places.[64,110] Given these considerations, the argument to include more modalities with little consideration to procedure or patient-specific needs in the ambit of opioid-free analgesia, seems counterintuitive.[111] Furthermore, the enthusiasm to implement these modalities can divert the attention from utilizing important components of multimodal analgesia. More importantly, the adverse effects of these approaches (e.g., orthostatic hypotension) and the cumbersome infusions attached to the patient can delay ambulation, which is one of the key components of enhanced recovery.[112] Thus, there can be misguided attention toward areas with smaller gains and missed opportunities for larger gains, especially from the surgical community, who feel that newer opioid-free analgesia techniques are the way out of the present crisis. This is reflected in the systematic review by Fiore et al.,[113] who set out to look for opioid-free prescriptions after surgery (where the real problem lies) and observed that a majority of randomized controlled trials (n = 117) compared opioid-free versus opioid analgesia during hospital stay, and only seven randomized controlled trials targeted analgesia postdischarge.

Postdischarge Analgesic Considerations and Challenges

It is not about Opioids but how we use Them. Pain is a common complaint after surgery and can interfere with recovery.[4,92] Surveys of mixed populations have shown that 70 to 80% of patients have moderate to severe pain during the first few days after surgery.[93,99,100] In many common day surgeries (inguinal hernia, cholecystectomy, arthroscopies, laparoscopic salpingooophorectomy), postdischarge pain can be adequately controlled with a combination of nonopioid analgesics given round the clock, with opioids as a rescue analgesic.[4,15,21,23] For major surgeries, such as arthroplasty, laparotomy, or thoracotomy, opioids are included in the combination of analgesics, until such time as to allow appropriate resolution.[3,4] Despite this knowledge, the practice of using two or more nonopioid analgesics is inconsistent and low.

In a large survey of 2,754 ambulatory surgery patients, only 14% of patients were prescribed a combination of two or more drugs, and 24% of adult patients continued to report pain even on day 7 after surgery.[114] Interestingly, there seems to be a clear distinction in how postoperative opioids are used in reference to their geography.[115] The per capita use of opioids in Scandinavian countries is half or less as compared with the United States.[23] Another observational study noted that postsurgical opioids are prescribed to 98.3% of patients in North America compared with 70.2% of patients in Europe; despite this, the mean worst pain scores were rated higher in North American patients (7.4 of 10) compared with patients from Europe (5.4 of 10).[116] There may also be cultural differences in pain expectations and limitations of pain intensity measures used to reflect the need for analgesics.[117,118] As pertinent to North America, there is abundance of literature suggesting that inappropriate opioid prescriptions, in the form of prolonged prescriptions with minimal oversight, have contributed to the ongoing opioid crisis.[9,10] A large observational study in 18,343 patients attempting to find the basis on which discharge prescriptions were made found no correlation between opioids prescribed at discharge with the opioids consumed in the last 24 h before discharge.[119] Other studies have shown that around 90% or more patients are provided with opioid prescriptions but only 20 to 30% actually used them[14,120] and less than 20% received instructions for safe disposal.[14] This overprescribing could lead to diversion and potentially to persistent opioid use.[9,120]

We would be shortsighted if we assume that the risk of misuse or diversion exists only with opioids or with certain opioids. The risk of misuse exists in 40 to 65% patients prescribed gabapentinoids.[121] Tramadol is a weak μ-opioid receptor agonist and is used as a schedule IV drug in the United States and an unscheduled drug in Canada, and many consider it to be a much safer drug with less addictive properties.[122] With this reasoning, physicians have used it in studies aimed to reduce opioid use,[15] and one randomized controlled trial even included it under nonopioid prescribing.[123] However, Thiels et al.[122] recently noted that patients receiving tramadol alone after surgery had similar or even higher risks of persistent opioid use compared with other patients receiving short-acting opioids.

Recognizing and Dealing With the Twin Issues of Persistent Opioid use and Persistent Postsurgical Pain. The observed incidence and the definition of persistent opioid use varies.[10,11,124] Brummett et al.[125] quoted an incidence of 5.9 to 6.5% in both minor and major surgeries. Goesling et al.[124] observed that among patients who were opioid-naïve at surgery, 8.2% of knee arthroplasty and 4.3% of hip arthroplasty patients were using opioids at 6 months. In another database study of 641,941 opioid-naïve surgical patients, the odds ratio of persistent opioid use (more than 90 days after surgery) ranged between 1.28 (95% CI, 1.12 to 1.46) for cesarean delivery to 5.10 (95% CI, 4.67 to 5.58) for knee arthroplasty.[11] Jivraj et al.[126] observed that among 39 studies, 29 different definitions of persistent opioid use were used with an incidence varying from 0.01 to 14.7% and a median of 0.7%. Although ideally persistent opioid use should reflect actual use of opioids, prescriptions or pharmacy claims have been considered as proxy to indicate persistent opioid use in major reviews or studies using large databases.[10,127] Most of them also do not report the reasons for persistent opioid use and if indeed an analgesic was needed for continuing pain.[128]

Let us now consider whether opioid reduction during surgery or in the hospital decreases persistent opioid use. Although studies do show reduction in inpatient opioid consumption, especially with implementation of enhanced recovery after surgery pathways,[129,130] there is no evidence to suggest that limiting intraoperative opioids influences the risk of persistent opioid use. In fact, even for regional analgesia, with nearly complete opioid avoidance, existing studies show no association with their use and persistent opioid use.[24,131,132] If there is any such possibility, the more relevant question would be how much opioid reduction makes a difference for the risk of persistent opioid use? Suzan et al.[133] present a concept of crucial timing that separates the beneficial and negative effects of opioids. They hypothesize that if an opioid effect is present in the central pain pathways during injury (surgery), opioids augment postoperative pain. Although this may give additional credence to opioid-induced hyperalgesia, there is no rationale presented to support the risk of persistent opioid use.

As much as we appreciate the need to tackle increased opioid use, we cannot ignore the issue of inadequately treated pain and its consequences, including persistent postsurgical pain.[17,27,96] Importantly, as pointed out by Kharasch and Clark,[128] "how do we interpret a 2 to 3% overall median frequency of persistent opioid use in the context of 10 to 60% frequency of" persistent postsurgical pain, in terms of overall priority and approach? There are also many features intricately linked between them, from pathophysiological, organizational, and health delivery perspectives.[128,134] For example, the presence of preoperative pain and being on preoperative opioids independently increase the risk of persistent postsurgical pain and persistent opioid use.[135,136] The burden of acute pain intensity and duration have been associated with persistent postsurgical pain development.[137] Murphy et al.[138] report persistent pain outcomes of two different study populations receiving intraoperative methadone. In their first trial on spinal fusion surgery, the patients were randomized to receive 0.2 mg/kg methadone (n = 62) at induction or 2 mg of hydromorphone (n = 53) at surgical closure, along with routine anesthetic management. In the second trial, fast-track cardiac surgery patients were randomized to receive 0.3 mg/kg of methadone (n = 77) or 12 μg/kg of fentanyl (n = 79) before cardiopulmonary bypass. In both trials, patients received multimodal analgesia postoperatively. Methadone improved postoperative pain control and also decreased the weekly frequency of chronic pain in spine-fusion patients at 3 months and for cardiac surgery patients at 1 month after surgery, indicating that better control of perioperative pain has the potential to decrease persistent postsurgical pain and the number of patients using opioids at 3 months after surgery.[138] The issues of persistent opioid use and persistent postsurgical pain are better understood by recognizing the trajectory of pain in surgical patients.[92,139] Studies have observed significant variation within the pain-resolution patterns among patients[10,140–142] and note that analgesic consumption during the acute postoperative period is dynamic and changes with time.[92] In a mixed surgical cohort of 371 patients, Hah et al.[141] observed that the average pain trajectory significantly predicted not only prolonged pain (hazard ratio, 0.63; 95% CI, 0.50 to 0.80; P < 0.001) but also delayed opioid cessation (hazard ratio, 0.52; 95% CI, 0.41 to 0.67; P < 0.001). It is very likely that at this time patients predisposed to persistent postsurgical pain and persistent opioid use are not clearly separable within the surgical cohorts until they establish themselves, which means it may be difficult to identify them at the time of discharge.[143]