Introduction Chronic Post-Surgical Pain (CPSP) is a significant complication that can arise after various surgical procedures, having an adverse impact on patients‘ quality of life and potentially leading to disability, prolonged suffering and increased healthcare use. It could be characterized a silent epidemic in the surgical population, as it may affect between 5 and 75% of patients. When the pain is neuropathic—between 6 and 68%, depending on the type of surgery— the impact in terms of quality of life and costs is even higher. Mean annualized adjusted direct and indirect costs per patient were recently estimated at US$11,846 and US$29,617, respectively. The prevention of CPSP is a critical aspect of perioperative care, necessitating a comprehensive approach that among other modalities includes a variety of pharmacological strategies. Effective prevention involves addressing multiple pain pathways and mechanisms, to reduce the risk of persistent pain after an operative procedure. While the transition of acute to chronic pain is a complex process —involving multiple mechanisms at different levels— the current strategies for prevention have primarily been restricted to perioperative pharmacological interventions. The results of the available randomized trials on CPSP pharmacological prevention are not encouraging and remain with inconclusive results. High-quality trials of multimodal interventions, matched to pain characteristics are needed to improve the effectiveness of applied preventive strategies.

The medications that have been most studied for the prevention of CPSP include: (a) N-methyl-D-aspartate (NMDA) receptor antagonists, mainly ketamine and memantine, (b) Gabapentinoids, (c) Corticosteroids, (d) iv Lidocaine, (e) Antidepressants, (f) Other drugs, such as Non-Steroidal Anti-inflammatory Drugs (NSAIDs), Nefopam, Clonidine, Dexmedetomidine and Anaesthetic Maintenance Agents. In this review, the current existing evidence for the agents listed will be presented.

NMDA Receptor Antagonists Ketamine

Ketamine is a broadly used NMDA receptor antagonist, possessing anaesthetic, analgesic, antihyperalgesic, and anti-inflammatory properties. NMDA receptors are a key player in the pathophysiological pathway of central sensitization post-surgery. Perioperative ketamine is one of the most promising drugs available, that might decrease not only acute postoperative pain intensity and opioid consumption, but also CPSP prevalence and development.

Several publications have examined the effect of iv ketamine on CPSP prevention, concluding that there is a modest but significant decrease in the CPSP incidence at 3 and 6 months after surgery. However, other studies have shown contradictory results, indicating an uncertain effect of ketamine on the prevalence of CPSP at 3-, 6- and 12-months post-surgery. Literature reports suggest that the effects of ketamine might be most marked after joint arthroplasties, whereas, in thoracotomy patients, although ketamine may significantly reduce acute pain intensity, there is little evidence supporting its preventive effect on CPSP.

The available evidence appears to be inconclusive, which could be attributed, at least in part, to the heterogeneity and small size of the studies, potentially leading to an overestimation of the effect. Additionally, variations in dosage, timing and duration of treatment, as well as lack of patient and type of surgery stratification and the variations in outcome measures might contribute to the inconsistency. Interestingly, these potentially beneficial effects of ketamine might be more apparent in patients receiving opioids before surgery. Importantly, post hoc analysis have shown that only patients consuming over 36 mg of morphine equivalents a day preoperatively benefited from the addition of ketamine. Therefore, ketamine can be considered for perioperative use, particularly in subgroups of patients such as those with chronic pain, those on high-dose opioids prior to surgery, or those who are opioid-dependent, as these patients appear to be the primary beneficiaries of ketamine use.

Memantine

The role of memantine (an oral NMDA receptor antagonist) has also been examined in the perioperative setting, although scarce reports exist in literature. According to some researchers the association of memantine, as an adjuvant in patients receiving a continuous brachial plexus block, reduced both the incidence and the intensity of upper limb phantom limb pain. In another trial, women undergoing mastectomy and receiving memantine for 4 weeks (2 weeks before, 2 weeks after surgery) reported significantly lower mean pain scores, as well as reduced need for analgesics 3 (but not 6) months after surgery. While these results can be considered promising, larger trials, involving different surgical procedures are still needed prior to recommending memantine as an effective pharmacological intervention for the prevention of CPSP.

Gabapentinoids

Gabapentin and pregabalin, though primarily antiepileptics, reduce nociceptive neurotransmission, by blocking the a2d subunits of voltage-gated calcium channels, with their main differences lying in their bioavailability. Both are recommended as a first-line treatment for managing chronic neuropathic pain. Numerous studies and reviews have also demonstrated that these medications reduce acute postoperative pain intensity and opioid consumption, making them valuable components of a multimodal analgesic plan as adjuvants.

Proponents of gabapentinoids initially advocated for their utilization in the prevention of CPSP. However, recently, their widespread use in this context has come under scrutiny due to concerns over their efficacy and safety. The potential benefits of gabapentin on CPSP prevalence have been extensively investigated. Some studies reported no significant impact on CPSP prevention at the 3-month mark, when gabapentin was included in the perioperative analgesic regimen.Other double-blinded, placebo-controlled RCTs highlighted that gabapentin does not offer protective effects against CPSP in knee arthroplasty and thoracotomy patients.

Systematic reviews and meta-analyses of trials investigating the role of perioperative pregabalin on the incidence of CPSP have yielded conflicting results as well. According to those, perioperative pregabalin administration does not affect CPSP prevalence at 3-, 6-, and 12-months post-surgery. Not surprisingly, discrepancies between the latest and earlier evidence can be explained by the inclusion of previously unpublished data in the latest systematic reviews and metanalysis. Interestingly, trials focusing exclusively on CPSP with neuropathic characteristics have reported a preventive effect of pregabalin. However, these findings should be interpreted with caution, as the authors acknowledge that both the number of studies included, and the quality of evidence are low.

In conclusion, the current evidence does not support the use of either gabapentin or pregabalin for the prevention of CPSP. Some researchers have raised safety and security concerns, particularly an increased risk of respiratory depression when gabapentinoids are combined with opioids. Nevertheless, gabapentinoids may be appropriate for certain patients undergoing procedures likely to result in nerve damage, such as complex spinal surgery, total knee arthroplasty, or cardiac surgery, due to their ability to reduce neuropathic pain. In these cases, pregabalin could reduce the risk of neuropathic CPSP, although further large-scale, well-designed studies are needed to clarify this potential benefit and provide firm conclusions.

Corticosteroids Corticosteroids have also been used as adjuvants for the prevention or minimization of CPSP. They block the expression of pro-inflammatory cytokines, that when secreted at or near the site of a nerve injury are involved in the development and maintenance of central sensitization. Corticosteroids also induce expression of anti-inflammatory cytokines, reduce prostaglandin synthesis, inhibit glial activation and have a direct effect on voltage-dependent calcium currents in dorsal root ganglion neurons.

RCTs examining the role of dexamethasone, methylprednisolone, and hydrocortisone in decreasing the incidence and intensity of CPSP leaded to inconclusive results, and heterogeneity precluded any meta-analysis. Also systematic reviews and metanalysis of the available studies conclude in negative results. Perioperative administration of dexamethasone is not associated with any impact on the incidence of chronic pain after mastectomy, whereas, similarly, a 500-mg bolus of methylprednisolone couldn’t demonstrate a benefit of on CPSP occurrence, 6 months after cardiac surgery. There were also no significant differences in pain intensity, impact on daily life or use of analgesics. Finally, 16 mg of dexamethasone, administered in patients scheduled for lumbar disk surgery resulted in no effect on CPSP at 3 months and 1 year after surgery.

In conclusion, the available literature shows conclusively that perioperative glucocorticoids do not reduce CPSP incidence and intensity, after a variety of surgical procedures.

iv Lidocaine Lidocaine is an amide local anesthetic with analgesic, antihyperalgesic, and anti-inflammatory properties. Lidocaine administered intravenously, has been studied extensively, as a part of a multimodal analgesic regimen. There is sound evidence of the benefits of iv lidocaine in terms of reduction of acute postoperative pain intensity, opioid requirements, length of hospital stay, and postoperative nausea. However, fewer studies have evaluated its impact on CPSP prevalence.

Administration of iv Lidocaine for 24 h or less potentially helps to reduce CPSP in patients undergoing breast surgery. While encouraging, the small number of patients included in such studies preclude from making definitive conclusions. Intravenous lidocaine could also be beneficial for other types of surgery, as literature reports provide promising results on the incidence of CPSP after robot-assisted thyroidectomy and nephrectomy.

In conclusion, the available literature suggests that intravenous lidocaine could help prevent CPSP after specific surgical procedures. However, no clear recommendation can be made, possible beneficial effects have to be confirmed, and an adequate dose and duration must be found.

Antidepressants Antidepressants are known modulators of the serotonin or noradrenaline signaling and represent the first recommended line of treatment for chronic neuropathic pain. Serotonin and noradrenaline are important neurotransmitters that regulate the nociceptive transmission in the spinal cord. The most important antidepressants are (a) the selective serotonin reuptake inhibitors (e.g., escitalopram), (b) the serotonin-norepinephrine reuptake inhibitors (e.g., duloxetine and venlafaxine), and (c) the tricyclic antidepressants (e.g., amitriptyline).

Their role in the decreasing or preventing acute or/and CPSP has been examined in literature. Despite some positive results in reference to acute pain outcomes, unfortunately, the clinical heterogeneity between the studies in relation to the type of drug, dosing regimen, and outcome measures precludes any firm conclusion. The potential for duloxetine, venlafaxine and escitalopram to reduce pain up to 6 months, after knee arthroplasty, breast cancer surgery, and coronary heart bypass respectively, has been examined, with only venlafaxine showing a promising effect, that is a reduction in movement-evoked pain intensity after breast cancer surgery. Other studies focusing on duloxetine, in addition to a multimodal analgesic regimen, showed that this antidepressant had no effect on subacute or chronic pain levels after knee arthroplasty. However, duloxetine was beneficial in patients with diabetic polyneuropathy, indicating an impact on descending pain modulation. In patients with an enhanced pain sensitivity, it could reduce postoperative pain 12 weeks after surgery. In conclusion, most of the available literature does not support firmly the clinical use of antidepressants for CPSP prevention.

Other Drugs The effects of drugs such as clonidine, dexmedetomidine, NSAID, nefopam and anaesthetic maintenance agents have not yet been studied adequately. As such, no recommendation for the prevention of CPCP for any of these drugs is currently possible.

Conclusion Chronic postsurgical pain is common after surgery, so identification of non-opioid analgesics with potential for preventing CPSP is important. The evidence for most pharmacological interventions targeting the prevention of CPSP is limited. Indeed, the currently applied strategies have not enabled us to reduce the incidence of CPSP, which unfortunately still affects 5 to 75% of patients, depending on the surgical procedure. Ketamine probably represents the most studied drug of the pharmacological modalities available in our armamentarium and can possibly have a preventive effect, at least in specific subgroups of patients. The role of gabapentinoids and antidepressants has been criticized lately, due to non – proven efficacy and potential safety concerns in some cases. Small trials with, memantine, intravenous lidocaine, dexamethasone, and nefopam have shown promising but limited results. According to more recent data of networking meta-analysis, a possible reduction in CPSP only up to 6 months has been exerted by lidocaine (most effective), gabapentinoids, ketamine, and possibly dexmedetomidine. The evidence is insufficient for longer-term outcomes, opioid use, or serious adverse events.

Researchers should continue to investigate the topic focusing on the ability of opioid-free anaesthesia to reduce the incidence of CPSP. For a better efficacy and more chances for a pharmacological CPSP prevention it is probably of paramount importance to better identify the patients at risk, personalize the management and tailor interventions to their risk factors and improve the approach of their transitional pain, including a follow up after discharge from hospital and beyond the immediate postoperative period. Also, high-quality trials of multimodal interventions matched to pain characteristics are still warrantied, to enrich. the evidence for treatment options that could minimize the incidence of CPSP. Indeed, it makes intuitive sense to reduce the intensity of acute pain by adopting multimodal strategies including the adjuvants with the firmest evidence and by limiting the use of pre- and perioperative opioids. Multidisciplinary concepts targeting the biopsychosocial aspects of the pain chronification process are promising but warrant further evaluation before integrating them routinely into clinical practice.

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