Introduction Acute pain following a surgical procedure remains a prominent healthcare concern.¹ Pain persistence or recurrence after surgery, in other words chronic post-surgical pain (CPSP), has received considerable interest since the first report in 1998 which stated that surgery contributed to pain in 22.5% of patients attending a chronic pain clinic.² With more than 313 million surgical procedures performed worldwide each year (over 15 million procedures in Europe), the socio-economic burden of CPSP may be large.³

The expected volume of CPSP has promoted its inclusion in the new version of the International Classification of Diseases (ICD-11). Therefore, a common definition of CPSP has been proposed: pain that persists or recurs longer than 3 months, is located in the surgical area, has a negative impact on the patient’s quality of life, and is directly related to the surgical procedure (other causes for the pain being excluded).⁴ Beyond pain intensity, CPSP diagnosis should taken into account pain severity which encompasses 3 dimensions: pain intensity, pain-related distress and pain-related interference with activities of daily living.⁵ Using the later definition i.e. intensity combined to functional interference, the incidence of CPSP was 3.3 to 4.1% in a large European cohort (PainOUT registry, N=2319). Similar incidence of persistent incisional pain (3.3%; 2.9% in patients without preoperative chronic pain condition and 7.3% in patients with a preoperative chronic pain condition) was found in a large international prospective cohort.⁶ All studies mention signs of neuropathic pain being present in 57%⁷ to 81%⁶ of CPSP patients, always associated to more severe pain, poorer quality of life and chronic analgesics intake. By consequence, ‘there are two pressing matters: accurately identifying patients with a high risk to develop CPSP and implementing effective prevention strategies’.¹ These two issues still remain unsolved.

Regional Anesthesia and CPSP prevention: the current picture

Regional Anesthesia (RA) techniques, i.e. neuraxial, peripheral nerve blocks and local infiltration, are part of multimodal anesthesia and analgesia protocoles. RA plays a key role in the control of postoperative nociceptive transmission caused by local and systemic inflammation as well as nerve injury. RA also allows a reduction of opioid analgesics consumption and is very effective to control severe pain during mobilization. The control of acute pain associated to earlier mobilization is important in the process of recovery. First, to prevent the occurrence of complications, including medical complications, which may promote persistent pain after the surgical procedure.⁸ Second, because the time spent in severe pain during the first 24h, rather than the pain intensity itself, may predict the risk to develop CPSP.⁷

Although effective RA promotes rapid recovery after a surgical procedure, RA longterm benefits in term of CPSP prevention are still debated.⁹ In their updated Cochrane systematic review (60 RCTs included) assessing the preventive effect of regional anesthesia techniques, Levene and colleagues¹⁰ have reported a possible benefit for thoracic surgery like thoracotomy and breast cancer surgery (moderate-quality evidence due to a majority of trials unpowered). After thoracotomy, epidural analgesia could prevent CPSP in one patient over 7 (OR 0.52; 95%CI 0.32 to 0.84) and similarly, paravertebral block and local infiltration prevented chronic post-mastectomy pain in one woman out of 7. Later, those preventive effects have been questioned in a novel systematic review.¹¹ In this meta-analysis,¹¹ statistical significance was only achieved for paravertebral block (OR 0.73; 95%CI 0.50-1.05). Interestingly, the protective effect of paravertebral block to reduce the intensity of the neuropathic component of CPSP after breast cancer surgery has been questioned in several meta-analysis¹² and in large RCTs¹³ but has not been confirmed.

Besides thoracic procedures, orthopedic surgery carries a very high risk of persistent pain and CPSP. These observations correlate with the published reports of the Transitional Pain Services where thoracic and orthopedic surgeries are the most common ones referred, severe pain involving a neuropathic component in 70% of the patients.¹⁴ RA techniques are particularly effective to control acute postoperative pain in orthopedic patients. Nevertheless, peripheral nerve blocks and local infiltrations have not proven their efficacy to prevent CPSP development or to reduce CPSP intensity after a major procedure like knee arthroplasty.¹⁵ As those patients endure severe longlasting pain before joint replacement, preoperative pain control at surgery site using radiofrequency ablation of genicular nerves has been attempted to reduce preoperative local and central sensitization. The failure of knee denervation to reduce CPSP after knee replacement deserves to be questioned.¹⁶ A large recent review (14 RCTs, N=90 666 with RA in 50 021 patients) has assessed the effect of upper extremity regional anesthesia (plexus blocks, IVRA and WALANT) on post-surgical outcomes such as pain intensity at 3 months, CRPS development, functioning and opioid intake.¹⁷ The conclusions of this large review were that upper extremity RA compared to general anesthesia is unlikely to change pain intensity at 3 months and later (overall moderate to low certainity of evidence). Further, RA was not protective against the development of CRPS at 6 months (1 RCT, N=301).

In summary, current analysis of the literature provides limited information and RA protective effects are unpredictable. As stated by some authors, the study designs are very often insufficient to address the complexity of CPSP, a multifactorial problem.¹⁸

Regional Anesthesia and CPSP prevention: what do we have missed?

The aforementioned deceiving reports should prompt us to question possible explanations regarding RA failures to prevent or even to reduce CPSP incidence and/or intensity. As part of multimodal analgesia, RA ability to control acute pain, particularly during mobilization, is an evidence. A recent network meta-analysis comparing preventive interventions (both systemic drugs and RA techniques) to each other’s instead of comparing interventions to controls, pointed out both the utility of multimodal analgesia and the fact that immediate postoperative analgesic benefit was an important mediator for the reduction of CPSP.¹⁹ Consequently, preventive failure of RA might be explained by inadequate selection of high risk patients, yielding to poor application and perhaps poor timing of RA application. As stated previously, identifying patient with high risk for CPSP development is mandatory because it is inextricably linked to the success or the failure of a treatment protective effect.

First, the actual incidence of severe acute postoperative pain strongly questions the effectiveness of multimodal analgesia treatments (evidence-based and procedure-specific treatments) used in the majority of the patients. Understanding why some patients fail to respond to a ‘standard treatment’ should help to improve health cares and perhaps may help to predict patients at higher risk to develop CPSP. A contrario, understanding the higher efficacy of a treatment in some patients may help to apply protective RA in high risk patients. The best example to date concerns the protective benefit of RA in cancer breast surgery. In these patients, the addition of a parietal block to multimodal analgesic regimen was associated both to better acute pain control and to reduced chronic pain severity at 12-months only in women with high baseline catastrophizing scores.²⁰ In the women with no/low baseline catastrophizing, addition of parietal block demonstrated less benefit, no significant impact on postoperative acute pain and chronic pain severity. Female sex, high anxiety and catastrophizing are well known risk factors for persistent pain and CPSP.^{6 21}

Second, patients who attribute their pain to a specific cause like trauma or surgery seem to suffer higher emotional distress and higher pain.² The preclinical literature suggests that the transition point from acute to chronic pain might be far earlier than the 3-months time point mentioned in the CPSP definition.²² More importantly, the transition might occur at time points near injury and may even concurrently occur with injury, hence before the surgical procedure to fix the trauma injury. The previous findings argue for RA administration earlier than perioperatively and some results seem to favor that hypothesis. Orthopedic surgery, specifically surgery in the context of trauma and fracture, critically doubles the risk for developing CPSP.^{6 7} Bone fracture induces severe acute pain, combining sharp nociceptive pain with neuropathic symptoms. Fractures convert to chronic pain in 43% to 65% of the patients.²³ In trauma patients, posttraumatic high pain intensity is considered to be a major risk factor for pain persistence²⁴ and posttraumatic pain rather than postsurgical origin promotes CPSP development.²³ The benefits of timely RA providing early pain relief have been highlighted in military personnel who suffered combat-related extremity injury.²⁵ In this prospective cohort study (N=358), early RA within the first 7-days after injury improved pain intensity (including neuropathic pain intensity) up to 12-months after trauma . RA benefits observed might rely on both psychological positive effect and opioid-sparing effect which could reduce neuroinflammation induced by trauma and maintained by postoperative repeated opioid administration. CPSP also occurs in elderly patients (overall incidence 19 – 23%) and contributes to increase their vulnerability. Regarding hip fracture repair, CPSP may concern up to 45% of the patients after 6 months.²⁶ Preoperative administration of an analgesic block (fascia iliaca compartment block) might help to decrease the severity of CPSP in those patients.²⁶

Finally, it is now evident that short-lasting perioperative interventions are inefficient to prevent CPSP development particularly in high risk patients. Those patients may require prolonged postoperative treatments based on drugs and techniques combinations. Pain intensity on postoperative day 14 as well as the presence of neuropathic pain features may be predictive of persistent postsurgical pain.²¹ At this stage, after hospital discharge, patients should be better oriented to the Transitional Pain Services (TPS) avoiding delay in evaluation and treatment of a subacute post-surgical pain condition. In TPS, an appropriate pain management including the use of RA techniques and a regular follow up might help to prevent the transition to a chronic pain state.²⁷

Conclusion The prevention of chronic pain after surgery remains an actual challenge in perioperative medicine. The identification of high risk patients and the implementation of effective preventive strategies are mandatory to solve the problem. While RA participates to the success of multimodal analgesia protocols for acute pain control, its protective effect on CPSP has brought deceiving results so far. However some observations regarding the failures and also the success of RA deserve to be questioned as they could help us to refine the perioperative utilization of RA in the aim to improve patients outcomes.

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