
==== Front
Curr Pain Headache Rep
Curr Pain Headache Rep
Current Pain and Headache Reports
1531-3433
1534-3081
Springer US New York

38865074
1276
10.1007/s11916-024-01276-w
Acute Pain Medicine (R Urman, Section Editor)
Adjuvant Analgesics in Acute Pain – Evaluation of Efficacy
Kummer Isabelle isabelle.kummer@kssg.ch

1
Lüthi Andreas 1
Klingler Gabriela 1
Andereggen Lukas 23
Urman Richard D. 4
Luedi Markus M. 15
Stieger Andrea 1
1 https://ror.org/00gpmb873 grid.413349.8 0000 0001 2294 4705 Department of Anesthesiology, Rescue- and Pain Medicine, Cantonal Hospital of St. Gallen, St. Gallen, Switzerland
2 grid.413357.7 0000 0000 8704 3732 Department of Neurosurgery, Cantonal Hospital of Aarau, Aarau, Switzerland
3 https://ror.org/02k7v4d05 grid.5734.5 0000 0001 0726 5157 Faculty of Medicine, University of Bern, Bern, Switzerland
4 https://ror.org/00rs6vg23 grid.261331.4 0000 0001 2285 7943 Department of Anesthesiology, The Ohio State University, Columbus, OH 43210 USA
5 grid.411656.1 0000 0004 0479 0855 Department of Anesthesiology and Pain Medicine, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland
12 6 2024
12 6 2024
2024
28 9 843852
15 5 2024
© The Author(s) 2024
2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Purpose of the Review

Acute postoperative pain impacts a significant number of patients and is associated with various complications, such as a higher occurrence of chronic postsurgical pain as well as increased morbidity and mortality.

Recent Findings

Opioids are often used to manage severe pain, but they come with serious adverse effects, such as sedation, respiratory depression, postoperative nausea and vomiting, and impaired bowel function. Therefore, most enhanced recovery after surgery protocols promote multimodal analgesia, which includes adjuvant analgesics, to provide optimal pain control. In this article, we aim to offer a comprehensive review of the contemporary literature on adjuvant analgesics in the management of acute pain, especially in the perioperative setting.

Summary

Adjuvant analgesics have proven efficacy in treating postoperative pain and reducing need for opioids. While ketamine is an established option for opioid-dependent patients, magnesium and α2-agonists have, in addition to their analgetic effect, the potential to attenuate hemodynamic responses, which make them especially useful in painful laparoscopic procedures. Furthermore, α2-agonists and dexamethasone can extend the analgesic effect of regional anesthesia techniques. However, findings for lidocaine remain inconclusive.

Keywords

Adjuvant analgesics
Co-analgesics
Perioperative pain management
Ketamine
Magnesium
α2-agonists
Dexamethasone
Intravenous lidocaine
University of BernOpen access funding provided by University of Bern

issue-copyright-statement© Springer Science+Business Media, LLC, part of Springer Nature 2024
==== Body
pmcBackground

The International Association for the Study of Pain (IASP) defines pain as an “unpleasant sensory and emotional experience associated with, or resembling that associated with, actual or potential tissue damage” [1]. Pain plays an integral part in the medical care of patients. Acute pain accounts for up to 70% of visits to the emergency departments which makes it one of the most common reasons for patients seeking medical care [2]. Besides, acute pain is of equal importance in the perioperative setting. Several studies have indicated that approximately 50% of patients suffer from moderate to severe pain within the initial 24 h following surgery [3–5].

Acute postoperative pain does not only affect patient satisfaction but might also lead to chronic postsurgical pain: several studies detected a correlation between the intensity of acute pain in the postoperative period and the emergence of chronic postsurgical pain [6–8]. In addition, inadequate analgesia can result in various other complications such as an increased incidence of pulmonary or cardiac complications and even increased morbidity and mortality [4]. Risk factors contributing to heightened pain levels after surgery include female gender and young age [3]. Preoperative quantitative sensory testing may anticipate postoperative pain in patients undergoing elective procedures and may help to find patients prone to experience severe pain after surgery [9].

Therefore, it is essential to effectively manage acute pain [10–14]. Although opioids are often used in the management of postoperative pain due to their effectiveness in alleviating even severe pain, their side effects, such as sedation, respiratory depression, postoperative nausea and vomiting (PONV) and impaired bowel function can extend the duration of hospitalization [15]. Furthermore, overuse of opioids can exacerbate opioid dependence in susceptible patients, even with short-term use [16]. Hence, most enhanced recovery after surgery (ERAS) protocols, as for example in cardiac surgery [17], promote multimodal analgesia, which incorporates various methods of pain management to attain effective pain relief while mitigating opioid-related side effects. [18].

Adjuvant analgesics, also known as co-analgesics, are important in the treatment of chronic pain: they may enhance the analgesic effect of conventional analgesics or have independent analgesic activity of their own in certain conditions such as neuropathic pain. When added to an opioid therapy, they can enhance pain relief, address refractory pain and lower opioid doses, which reduces opioid’s adverse effects [19]. However, their contribution to perioperative pain management remains elusive.

This narrative review aims to offer an overview of the current literature on the role of adjuvant analgesics in the multi-modality management of acute pain, in particular within the perioperative context. We seek to explore the efficacy of adjuvant analgesics, both for parenteral administration and as adjuncts to regional anesthesia, where appropriate.

N-methyl-D-aspartate (NMDA) Receptor Antagonists

The amino acid glutamate is the most important excitatory neurotransmitter within the central nervous system. Glutamate activates NMDA receptors in the spinal cord causing the spinal cord neuron to become more responsive to its inputs, which eventually leads to central sensitization [20]. Therefore, NMDA receptor antagonists have been pivotal in preventing hyperalgesia and in managing chronic pain. However, as multimodal analgesia gains importance, NMDA receptor antagonists are also becoming integral in the treatment of acute pain, as their blockade is believed to enhance the efficacy of opioids [21].

The most important NMDA receptor antagonists used as adjuvant analgesics in acute pain management are ketamine and magnesium sulfate.

Ketamine

Ketamine is a phencyclidine derivative and dissociative anesthetic agent. It exerts its analgesic effect via its reversible antagonism on the NMDA receptor, although it has some effect on the μ-opioid, muscarinic, monoaminergic and γ-aminobutyric acid receptors as well [22].

In the perioperative setting, ketamine is mainly used as an adjuvant analgesic in painful procedures, including abdominal, thoracic, and major orthopedic surgery, as well as in opioid-tolerant or -dependent patients presenting for surgery [23]. Several smaller randomized controlled trials (RCT) suggest that subanesthetic doses of ketamine reduce postoperative pain scores and the need for opioids [24–26]. A systematic review conducted by Laskowski et al. demonstrated a significant decrease in total opioid consumption and an increase in the interval until the first analgesic was administered in patients receiving intravenous ketamine across all studies. The greatest efficacy was found in painful procedures like thoracic and upper abdominal, where the greatest reduction in opioid use was seen, as well as in lower abdominal and major orthopedic surgeries [21].

There is limited evidence for opioid-dependent patients, based on a few RCTs with conflicting results: One RCT by Loftus et al. showed that ketamine decreased opioid consumption at 48 h postoperatively as well as pain intensity in the postanesthesia-care unit (PACU) in opioid-dependant patients undergoing back surgery [27]. However, another study in the same patient population showed no benefit [28].

Based on the existing evidence, the consensus guidelines on the use of intravenous ketamine infusions for acute pain management from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine and the American Society of Anesthesiologists, published by Schwenk et al. in 2018, suggest that “subanesthetic ketamine infusions should be considered for patients undergoing painful surgery and ketamine may be considered for opioid-dependent or opioid-tolerant patients undergoing surgery” [23].

Apart from its role in the perioperative setting, ketamine has been used in prehospital trauma care for a long time. In the trauma setting, it is especially useful as it has analgesic features but also affects the sympathetic nervous system and increases the average heart rate and blood pressure [29].

Adverse Events

Most studies on ketamine use for acute pain management provide some insight on adverse events. The most reported adverse events of ketamine use are nausea, vomiting, vivid dreams, and hallucinations. However, in most studies, the incidence of adverse events is only slightly higher compared with placebo [21, 30].

According to the guidelines by Schwenk et al. ketamine usage is discouraged in patients with poorly managed cardiovascular disease, psychosis, or severe hepatic disease as well as in pregnant women [23].

Magnesium Sulfate

The analgesic effects of magnesium are believed to be associated with the control of calcium influx into the cell [31] and its antagonistic effect on the NMDA receptor in the central nervous system [32, 33].

Several studies demonstrated that administering magnesium sulfate perioperatively reduced postoperative opioid consumption as well as pain scores at rest and on movement, whether it was given as a continuous infusion or as a single bolus dose [34–36].

The rising prevalence of laparoscopic techniques has prompted investigations into the effects of magnesium sulfate on cardiovascular reactions. It has been shown that the perioperative administration of magnesium sulfate was associated with a diminished hemodynamic response, characterized by decreased blood pressure and heart rate, following the induction of pneumoperitoneum [37–39]. They found that patients receiving high doses of magnesium sulfate had significantly lower systemic vascular resistance, mean arterial blood pressure and central venous pressure while the cardiac output was significantly increased compared to the control group that was given normal saline [39]. Furthermore, the group administered high doses of magnesium sulfate experienced better pain control, as indicated by a lower visual analogue scale (VAS) score.

Therefore, magnesium sulfate could serve as a crucial component in the perioperative period, not only to alleviate pain but also to attenuate hemodynamic responses to pneumoperitoneum, making it a good adjuvant for (painful) laparoscopic surgeries.

Apart from its use in the perioperative setting, magnesium sulfate might be beneficial in the pain management of patients with dysmenorrhea [40] and migraine [41]. However, high quality evidence is missing and there is the need for further randomized controlled trials evaluating the effect of magnesium sulfate in this regard.

Adverse Events

Magnesium sulfate has a broad therapeutic index. Known adverse events of magnesium sulfate include prolongation of neuromuscular blockade after administration of non-depolarizing neuromuscular blocking agents [42, 43], sedation [44], dizziness and rarely respiratory depression [45]. Serious cardiovascular events have been described in relation with iatrogenic overdose [46]. The systematic review of Albrecht et al. showed that bradycardia was common after magnesium administration but there were no reports of persistent hemodynamic instability although doses as high as 23.5 g over a period of 24 h have been administered in one study included in the review. No difference in the occurrence of sedation or hypotension was noted. However, the incidence of adverse events might be underestimated as only six studies evaluated the incidence of hypotension and bradycardia and only two studies evaluated the incidence of sedation [35].

α2 Agonists

Clonidine and dexmedetomidine are α2-adrenoceptor agonists. Apart from analgesia, they have further effects such as sedation, anxiolysis and sympatholysis, which make them interesting adjuvants in multimodal analgesia regimens [47]. The stimulation of α2-receptors in the dorsal horn of the spinal column, leading to the inhibition of nociceptive neurons and decrease in the release of substance P, is held responsible for their analgesic effect [48]. In addition, they act on presynaptic α2-adrenoceptors in the vasomotor centre of the brainstem. Through activation of these receptors, a negative feedback loop is activated, resulting in a decrease in sympathetic activity [49].

Clonidine and dexmedetomidine have different selectivity for α2-adrenoceptors, with dexmedetomidine being approximately 8-times more specific to alpha-2 adrenoceptors than clonidine [50].

Several studies demonstrated an opioid-sparing and analgesic effect of the perioperative systemic administration of α2-agonists [51–56]. In a systematic review and meta-analysis, Blaudszun et al. investigated the impact of perioperative systemic α2-agonists on postoperative pain severity and morphine usage. They revealed that both clonidine and dexmedetomidine exerted a morphine-sparing effect and lead to a decrease of pain intensity, with the effect being more pronounced for dexmedetomidine than clonidine [53]. At 48 h postoperatively, α2-agonists seemed to have lost their pain-relieving effect. In addition, the incidence of early nausea diminished with both agents with a number needed to treat (NNT) of approximately 9. Although α2-agonists have sedative effects, there was no evidence of a lengthened recovery time. Similar results were seen in a systematic review and meta-analysis, including 57 trials, on clonidine [55]. Although they could not show a reduction in pain scores at rest, clonidine reduced cumulative analgesic consumption at 24 and 36 h, as well as postoperative shivering and PONV. Awakening time was not prolonged.

Apart from the sole analgesic effects, α2-agonists have been used to attenuate hemodynamic stress. Clonidine could be shown to improve hemodynamic stability after tracheal intubation [55], during laparoscopic cholecystectomy [57, 58] and during thyroidectomy surgery [59]. Similar effects could be shown for dexmedetomidine [60]. Furthermore, Wang et al. conducted a study on the effects of dexmedetomidine on inflammation, immune function and perioperative stress in surgical patients [61]. They concluded that dexmedetomidine attenuates perioperative stress and inflammation and preserves immune function.

In summary, perioperative administration of clonidine or dexmedetomidine might be especially beneficial in patients and surgeries, where attenuation of sympathetic stimulation is desired, such as in thyroid or laparoscopic surgery.

Apart from the systemic application, α2-agonists are also useful as an adjunct for regional anesthesia leading to a prolongation of the duration of sensory block and analgesia, as several studies have shown [62–64].

Adverse Events

The most important perioperative adverse events are hypotension and, especially for dexmedetomidine, bradycardia. In their systematic review, Blaudszun et al. showed that intraoperative and postoperative hypotension was more common after clonidine administration, with a number needed to harm (NNH) of approximately 9 and 20 respectively, whereas there was a higher risk of postoperative bradycardia with dexmedetomidine use with a NNH of 3 [53]. Similar effects could be seen if used as adjuncts for brachial plexus nerve block: dexmedetomidine was associated with bradycardia requiring intervention and both dexmedetomidine and clonidine were associated with hypotension [62]. In 2019, Demiri et al. conducted a study with similar results [65]. The risk of hypotension and bradycardia persisted even after cessation of treatment. However, when looking at dexmedetomidine, a dose-dependency was detected: intraoperative hypotension and postoperative bradycardia were not observed with a bolus dosage of dexmedetomidine of less than 0.5 μg/kg or with continuous administration alone.

Therefore, hemodynamic monitoring is essential when administering clonidine or dexmedetomidine and this must be continued for a prolonged period even after cessation of treatment. The hemodynamic effects must be considered, especially in patients where hypotension and bradycardia might be deleterious, and α2-agonists should be administered with caution in surgeries where a high blood loss is expected.

Glucocorticoids

The analgesic effects of glucocorticoids are thought to originate from their anti-inflammatory actions, including the suppression of inflammatory cytokines and prostaglandine synthesis as well as induction of anti-inflammatory cytokines. Furthermore, rapid antihyperalgesic effects are believed to be a result of nongenomic effects which reduce the excitability of nerve cells by decreasing glutamate release and increasing the release of γ-aminobutyric acid [66].

Although there are a few trials suggesting that methylprednisolone might have analgesic properties when given perioperatively [67–69], and a recent systematic review and meta-analysis showed similar efficacy of methylprednisolone and dexamethasone in reducing postoperative pain after third molar surgery [70], most studies focused on dexamethasone as a possible adjuvant analgesic in the perioperative setting.

Dexamethasone is commonly used for the prevention of postoperative nausea and vomiting [71], but there is evidence that it has analgesic properties as well. In a meta-analysis of 24 RCTs, dexamethasone in doses larger than 0.1 mg/kg were found to decrease opioid consumption and postoperative pain [72]. Preoperative administration of dexamethasone seemed to provide a greater effect than intraoperative administration. Similar effects could be demonstrated in another systematic review [73]. Waldron et al. showed that a single dose of dexamethasone provided minor yet statistically significant analgesic advantages: patients who were administered dexamethasone exhibited reduced pain scores at 2 and 24 h, along with decreased opioid usage, diminished requirement for rescue analgesia, prolonged time to the first analgesic dose and shorter stays in the post-anesthesia care unit (PACU). In contrast to the study of De Oliveira at el. they showed no dose responsiveness regarding opioid consumption and only a small, probably only minimally clinically significant dose responsiveness regarding pain scores. However, the study is limited by a significant heterogeneity of I2 = 94% for VAS pain scores at 2 h and I2 = 97% for VAS pain scores at 24 h.

In addition to its analgesic effect when given systemically, dexamethasone can be used to prolong the analgesic duration of peripheral nerve blocks [74]. Pehora et al. showed that both perineural and intravenous dexamethasone led to a prolonged duration of sensory block as well as a reduction in pain intensity at 12 and 24 h postoperatively when given as an adjuvant to peripheral nerve block in upper-limb surgery [75]. At 48 h, no more effect could be detected. Although the duration of block was significantly longer by three hours, and the postoperative pain intensity was significantly lower when dexamethasone was given perineurally compared to intravenously, the mean difference in reduction of postoperative pain intensity did not surpass the predetermined minimally important difference, suggesting the result might not be clinically significant. There was not enough evidence to make a conclusion about dexamethasone adjunct in lower-limb surgery as only two of the included trials reported on that subject.

In contrast to the use as a systemic analgesic, the timing of administration doesn’t seem to be important: Xu et al. compared pre- and postoperative administration of dexamethasone in addition to an interscalene brachial plexus block in shoulder surgery [76]. The mean duration of analgesia, time to first analgesia as well as opioid consumption did not significantly differ between the two groups.

Unlike α2-agonists, there is no risk of hypotension when dexamethasone is used as an adjunct to peripheral nerve blocks, and there is low-quality evidence that dexamethasone might be a superior adjunct compared to dexmedetomidine as it improves the duration of analgesia by a statistically significant increase of approximately 2.5 h more than dexmedetomidine without the risk of hypotension [77].

Adverse Events

Long-term treatment with corticosteroids is associated with many side effects, such as adrenal insufficiency, hypertension, osteoporosis, delayed wound healing, hyperglycaemia and even diabetes mellitus [78, 79].

Regarding the perioperative use of dexamethasone, there is no evidence of an increased incidence in wound infection and delayed healing, but dexamethasone might elevate blood glucose levels [72, 73, 80]. In a systematic review, Polderman et al. detected an increase in blood glucose levels after dexamethasone administration but no difference in the rate of postoperative wound or systemic infections (Peto odds ratio (OR) 1.01, I2 = 27%) [81]. Due to imprecision in trial results, no statement about the effect on delayed wound healing could be made. A recent non-inferiority trial including 8725 participants with and without diabetes mellitus confirmed these results: There was no increased risk of surgical-site infection after administration of 8 mg dexamethasone, not even in patients with diabetes mellitus [82].

Although no serious adverse events could be detected in the studies on perioperative dexamethasone, rare events might have been missed due to the study design. There is evidence that dexamethasone might increase invasion, proliferation, and angiogenesis in glioblastoma-derived orthotopic tumors, which might worsen prognoses of glioblastoma patients [83–85]. Further studies are needed to determine the clinical significance of this potentially dangerous effect of dexamethasone.

Lidocaine Infusions

Lidocaine is an amide-type local anesthetic. While the principal mechanism of action of lidocaine as a local anesthetic is by blocking the voltage-gated sodium channels and hence blockade of action potential propagation, the analgesic mechanism of intravenous lidocaine remains uncertain. Several mechanisms have been suggested, such as inhibition of voltage-gated sodium-channels, suppression of inflammatory mediators, and modulation of excitatory as well as inhibitory neurotransmission [86].

Several RCTs have studied the analgesic effects of intravenous lidocaine administered perioperatively in different surgical fields, and subsequent systematic reviews and meta-analyses have been conducted with varying results [87–95]. In a systematic review including 16 RCTs, McCarthy et al. found significant reductions in postoperative pain intensity and opioid consumption in open and laparoscopic abdominal surgery as well as in ambulatory surgery, whereas lidocaine had no impact on patients undergoing tonsillectomy, total hip arthroplasty or cardiopulmonary bypass surgery [87]. These results were confirmed by other meta-analyses focusing on abdominal and elective colorectal surgery, respectively [89, 90]. Systemic lidocaine reduced postoperative pain intensity at early time points, although the difference seen by Rollins et al. did not meet the threshold for a clinically relevant difference. While cumulative opioid consumption was reduced in the study conducted by Sun et al. [90], no difference in postoperative opioid requirement was seen in elective colorectal surgery [89]. Apart from the analgesic benefit, a significant reduction in time to defecation and hospital length of stay was seen in both studies. However, an important limitation of these studies was the significant heterogeneity.

In contrast to these results, more recent studies focusing on bariatric surgery detected only little [95] or no benefit [97] of lidocaine infusions administered perioperatively. These different results might be partly explained by different dosing regimens and length of lidocaine infusions. Yang et al. found that only prolonged lidocaine infusions of a duration of more than 24 h provided beneficial effects such as faster time to first defecation, reduced pain scores and reduced hospitalization duration, while neither short nor long term infusions significantly decreased analgesic requirements [93].

Furthermore, some studies explored the impact of lidocaine infusion in spine surgery and breast surgery with conflicting results as well. While the meta-analyses conducted by Licina et al. and Bi et al. showed a significantly reduced postoperative pain intensity up to 48 h after spine surgery and decreased opioid requirements [92, 94], another meta-analysis showed no such effect [95]. One study investigating the effect of lidocaine in breast surgery found that the incidence of chronic postsurgical pain (CPSP) was significantly reduced and pain scores at rest were lower [95], whereas no such effect was shown by another study [91].

The latest Cochrane review on perioperative systemic lidocaine seems to reflect the conflicting results and often low-quality evidence [88]. There was only sparsely significant evidence on lidocaine’s positive effect regarding postoperative pain intensity and secondary outcomes such as opioid requirements and bowel function, and a reduction in pain intensity was only detectable up to four hours postoperatively. The authors concluded that the evidence was insufficient to demonstrate clear improvements in postoperative pain, gastrointestinal recovery, and opioid consumption with intravenous lidocaine. Therefore, further high-quality studies are needed to determine the analgesic effects of systemic lidocaine in the perioperative setting.

Adverse Events

As intravenous administration of lidocaine poses a risk of toxicity with a possibly catastrophic outcome, consideration of adverse events is important. Adverse events that could be seen include mild headaches, higher incidence of light-headedness and dry mouth [90], dizziness, visual disturbances and a metallic taste [91] and transient sensory disturbance [92]. Of the 68 studies included in the most recent Cochrane review, 50 commented on adverse events. While 23 of these reported no significant adverse events, the adverse events reported in the remaining 27 studies included light-headedness, drowsiness, bradycardia, or perioral numbness [88]. A meta-analysis could not be performed because of the great heterogeneity of the presented data.

Relative contraindications for the administration of intravenous lidocaine, including cardiac disease or conduction block, electrolyte disorders, renal or hepatic disease, seizure or other neurological disorders, as well as pregnancy and breast-feeding should be taken into account [97] [95], and one has to keep in mind that early signs of toxicity might be missed during general anesthesia.

Others

Gabapentinoids

Pregabalin and gabapentin have been extensively used in the management of chronic pain conditions and are, beside antidepressants, considered co-analgesics of choice for neuropathic pain [97]. There is little evidence examining the use in the perioperative setting. A systematic review by Tiippana et al. indicates an opioid-sparing effect within the first 24 h post-surgery and a reduction of opioid-related adverse events. However, other trials examining the perioperative use in various surgical populations yielded conflicting results [95, 97, 95]. The use of gabapentinoids was even associated with a greater risk of side effects such as visual disturbances, dizziness and respiratory depression [97]. Based on this evidence, the routine use of gabapentinoids in perioperative pain management cannot be generally recommended.

Antidepressants

Although antidepressants play an important role in the management of chronic neuropathic pain [95], they are not commonly used perioperatively. Despite a limited number of systematic reviews indicating a favorable effect, including lower postoperative pain scores and reduced opioid consumption, when duloxetine or selective serotonin norepinephrine reuptake inhibitors in general were administered perioperatively [97, 95, 109], overall quality of evidence is considered low because of high interstudy heterogeneity and high risk of bias. Therefore, further high quality randomized controlled trials are needed to support or refute these results.

Cannabinoids

During the last decades, interest in the medicinal use of cannabinoids has risen, including their use in the management of acute pain. However, evidence is still sparse. While there are a few trials suggesting a beneficial effect [97, 95], other trials showed no [109] or even a negative effect, i.e. an increase in pain scores [97]. A recent systematic review including six trials revealed a small but statistically significant decrease in postoperative pain score with the administration of cannabinoids [95], but overall quality of evidence was considered low. Therefore, the use of cannabinoids in acute pain management must be examined in future high-quality studies.

Conclusion

In summary, adjuvant analgesics are an important part of multimodal analgesia regimens, especially for painful procedures, as they can reduce postoperative pain intensity as well as opioid requirements.

Ketamine has been proven effective in painful procedures such as thoracic, abdominal, and major orthopedic surgery and might be beneficial in opioid-dependent patients requiring surgery. Besides their analgesic effect, magnesium and α2-agonists can attenuate hemodynamic response, which make them especially useful in laparoscopic procedures. Furthermore, α2-agonists can prolong the analgesic effect when given as an adjunct to regional anesthesia techniques, an effect that could also be shown for dexamethasone, even when administered systemically. While hypotension is an important side effect of α2-agonists, no effect on blood pressure is seen with dexamethasone use, which may make it the more suitable option in patients where hypotension must be avoided. Systemic lidocaine may reduce postoperative pain intensity in abdominal surgery, but evidence remains conflicting.

Although several studies demonstrated the positive effects of various adjuvant analgesics, several unresolved questions persist, awaiting future exploration. There is still uncertainty concerning the optimal dosing of many of adjuvant analgesics in the perioperative setting. In addition, serious adverse events might have been missed due to small sample sizes. Therefore, additional high-quality studies are needed to assess the optimal dosing and the potential risks of the different co-analgesic agents to specify the optimal treatment in different patient groups.

Abbreviations

CPSP Chronic postsurgical pain

ERAS Enhanced recovery after surgery

IASP International Association for the Study of Pain

NMDA N-methyl-D-aspartate

NNH Number needed to harm

NNT Number needed to treat

PACU Post-anesthesia care unit

PONV Postoperative nausea and vomiting

RCT Randomized controlled trial

VAS Visual Analogue Scale

Author Contributions

Isabelle Kummer, Andreas Lüthi, Gabriela Klingler, Lukas Andereggen, Richard D. Urman, Markus M. Luedi, and Andrea Stieger conducted literature searches, wrote the article, and approved the final version.

Funding

Open access funding provided by University of Bern

Data Availability

No datasets were generated or analysed during the current study.

Code Availability

Not applicable.

Compliance with Ethical Standards

Ethics Approval

As a review article, ethical approval is not required by Swiss law.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interests

Dr. Richard Urman reports fees/funding from AcelRx and Merck and serves as a Section Editor for this journal.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Raja SN The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises Pain 2020 161 9 1976 1982 10.1097/j.pain.0000000000001939 32694387
Raja SN, et al. The revised International Association for the Study of Pain definition of pain: concepts, challenges, and compromises. Pain. 2020;161(9):1976–82.32694387
2. Keating L Smith S Acute pain in the emergency department: The challenges Rev Pain 2011 5 3 13 17 10.1177/204946371100500304 26526458
Keating L, Smith S. Acute pain in the emergency department: The challenges. Rev Pain. 2011;5(3):13–7.26526458
3. Walker EMK Patient reported outcome of adult perioperative anaesthesia in the United Kingdom: a cross-sectional observational study Br J Anaesth 2016 117 6 758 766 10.1093/bja/aew381 27956674
Walker EMK, et al. Patient reported outcome of adult perioperative anaesthesia in the United Kingdom: a cross-sectional observational study. Br J Anaesth. 2016;117(6):758–66.27956674
4. Gerbershagen HJ Pain intensity on the first day after surgery: a prospective cohort study comparing 179 surgical procedures Anesthesiology 2013 118 4 934 944 10.1097/ALN.0b013e31828866b3 23392233
Gerbershagen HJ, et al. Pain intensity on the first day after surgery: a prospective cohort study comparing 179 surgical procedures. Anesthesiology. 2013;118(4):934–44.23392233
5. van Boekel RLM Relationship between postoperative pain and overall 30-day complications in a broad surgical population: an observational study Ann Surg 2019 269 5 856 865 10.1097/SLA.0000000000002583 29135493
van Boekel RLM, et al. Relationship between postoperative pain and overall 30-day complications in a broad surgical population: an observational study. Ann Surg. 2019;269(5):856–65.29135493
6. Callesen T Bech K Kehlet H Prospective study of chronic pain after groin hernia repair Br J Surg 1999 86 12 1528 1531 10.1046/j.1365-2168.1999.01320.x 10594500
Callesen T, Bech K, Kehlet H. Prospective study of chronic pain after groin hernia repair. Br J Surg. 1999;86(12):1528–31.10594500
7. Katz J Acute pain after thoracic surgery predicts long-term post-thoracotomy pain Clin J Pain 1996 12 1 50 55 10.1097/00002508-199603000-00009 8722735
Katz J, et al. Acute pain after thoracic surgery predicts long-term post-thoracotomy pain. Clin J Pain. 1996;12(1):50–5.8722735
8. Tasmuth T Estlanderb AM Kalso E Effect of present pain and mood on the memory of past postoperative pain in women treated surgically for breast cancer Pain 1996 68 2–3 343 347 10.1016/S0304-3959(96)03219-8 9121823
Tasmuth T, Estlanderb AM, Kalso E. Effect of present pain and mood on the memory of past postoperative pain in women treated surgically for breast cancer. Pain. 1996;68(2–3):343–7.9121823
9. Luedi MM Preoperative pressure pain threshold is associated with postoperative pain in short-stay anorectal surgery: a prospective observational study Anesth Analg 2021 132 3 656 662 10.1213/ANE.0000000000005072 32675636
Luedi MM, et al. Preoperative pressure pain threshold is associated with postoperative pain in short-stay anorectal surgery: a prospective observational study. Anesth Analg. 2021;132(3):656–62. A prospective single-center observational study assessing the relationship between preoperative pressure pain threshold and postoperative pain in patients undergoing anorectal surgery. 32675636
10. Botea MO Cannabinoids for Acute Pain Management: Approaches and Rationale Curr Pain Headache Rep. 2024 10.1007/s11916-024-01252-4 38607548
Botea MO, et al. Cannabinoids for Acute Pain Management: Approaches and Rationale. Curr Pain Headache Rep. 2024. 10.1007/s11916-024-01252-4. Epub ahead of print. PMID: 38607548.38607548
11. Stieger A Nerve Blocks for Craniotomy Curr Pain Headache Rep. 2024 28 5 307 313 10.1007/s11916-024-01236-4 38472617
Stieger A, et al. Nerve Blocks for Craniotomy. Curr Pain Headache Rep. 2024;28(5):307–13. 10.1007/s11916-024-01236-4. Epub 2024 Mar 12. PMID: 38472617.38472617
12. Wipplinger F Meditation as an adjunct to the management of acute pain Curr Pain Headache Rep 2023 27 8 209 216 10.1007/s11916-023-01119-0 37285010
Wipplinger F, et al. Meditation as an adjunct to the management of acute pain. Curr Pain Headache Rep. 2023;27(8):209–16.37285010
13. Bello C Anesthesia care in the interventional neuroradiology suite: an update Curr Opin Anaesthesiol 2022 35 4 457 464 10.1097/ACO.0000000000001151 35861472
Bello C, et al. Anesthesia care in the interventional neuroradiology suite: an update. Curr Opin Anaesthesiol. 2022;35(4):457–64.35861472
14. Bello C Postcraniotomy headache: Etiologies and treatments Curr Pain Headache Rep 2022 26 5 357 364 10.1007/s11916-022-01036-8 35230591
Bello C, et al. Postcraniotomy headache: Etiologies and treatments. Curr Pain Headache Rep. 2022;26(5):357–64.35230591
15. Oderda GM Cost of opioid-related adverse drug events in surgical patients J Pain Symptom Manag 2003 25 3 276 283 10.1016/S0885-3924(02)00691-7
Oderda GM, et al. Cost of opioid-related adverse drug events in surgical patients. J Pain Symptom Manag. 2003;25(3):276–83.
16. Baumann L Acute pain and development of opioid use disorder: Patient risk factors Curr Pain Headache Rep 2023 27 9 437 444 10.1007/s11916-023-01127-0 37392334
Baumann L, et al. Acute pain and development of opioid use disorder: Patient risk factors. Curr Pain Headache Rep. 2023;27(9):437–44. A recent overview of patient-derived risk factors for developing opioid dependency. 37392334
17. Yang L Enhanced recovery after cardiac surgery: an update on clinical implications Int Anesthesiol Clin 2017 55 4 148 162 10.1097/AIA.0000000000000168 28901988
Yang L, et al. Enhanced recovery after cardiac surgery: an update on clinical implications. Int Anesthesiol Clin. 2017;55(4):148–62.28901988
18. Tan M Law LS Gan TJ Optimizing pain management to facilitate Enhanced Recovery After Surgery pathways Can J Anaesth 2015 62 2 203 218 10.1007/s12630-014-0275-x 25501696
Tan M, Law LS, Gan TJ. Optimizing pain management to facilitate Enhanced Recovery After Surgery pathways. Can J Anaesth. 2015;62(2):203–18.25501696
19. Bair MJ Sanderson TR Coanalgesics for chronic pain therapy: a narrative review Postgrad Med 2011 123 6 140 150 10.3810/pgm.2011.11.2504 22104463
Bair MJ, Sanderson TR. Coanalgesics for chronic pain therapy: a narrative review. Postgrad Med. 2011;123(6):140–50.22104463
20. Bennett GJ Update on the neurophysiology of pain transmission and modulation: Focus on the NMDA-receptor J Pain Symptom Manag 2000 19 1 Suppl S2 6 10.1016/S0885-3924(99)00120-7
Bennett GJ. Update on the neurophysiology of pain transmission and modulation: Focus on the NMDA-receptor. J Pain Symptom Manag. 2000;19(1 Suppl):S2–6.
21. Laskowski K A systematic review of intravenous ketamine for postoperative analgesia Can J Anaesth 2011 58 10 911 923 10.1007/s12630-011-9560-0 21773855
Laskowski K, et al. A systematic review of intravenous ketamine for postoperative analgesia. Can J Anaesth. 2011;58(10):911–23.21773855
22. Maher DP Chen L Mao J Intravenous ketamine infusions for neuropathic pain management: a promising therapy in need of optimization Anesth Analg 2017 124 2 661 674 10.1213/ANE.0000000000001787 28067704
Maher DP, Chen L, Mao J. Intravenous ketamine infusions for neuropathic pain management: a promising therapy in need of optimization. Anesth Analg. 2017;124(2):661–74.28067704
23. Schwenk ES Consensus guidelines on the use of intravenous ketamine infusions for acute pain management from the american society of regional anesthesia and pain medicine, the american academy of pain medicine, and the american society of anesthesiologists Reg Anesth Pain Med 2018 43 5 456 466 29870457
Schwenk ES, et al. Consensus guidelines on the use of intravenous ketamine infusions for acute pain management from the american society of regional anesthesia and pain medicine, the american academy of pain medicine, and the american society of anesthesiologists. Reg Anesth Pain Med. 2018;43(5):456–66.29870457
24. Aida S Preemptive analgesia by intravenous low-dose ketamine and epidural morphine in gastrectomy: a randomized double-blind study Anesthesiology 2000 92 6 1624 1630 10.1097/00000542-200006000-00020 10839912
Aida S, et al. Preemptive analgesia by intravenous low-dose ketamine and epidural morphine in gastrectomy: a randomized double-blind study. Anesthesiology. 2000;92(6):1624–30.10839912
25. Aveline C Postoperative analgesia and early rehabilitation after total knee replacement: a comparison of continuous low-dose intravenous ketamine versus nefopam Eur J Pain 2009 13 6 613 619 10.1016/j.ejpain.2008.08.003 18793861
Aveline C, et al. Postoperative analgesia and early rehabilitation after total knee replacement: a comparison of continuous low-dose intravenous ketamine versus nefopam. Eur J Pain. 2009;13(6):613–9.18793861
26. Menigaux C Intraoperative small-dose ketamine enhances analgesia after outpatient knee arthroscopy Anesth Analg 2001 93 3 606 612 10.1097/00000539-200109000-00016 11524327
Menigaux C, et al. Intraoperative small-dose ketamine enhances analgesia after outpatient knee arthroscopy. Anesth Analg. 2001;93(3):606–12.11524327
27. Loftus RW Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery Anesthesiology 2010 113 3 639 646 10.1097/ALN.0b013e3181e90914 20693876
Loftus RW, et al. Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology. 2010;113(3):639–46.20693876
28. Subramaniam K Intra- and postoperative very low dose intravenous ketamine infusion does not increase pain relief after major spine surgery in patients with preoperative narcotic analgesic intake Pain Med 2011 12 8 1276 1283 10.1111/j.1526-4637.2011.01144.x 21668751
Subramaniam K, et al. Intra- and postoperative very low dose intravenous ketamine infusion does not increase pain relief after major spine surgery in patients with preoperative narcotic analgesic intake. Pain Med. 2011;12(8):1276–83.21668751
29. Riva-Posse P Blood pressure safety of subanesthetic ketamine for depression: a report on 684 infusions J Affect Disord 2018 236 291 297 10.1016/j.jad.2018.02.025 29525051
Riva-Posse P, et al. Blood pressure safety of subanesthetic ketamine for depression: a report on 684 infusions. J Affect Disord. 2018;236:291–7.29525051
30. Bell RF Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systematic review (Cochrane review) Acta Anaesthesiol Scand 2005 49 10 1405 1428 10.1111/j.1399-6576.2005.00814.x 16223384
Bell RF, et al. Peri-operative ketamine for acute post-operative pain: a quantitative and qualitative systematic review (Cochrane review). Acta Anaesthesiol Scand. 2005;49(10):1405–28.16223384
31. Iseri LT French JH Magnesium: nature's physiologic calcium blocker Am Heart J 1984 108 1 188 193 10.1016/0002-8703(84)90572-6 6375330
Iseri LT, French JH. Magnesium: nature’s physiologic calcium blocker. Am Heart J. 1984;108(1):188–93.6375330
32. Feria M Magnesium sulphate injected subcutaneously suppresses autotomy in peripherally deafferented rats Pain 1993 53 3 287 293 10.1016/0304-3959(93)90225-E 8351158
Feria M, et al. Magnesium sulphate injected subcutaneously suppresses autotomy in peripherally deafferented rats. Pain. 1993;53(3):287–93.8351158
33. Woolf CJ Thompson SWN The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states Pain 1991 44 3 293 299 10.1016/0304-3959(91)90100-C 1828878
Woolf CJ, Thompson SWN. The induction and maintenance of central sensitization is dependent on N-methyl-D-aspartic acid receptor activation; implications for the treatment of post-injury pain hypersensitivity states. Pain. 1991;44(3):293–9.1828878
34. De Oliveira GS Jr Perioperative systemic magnesium to minimize postoperative pain: a meta-analysis of randomized controlled trials Anesthesiology 2013 119 1 178 90 10.1097/ALN.0b013e318297630d 23669270
De Oliveira GS Jr, et al. Perioperative systemic magnesium to minimize postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology. 2013;119(1):178–90.23669270
35. Albrecht E Peri-operative intravenous administration of magnesium sulphate and postoperative pain: a meta-analysis Anaesthesia 2013 68 1 79 90 10.1111/j.1365-2044.2012.07335.x 23121612
Albrecht E, et al. Peri-operative intravenous administration of magnesium sulphate and postoperative pain: a meta-analysis. Anaesthesia. 2013;68(1):79–90.23121612
36. Taheri A Effect of low-dose (single-dose) magnesium sulfate on postoperative analgesia in hysterectomy patients receiving balanced general anesthesia Anesthesiol Res Pract 2015 2015 306145 25705223
Taheri A, et al. Effect of low-dose (single-dose) magnesium sulfate on postoperative analgesia in hysterectomy patients receiving balanced general anesthesia. Anesthesiol Res Pract. 2015;2015:306145.25705223
37. Zhang J Influence of magnesium sulfate on hemodynamic responses during laparoscopic cholecystectomy: A meta-analysis of randomized controlled studies Medicine (Baltimore) 2018 97 45 e12747 10.1097/MD.0000000000012747 30407279
Zhang J, et al. Influence of magnesium sulfate on hemodynamic responses during laparoscopic cholecystectomy: A meta-analysis of randomized controlled studies. Medicine (Baltimore). 2018;97(45):e12747.30407279
38. Greenwood J Nygard B Brickey D Effectiveness of intravenous magnesium sulfate to attenuate hemodynamic changes in laparoscopic surgery: a systematic review and meta-analysis JBI Evid Synth 2021 19 3 578 603 10.11124/JBISRIR-D-19-00414 33074990
Greenwood J, Nygard B, Brickey D. Effectiveness of intravenous magnesium sulfate to attenuate hemodynamic changes in laparoscopic surgery: a systematic review and meta-analysis. JBI Evid Synth. 2021;19(3):578–603. A recent systematic review and meta-analysis about the effects of intravenous magnesium on hemodynamic changes during laparoscopic surgery. 33074990
39. Tan W Effects of different doses of magnesium sulfate on pneumoperitoneum-related hemodynamic changes in patients undergoing gastrointestinal laparoscopy: a randomized, double-blind, controlled trial BMC Anesthesiol 2019 19 1 237 10.1186/s12871-019-0886-4 31862004
Tan W, et al. Effects of different doses of magnesium sulfate on pneumoperitoneum-related hemodynamic changes in patients undergoing gastrointestinal laparoscopy: a randomized, double-blind, controlled trial. BMC Anesthesiol. 2019;19(1):237.31862004
40. Fontana-Klaiber H Hogg B Therapeutic effects of magnesium in dysmenorrhea Schweiz Rundsch Med Prax 1990 79 16 491 494 2349410
Fontana-Klaiber H, Hogg B. Therapeutic effects of magnesium in dysmenorrhea. Schweiz Rundsch Med Prax. 1990;79(16):491–4.2349410
41. Baratloo A Intravenous caffeine citrate vs. magnesium sulfate for reducing pain in patients with acute migraine headache; a prospective quasi-experimental study Korean J Pain 2017 30 3 176 182 10.3344/kjp.2017.30.3.176 28757917
Baratloo A, et al. Intravenous caffeine citrate vs. magnesium sulfate for reducing pain in patients with acute migraine headache; a prospective quasi-experimental study. Korean J Pain. 2017;30(3):176–82.28757917
42. Kussman B Administration of magnesium sulphate before rocuronium: effects on speed of onset and duration of neuromuscular block Br J Anaesth 1997 79 1 122 124 10.1093/bja/79.1.122 9301400
Kussman B, et al. Administration of magnesium sulphate before rocuronium: effects on speed of onset and duration of neuromuscular block. Br J Anaesth. 1997;79(1):122–4.9301400
43. Fuchs-Buder T Interaction of magnesium sulphate with vecuronium-induced neuromuscular block Br J Anaesth 1995 74 4 405 409 10.1093/bja/74.4.405 7734259
Fuchs-Buder T, et al. Interaction of magnesium sulphate with vecuronium-induced neuromuscular block. Br J Anaesth. 1995;74(4):405–9.7734259
44. Kiran S Gupta R Verma D Evaluation of a single-dose of intravenous magnesium sulphate for prevention of postoperative pain after inguinal surgery Indian J Anaesth 2011 55 1 31 35 10.4103/0019-5049.76605 21431050
Kiran S, Gupta R, Verma D. Evaluation of a single-dose of intravenous magnesium sulphate for prevention of postoperative pain after inguinal surgery. Indian J Anaesth. 2011;55(1):31–5.21431050
45. Smith JM An integrative review of the side effects related to the use of magnesium sulfate for pre-eclampsia and eclampsia management BMC Pregnancy Childbirth 2013 13 34 10.1186/1471-2393-13-34 23383864
Smith JM, et al. An integrative review of the side effects related to the use of magnesium sulfate for pre-eclampsia and eclampsia management. BMC Pregnancy Childbirth. 2013;13:34.23383864
46. Vissers RJ Purssell R Iatrogenic magnesium overdose: two case reports J Emerg Med 1996 14 2 187 191 10.1016/0736-4679(95)02115-9 8740750
Vissers RJ, Purssell R. Iatrogenic magnesium overdose: two case reports. J Emerg Med. 1996;14(2):187–91.8740750
47. Kamibayashi T Maze M Clinical uses of alpha2 -adrenergic agonists Anesthesiology 2000 93 5 1345 1349 10.1097/00000542-200011000-00030 11046225
Kamibayashi T, Maze M. Clinical uses of alpha2 -adrenergic agonists. Anesthesiology. 2000;93(5):1345–9.11046225
48. Giovannitti JA Jr Thoms SM Crawford JJ Alpha-2 adrenergic receptor agonists: a review of current clinical applications Anesth Prog 2015 62 1 31 9 10.2344/0003-3006-62.1.31 25849473
Giovannitti JA Jr, Thoms SM, Crawford JJ. Alpha-2 adrenergic receptor agonists: a review of current clinical applications. Anesth Prog. 2015;62(1):31–9.25849473
49. Muzi M Clonidine reduces sympathetic activity but maintains baroreflex responses in normotensive humans Anesthesiology 1992 77 5 864 871 10.1097/00000542-199211000-00005 1443738
Muzi M, et al. Clonidine reduces sympathetic activity but maintains baroreflex responses in normotensive humans. Anesthesiology. 1992;77(5):864–71.1443738
50. Chan AK Cheung CW Chong YK Alpha-2 agonists in acute pain management Expert Opin Pharmacother 2010 11 17 2849 2868 10.1517/14656566.2010.511613 20707597
Chan AK, Cheung CW, Chong YK. Alpha-2 agonists in acute pain management. Expert Opin Pharmacother. 2010;11(17):2849–68.20707597
51. Bernard JM Postoperative analgesia by intravenous clonidine Anesthesiology 1991 75 4 577 582 10.1097/00000542-199110000-00006 1928767
Bernard JM, et al. Postoperative analgesia by intravenous clonidine. Anesthesiology. 1991;75(4):577–82.1928767
52. De Kock MF Pichon G Scholtes JL Intraoperative clonidine enhances postoperative morphine patient-controlled analgesia Can J Anaesth 1992 39 6 537 544 10.1007/BF03008314 1643675
De Kock MF, Pichon G, Scholtes JL. Intraoperative clonidine enhances postoperative morphine patient-controlled analgesia. Can J Anaesth. 1992;39(6):537–44.1643675
53. Blaudszun G Effect of perioperative systemic alpha2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials Anesthesiology 2012 116 6 1312 1322 10.1097/ALN.0b013e31825681cb 22546966
Blaudszun G, et al. Effect of perioperative systemic alpha2 agonists on postoperative morphine consumption and pain intensity: systematic review and meta-analysis of randomized controlled trials. Anesthesiology. 2012;116(6):1312–22.22546966
54. Schnabel A Is intraoperative dexmedetomidine a new option for postoperative pain treatment? A meta-analysis of randomized controlled trials Pain 2013 154 7 1140 1149 10.1016/j.pain.2013.03.029 23706726
Schnabel A, et al. Is intraoperative dexmedetomidine a new option for postoperative pain treatment? A meta-analysis of randomized controlled trials. Pain. 2013;154(7):1140–9.23706726
55. Sanchez Munoz MC De Kock M Forget P What is the place of clonidine in anesthesia? Systematic review and meta-analyses of randomized controlled trials J Clin Anesth 2017 38 140 153 10.1016/j.jclinane.2017.02.003 28372656
Sanchez Munoz MC, De Kock M, Forget P. What is the place of clonidine in anesthesia? Systematic review and meta-analyses of randomized controlled trials. J Clin Anesth. 2017;38:140–53.28372656
56. Liu Y Dexmedetomidine reduces perioperative opioid consumption and postoperative pain intensity in neurosurgery: a meta-analysis J Neurosurg Anesthesiol 2018 30 2 146 155 10.1097/ANA.0000000000000403 28079737
Liu Y, et al. Dexmedetomidine reduces perioperative opioid consumption and postoperative pain intensity in neurosurgery: a meta-analysis. J Neurosurg Anesthesiol. 2018;30(2):146–55.28079737
57. Sung CS Effect of oral clonidine premedication on perioperative hemodynamic response and postoperative analgesic requirement for patients undergoing laparoscopic cholecystectomy Acta Anaesthesiol Sin 2000 38 1 23 29 11000660
Sung CS, et al. Effect of oral clonidine premedication on perioperative hemodynamic response and postoperative analgesic requirement for patients undergoing laparoscopic cholecystectomy. Acta Anaesthesiol Sin. 2000;38(1):23–9.11000660
58. Singh S Arora K Effect of oral clonidine premedication on perioperative haemodynamic response and postoperative analgesic requirement for patients undergoing laparoscopic cholecystectomy Indian J Anaesth 2011 55 1 26 30 10.4103/0019-5049.76583 21431049
Singh S, Arora K. Effect of oral clonidine premedication on perioperative haemodynamic response and postoperative analgesic requirement for patients undergoing laparoscopic cholecystectomy. Indian J Anaesth. 2011;55(1):26–30.21431049
59. Zahedi SS Effectiveness of the oral Clonidine as a pre-anesthetic medicine for thyroidectomy surgery; a randomized clinical trial J Cardiovasc Thorac Res 2023 15 3 132 137 10.34172/jcvtr.2023.31680 38028717
Zahedi SS, et al. Effectiveness of the oral Clonidine as a pre-anesthetic medicine for thyroidectomy surgery; a randomized clinical trial. J Cardiovasc Thorac Res. 2023;15(3):132–7.38028717
60. Keniya VM Ladi S Naphade R Dexmedetomidine attenuates sympathoadrenal response to tracheal intubation and reduces perioperative anaesthetic requirement Indian J Anaesth 2011 55 4 352 357 10.4103/0019-5049.84846 22013250
Keniya VM, Ladi S, Naphade R. Dexmedetomidine attenuates sympathoadrenal response to tracheal intubation and reduces perioperative anaesthetic requirement. Indian J Anaesth. 2011;55(4):352–7.22013250
61. Wang K Effects of dexmedetomidine on perioperative stress, inflammation, and immune function: systematic review and meta-analysis Br J Anaesth 2019 123 6 777 794 10.1016/j.bja.2019.07.027 31668347
Wang K, et al. Effects of dexmedetomidine on perioperative stress, inflammation, and immune function: systematic review and meta-analysis. Br J Anaesth. 2019;123(6):777–94.31668347
62. Andersen JH Alpha(2) -receptor agonists as adjuvants for brachial plexus nerve blocks-A systematic review with meta-analyses Acta Anaesthesiol Scand 2022 66 2 186 206 10.1111/aas.14002 34811722
Andersen JH, et al. Alpha(2) -receptor agonists as adjuvants for brachial plexus nerve blocks-A systematic review with meta-analyses. Acta Anaesthesiol Scand. 2022;66(2):186–206.34811722
63. Kumar S A systematic review and meta-analysis of efficacy and safety of dexmedetomidine combined with intrathecal bupivacaine compared to placebo Cureus 2022 14 12 e32425 36644042
Kumar S, et al. A systematic review and meta-analysis of efficacy and safety of dexmedetomidine combined with intrathecal bupivacaine compared to placebo. Cureus. 2022;14(12):e32425.36644042
64. Elia N Clonidine as an adjuvant to intrathecal local anesthetics for surgery: systematic review of randomized trials Reg Anesth Pain Med 2008 33 2 159 167 18299097
Elia N, et al. Clonidine as an adjuvant to intrathecal local anesthetics for surgery: systematic review of randomized trials. Reg Anesth Pain Med. 2008;33(2):159–67.18299097
65. Demiri M Perioperative adverse events attributed to alpha2-adrenoceptor agonists in patients not at risk of cardiovascular events: systematic review and meta-analysis Br J Anaesth 2019 123 6 795 807 10.1016/j.bja.2019.07.029 31623842
Demiri M, et al. Perioperative adverse events attributed to alpha2-adrenoceptor agonists in patients not at risk of cardiovascular events: systematic review and meta-analysis. Br J Anaesth. 2019;123(6):795–807.31623842
66. Romundstad L Stubhaug A Glucocorticoids for acute and persistent postoperative neuropathic pain: what is the evidence? Anesthesiology 2007 107 3 371 373 10.1097/01.anes.0000279487.27940.5c 17721239
Romundstad L, Stubhaug A. Glucocorticoids for acute and persistent postoperative neuropathic pain: what is the evidence? Anesthesiology. 2007;107(3):371–3.17721239
67. Romundstad L Methylprednisolone reduces pain, emesis, and fatigue after breast augmentation surgery: a single-dose, randomized, parallel-group study with methylprednisolone 125 mg, parecoxib 40 mg, and placebo Anesth Analg 2006 102 2 418 425 10.1213/01.ane.0000194358.46119.e1 16428536
Romundstad L, et al. Methylprednisolone reduces pain, emesis, and fatigue after breast augmentation surgery: a single-dose, randomized, parallel-group study with methylprednisolone 125 mg, parecoxib 40 mg, and placebo. Anesth Analg. 2006;102(2):418–25.16428536
68. Lunn TH Effect of high-dose preoperative methylprednisolone on pain and recovery after total knee arthroplasty: a randomized, placebo-controlled trial Br J Anaesth 2011 106 2 230 238 10.1093/bja/aeq333 21131371
Lunn TH, et al. Effect of high-dose preoperative methylprednisolone on pain and recovery after total knee arthroplasty: a randomized, placebo-controlled trial. Br J Anaesth. 2011;106(2):230–8.21131371
69. Shen S Gao Z Liu J The efficacy and safety of methylprednisolone for pain control after total knee arthroplasty: A meta-analysis of randomized controlled trials Int J Surg 2018 57 91 100 10.1016/j.ijsu.2018.07.009 30120990
Shen S, Gao Z, Liu J. The efficacy and safety of methylprednisolone for pain control after total knee arthroplasty: A meta-analysis of randomized controlled trials. Int J Surg. 2018;57:91–100.30120990
70. Singh A Efficacy of preemptive dexamethasone versus methylprednisolone in the management of postoperative discomfort and pain after mandibular third molar surgery: a systematic review and meta-analysis ScientificWorldJournal 2023 2023 7412026 10.1155/2023/7412026 37168455
Singh A, et al. Efficacy of preemptive dexamethasone versus methylprednisolone in the management of postoperative discomfort and pain after mandibular third molar surgery: a systematic review and meta-analysis. ScientificWorldJournal. 2023;2023:7412026.37168455
71. Kienbaum P Update on PONV-What is new in prophylaxis and treatment of postoperative nausea and vomiting? : Summary of recent consensus recommendations and Cochrane reviews on prophylaxis and treatment of postoperative nausea and vomiting Anaesthesist 2022 71 2 123 128 10.1007/s00101-021-01045-z 34596699
Kienbaum P, et al. Update on PONV-What is new in prophylaxis and treatment of postoperative nausea and vomiting? : Summary of recent consensus recommendations and Cochrane reviews on prophylaxis and treatment of postoperative nausea and vomiting. Anaesthesist. 2022;71(2):123–8.34596699
72. De Oliveira GS Jr Perioperative single dose systemic dexamethasone for postoperative pain: a meta-analysis of randomized controlled trials Anesthesiology 2011 115 3 575 88 10.1097/ALN.0b013e31822a24c2 21799397
De Oliveira GS Jr, et al. Perioperative single dose systemic dexamethasone for postoperative pain: a meta-analysis of randomized controlled trials. Anesthesiology. 2011;115(3):575–88.21799397
73. Waldron NH Impact of perioperative dexamethasone on postoperative analgesia and side-effects: systematic review and meta-analysis Br J Anaesth 2013 110 2 191 200 10.1093/bja/aes431 23220857
Waldron NH, et al. Impact of perioperative dexamethasone on postoperative analgesia and side-effects: systematic review and meta-analysis. Br J Anaesth. 2013;110(2):191–200.23220857
74. Huynh TM Marret E Bonnet F Combination of dexamethasone and local anaesthetic solution in peripheral nerve blocks: A meta-analysis of randomised controlled trials Eur J Anaesthesiol 2015 32 11 751 758 10.1097/EJA.0000000000000248 25774458
Huynh TM, Marret E, Bonnet F. Combination of dexamethasone and local anaesthetic solution in peripheral nerve blocks: A meta-analysis of randomised controlled trials. Eur J Anaesthesiol. 2015;32(11):751–8.25774458
75. Pehora C Dexamethasone as an adjuvant to peripheral nerve block Cochrane Database Syst Rev 2017 11 11 CD011770 29121400
Pehora C, et al. Dexamethasone as an adjuvant to peripheral nerve block. Cochrane Database Syst Rev. 2017;11(11):CD011770.29121400
76. Xu C Comparing preoperative and postoperative dexamethasone effects on analgesia duration in shoulder surgery iScience 2024 27 2 109019 10.1016/j.isci.2024.109019 38352222
Xu C, et al. Comparing preoperative and postoperative dexamethasone effects on analgesia duration in shoulder surgery. iScience. 2024;27(2):109019.38352222
77. Albrecht E Dexamethasone is superior to dexmedetomidine as a perineural adjunct for supraclavicular brachial plexus block: systematic review and indirect meta-analysis Anesth Analg 2019 128 3 543 554 10.1213/ANE.0000000000003860 30303864
Albrecht E, et al. Dexamethasone is superior to dexmedetomidine as a perineural adjunct for supraclavicular brachial plexus block: systematic review and indirect meta-analysis. Anesth Analg. 2019;128(3):543–54.30303864
78. Oray M Long-term side effects of glucocorticoids Expert Opin Drug Saf 2016 15 4 457 465 10.1517/14740338.2016.1140743 26789102
Oray M, et al. Long-term side effects of glucocorticoids. Expert Opin Drug Saf. 2016;15(4):457–65.26789102
79. Liu XX Hyperglycemia induced by glucocorticoids in nondiabetic patients: a meta-analysis Ann Nutr Metab 2014 65 4 324 332 10.1159/000365892 25402408
Liu XX, et al. Hyperglycemia induced by glucocorticoids in nondiabetic patients: a meta-analysis. Ann Nutr Metab. 2014;65(4):324–32.25402408
80. Toner AJ Safety of perioperative glucocorticoids in elective noncardiac surgery: a systematic review and meta-analysis Anesthesiology 2017 126 2 234 248 10.1097/ALN.0000000000001466 27922839
Toner AJ, et al. Safety of perioperative glucocorticoids in elective noncardiac surgery: a systematic review and meta-analysis. Anesthesiology. 2017;126(2):234–48.27922839
81. Polderman JA Adverse side effects of dexamethasone in surgical patients Cochrane Database Syst Rev 2018 11 11 CD011940 30480776
Polderman JA, et al. Adverse side effects of dexamethasone in surgical patients. Cochrane Database Syst Rev. 2018;11(11):CD011940.30480776
82. Corcoran TB Dexamethasone and surgical-site infection N Engl J Med 2021 384 18 1731 1741 10.1056/NEJMoa2028982 33951362
Corcoran TB, et al. Dexamethasone and surgical-site infection. N Engl J Med. 2021;384(18):1731–41.33951362
83. Luedi MM A dexamethasone-regulated gene signature is prognostic for poor survival in glioblastoma patients J Neurosurg Anesthesiol 2017 29 1 46 58 10.1097/ANA.0000000000000368 27653222
Luedi MM, et al. A dexamethasone-regulated gene signature is prognostic for poor survival in glioblastoma patients. J Neurosurg Anesthesiol. 2017;29(1):46–58.27653222
84. Luedi MM Dexamethasone-mediated oncogenicity in vitro and in an animal model of glioblastoma J Neurosurg 2018 129 6 1446 1455 10.3171/2017.7.JNS17668 29328002
Luedi MM, et al. Dexamethasone-mediated oncogenicity in vitro and in an animal model of glioblastoma. J Neurosurg. 2018;129(6):1446–55.29328002
85. Andereggen L Zinn PO Luedi MM Anesthesia-related oncological outcomes: Beyond volatiles and total intravenous anesthesia Anesth Analg 2021 132 6 e119 e120 10.1213/ANE.0000000000005549 34032685
Andereggen L, Zinn PO, Luedi MM. Anesthesia-related oncological outcomes: Beyond volatiles and total intravenous anesthesia. Anesth Analg. 2021;132(6):e119–20.34032685
86. Hermanns H Molecular mechanisms of action of systemic lidocaine in acute and chronic pain: a narrative review Br J Anaesth 2019 123 3 335 349 10.1016/j.bja.2019.06.014 31303268
Hermanns H, et al. Molecular mechanisms of action of systemic lidocaine in acute and chronic pain: a narrative review. Br J Anaesth. 2019;123(3):335–49.31303268
87. McCarthy GC Megalla SA Habib AS Impact of intravenous lidocaine infusion on postoperative analgesia and recovery from surgery: a systematic review of randomized controlled trials Drugs 2010 70 9 1149 1163 10.2165/10898560-000000000-00000 20518581
McCarthy GC, Megalla SA, Habib AS. Impact of intravenous lidocaine infusion on postoperative analgesia and recovery from surgery: a systematic review of randomized controlled trials. Drugs. 2010;70(9):1149–63.20518581
88. Weibel S Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery in adults Cochrane Database Syst Rev 2018 6 6 CD009642 29864216
Weibel S, et al. Continuous intravenous perioperative lidocaine infusion for postoperative pain and recovery in adults. Cochrane Database Syst Rev. 2018;6(6):CD009642.29864216
89. Rollins KE The impact of peri-operative intravenous lidocaine on postoperative outcome after elective colorectal surgery: a meta-analysis of randomised controlled trials Eur J Anaesthesiol 2020 37 8 659 670 10.1097/EJA.0000000000001165 32141934
Rollins KE, et al. The impact of peri-operative intravenous lidocaine on postoperative outcome after elective colorectal surgery: a meta-analysis of randomised controlled trials. Eur J Anaesthesiol. 2020;37(8):659–70.32141934
90. Sun Y Perioperative systemic lidocaine for postoperative analgesia and recovery after abdominal surgery: a meta-analysis of randomized controlled trials Dis Colon Rectum 2012 55 11 1183 1194 10.1097/DCR.0b013e318259bcd8 23044681
Sun Y, et al. Perioperative systemic lidocaine for postoperative analgesia and recovery after abdominal surgery: a meta-analysis of randomized controlled trials. Dis Colon Rectum. 2012;55(11):1183–94.23044681
91. Hussain N The analgesic effectiveness of perioperative lidocaine infusions for acute and chronic persistent postsurgical pain in patients undergoing breast cancer surgery: a systematic review and meta-analysis Br J Anaesth 2024 132 3 575 587 10.1016/j.bja.2023.12.005 38199928
Hussain N, et al. The analgesic effectiveness of perioperative lidocaine infusions for acute and chronic persistent postsurgical pain in patients undergoing breast cancer surgery: a systematic review and meta-analysis. Br J Anaesth. 2024;132(3):575–87. A very recent systematic review and meta-analysis evaluating the effectiveness of perioperative lidocaine infusions in preventing the development of chronic postsurgical pain as well as their effects on acute postoperative pain in patients undergoing breast cancer surgery. 38199928
92. Licina A Silvers A Perioperative intravenous lidocaine infusion for postoperative analgesia in patients undergoing surgery of the spine: systematic review and meta-analysis Pain Med 2022 23 1 45 56 10.1093/pm/pnab210 34196720
Licina A, Silvers A. Perioperative intravenous lidocaine infusion for postoperative analgesia in patients undergoing surgery of the spine: systematic review and meta-analysis. Pain Med. 2022;23(1):45–56.34196720
93. Yang W Appropriate duration of perioperative intravenous administration of lidocaine to provide satisfactory analgesia for adult patients undergoing colorectal surgery: a meta-analysis of randomized controlled trials Anesth Analg. 2023 136 3 494 506 36727863
Yang W, et al. Appropriate duration of perioperative intravenous administration of lidocaine to provide satisfactory analgesia for adult patients undergoing colorectal surgery: a meta-analysis of randomized controlled trials. Anesth Analg. 2023;136(3):494–506.36727863
94. Bi Y Effect of perioperative intravenous lidocaine for patients undergoing spine surgery: a meta-analysis and systematic review Medicine (Baltimore) 2020 99 48 e23332 10.1097/MD.0000000000023332 33235097
Bi Y, et al. Effect of perioperative intravenous lidocaine for patients undergoing spine surgery: a meta-analysis and systematic review. Medicine (Baltimore). 2020;99(48):e23332.33235097
95. Plass F Effect of intra-operative intravenous lidocaine on opioid consumption after bariatric surgery: a prospective, randomised, blinded, placebo-controlled study Anaesthesia 2021 76 2 189 198 10.1111/anae.15150 32564365
Plass F, et al. Effect of intra-operative intravenous lidocaine on opioid consumption after bariatric surgery: a prospective, randomised, blinded, placebo-controlled study. Anaesthesia. 2021;76(2):189–98.32564365
96. Haratian A Intravenous lidocaine in spine surgery: A meta-analysis of randomized controlled trials N Am Spine Soc J 2021 7 100079 35141644
Haratian A, et al. Intravenous lidocaine in spine surgery: A meta-analysis of randomized controlled trials. N Am Spine Soc J. 2021;7:100079.35141644
97. Lee IW Schraag S The Use of Intravenous Lidocaine in Perioperative Medicine: Anaesthetic, Analgesic and Immune-Modulatory Aspects J Clin Med. 2022 11 12 3543 10.3390/jcm11123543 35743617
Lee IW, Schraag S. The Use of Intravenous Lidocaine in Perioperative Medicine: Anaesthetic, Analgesic and Immune-Modulatory Aspects. J Clin Med. 2022;11(12):3543. 10.3390/jcm11123543. PMID: 35743617; PMCID: PMC9224677.35743617
98. Foo I The use of intravenous lidocaine for postoperative pain and recovery: international consensus statement on efficacy and safety Anaesthesia 2021 76 2 238 250 10.1111/anae.15270 33141959
Foo I, et al. The use of intravenous lidocaine for postoperative pain and recovery: international consensus statement on efficacy and safety. Anaesthesia. 2021;76(2):238–50.33141959
99. Yaksh TL Calcium channels as therapeutic targets in neuropathic pain J Pain 2006 7 1 Suppl 1 S13 30 10.1016/j.jpain.2005.09.007 16426997
Yaksh TL. Calcium channels as therapeutic targets in neuropathic pain. J Pain. 2006;7(1 Suppl 1):S13–30.16426997
100. Ucak A The effects of gabapentin on acute and chronic postoperative pain after coronary artery bypass graft surgery J Cardiothorac Vasc Anesth 2011 25 5 824 829 10.1053/j.jvca.2010.11.017 21232979
Ucak A, et al. The effects of gabapentin on acute and chronic postoperative pain after coronary artery bypass graft surgery. J Cardiothorac Vasc Anesth. 2011;25(5):824–9.21232979
101. Misra S Parthasarathi G Vilanilam GC The effect of gabapentin premedication on postoperative nausea, vomiting, and pain in patients on preoperative dexamethasone undergoing craniotomy for intracranial tumors J Neurosurg Anesthesiol 2013 25 4 386 391 10.1097/ANA.0b013e31829327eb 23603887
Misra S, Parthasarathi G, Vilanilam GC. The effect of gabapentin premedication on postoperative nausea, vomiting, and pain in patients on preoperative dexamethasone undergoing craniotomy for intracranial tumors. J Neurosurg Anesthesiol. 2013;25(4):386–91.23603887
102. Yu L Gabapentin and pregabalin in the management of postoperative pain after lumbar spinal surgery: a systematic review and meta-analysis Spine (Phila Pa 1976) 2013 38 22 1947 52 10.1097/BRS.0b013e3182a69b90 23921329
Yu L, et al. Gabapentin and pregabalin in the management of postoperative pain after lumbar spinal surgery: a systematic review and meta-analysis. Spine (Phila Pa 1976). 2013;38(22):1947–52.23921329
103. Patel AS Abrecht CR Urman RD Gabapentinoid use in perioperative care and current controversies Curr Pain Headache Rep 2022 26 2 139 144 10.1007/s11916-022-01012-2 35084656
Patel AS, Abrecht CR, Urman RD. Gabapentinoid use in perioperative care and current controversies. Curr Pain Headache Rep. 2022;26(2):139–44. A recently published review on the use of gabapentinoids in the perioperative setting and current controversies. 35084656
104. Gilron I Baron R Jensen T Neuropathic pain: principles of diagnosis and treatment Mayo Clin Proc 2015 90 4 532 545 10.1016/j.mayocp.2015.01.018 25841257
Gilron I, Baron R, Jensen T. Neuropathic pain: principles of diagnosis and treatment. Mayo Clin Proc. 2015;90(4):532–45.25841257
105. de Oliveira Filho GR Kammer RS Dos Santos HC Duloxetine for the treatment acute postoperative pain in adult patients: a systematic review with meta-analysis J Clin Anesth 2020 63 109785 10.1016/j.jclinane.2020.109785 32179396
de Oliveira Filho GR, Kammer RS, Dos Santos HC. Duloxetine for the treatment acute postoperative pain in adult patients: a systematic review with meta-analysis. J Clin Anesth. 2020;63:109785.32179396
106. Govil N Postoperative acute pain management with duloxetine as compared to placebo: A systematic review with meta-analysis of randomized clinical trials Pain Pract 2023 23 7 818 837 10.1111/papr.13253 37246352
Govil N, et al. Postoperative acute pain management with duloxetine as compared to placebo: A systematic review with meta-analysis of randomized clinical trials. Pain Pract. 2023;23(7):818–37. A very recent systematic review and meta-analysis assessing the postoperative pain management with duloxetine. 37246352
107. Jain AK Evaluation of intramuscular levonantradol and placebo in acute postoperative pain J Clin Pharmacol 1981 21 S1 320S 326S 10.1002/j.1552-4604.1981.tb02610.x 7028791
Jain AK, et al. Evaluation of intramuscular levonantradol and placebo in acute postoperative pain. J Clin Pharmacol. 1981;21(S1):320S-326S.7028791
108. Holdcroft A A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management Anesthesiology 2006 104 5 1040 1046 10.1097/00000542-200605000-00021 16645457
Holdcroft A, et al. A multicenter dose-escalation study of the analgesic and adverse effects of an oral cannabis extract (Cannador) for postoperative pain management. Anesthesiology. 2006;104(5):1040–6.16645457
109. Buggy DJ Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain Pain 2003 106 1–2 169 172 10.1016/S0304-3959(03)00331-2 14581124
Buggy DJ, et al. Lack of analgesic efficacy of oral delta-9-tetrahydrocannabinol in postoperative pain. Pain. 2003;106(1–2):169–72.14581124
110. Beaulieu P Effects of nabilone, a synthetic cannabinoid, on postoperative pain Can J Anaesth 2006 53 8 769 775 10.1007/BF03022793 16873343
Beaulieu P. Effects of nabilone, a synthetic cannabinoid, on postoperative pain. Can J Anaesth. 2006;53(8):769–75.16873343
111. Gazendam A Cannabinoids in the management of acute pain: a systematic review and meta-analysis Cannabis Cannabinoid Res 2020 5 4 290 297 10.1089/can.2019.0079 33381643
Gazendam A, et al. Cannabinoids in the management of acute pain: a systematic review and meta-analysis. Cannabis Cannabinoid Res. 2020;5(4):290–7.33381643
