Persistent Postsurgical Pain: Pathophysiology and Preventative Pharmacologic Considerations

Philippe Richebé, M.D., Ph.D.; Xavier Capdevila, M.D., Ph.D.; Cyril Rivat, Ph.D.


Anesthesiology. 2018;129(3):590-607. 

In This Article

Abstract and Introduction


The development of chronic pain is considered a major complication after surgery. Basic science research in animal models helps us understand the transition from acute to chronic pain by identifying the numerous molecular and cellular changes that occur in the peripheral and central nervous systems. It is now well recognized that inflammation and nerve injury lead to long-term synaptic plasticity that amplifies and also maintains pain signaling, a phenomenon referred to as pain sensitization. In the context of surgery in humans, pain sensitization is both responsible for an increase in postoperative pain via the expression of wound hyperalgesia and considered a critical factor for the development of persistent postsurgical pain. Using specific drugs that block the processes of pain sensitization reduces postoperative pain and prevents the development of persistent postoperative pain. This narrative review of the literature describes clinical investigations evaluating different preventative pharmacologic strategies that are routinely used by anesthesiologists in their daily clinical practices for preventing persistent postoperative pain. Nevertheless, further efforts are needed in both basic and clinical science research to identify preclinical models and novel therapeutics targets. There remains a need for more patient numbers in clinical research, for more reliable data, and for the development of the safest and the most effective strategies to limit the incidence of persistent postoperative pain.


More than 100 million people in the United States and Europe and 312 million worldwide undergo surgical procedures each year.[1] The number of surgical procedures increased 34% between 2004 and 2012.[1] These numbers are expected to grow in all economic environments as the elderly population, which is overrepresented among surgical populations, continues to grow worldwide. Complete clinical recovery without complications is important to patients. Pain caused by surgical procedures remains a significant clinical problem that seriously impacts postoperative rehabilitation and health-related quality of life. Despite increased preclinical and clinical research on the pathophysiology of postoperative pain and recent advances in analgesic therapies, many patients still complain about severe acute postoperative pain and feel they did not receive adequate postoperative analgesia. Recently, Fletcher et al.[2] reported that every 10% increase in the time spent in severe postoperative pain was associated with a 30% increase in chronic pain 12 months after surgery. Authors also reported that acute postoperative pain is a predictive factor for chronic pain after hernia repair, sternotomy, knee replacement, and limb amputation.[3–5] The development of chronic pain after surgery, also called persistent postoperative pain, is recognized as a significant health problem affecting the postoperative outcome of patients, their rehabilitation, and their quality of life with important legal and medicoeconomic consequences. Persistent postoperative pain has been defined by the International Association for the Study of Pain as a clinical discomfort that lasts more than 2 months postsurgery without other causes of pain such as chronic infection or pain from a chronic condition preceding the surgery.[6] According to the International Classification of Diseases,[7] persistent postoperative pain has greater intensity or different pain characteristics than preoperative pain and is a continuum of acute postoperative pain that may develop after an asymptomatic period. International Classification of Diseases defines the duration for persistent postoperative pain at 3 months postsurgery because healing times differ among different procedures.

Table 1 shows that the incidence of both acute postsurgical pain and persistent postoperative pain varies across individuals and procedures. What is clear is that as many as 20 to 56% of patients develop chronic pain after surgery.[8,9] In a study that evaluated[2] persistent postoperative pain at 12 months after surgery, the incidence of moderate to severe persistent postoperative pain was 11.8% (95% CI, 9.7 to 13.9), the incidence of severe pain (numerical rating scale greater than or equal to 6) was 2.2% (95% CI, 1.2 to 3.3), and signs of neuropathic pain were recorded in 35.4 to 57.1% of patients with persistent postoperative pain. Patients may develop persistent postoperative pain after "common surgical procedures" including amputation, breast surgery, thoracotomy, inguinal hernia repair, coronary artery bypass, and caesarean section. Among surgical patients, 2 to 10% have persistent severe chronic pain (pain greater than 5 on a visual analogue scale up to 10) at 6 months postsurgery.[8,10–14] Nevertheless, how persistent postoperative pain is variously defined and described may play a role in the variability of the reported incidence. In 2012, Schug[15] reported a reduction from 40 to 18% in the prevalence of persistent postoperative pain when only moderate or severe pain in the area of surgery was taken into consideration (numerical rating scale more than 3 of 10). However, when Schug excluded patients who had pain in the area of surgery before the operation, the prevalence of persistent postoperative pain fell to 6%. Persistent postoperative pain affects millions of patients every year; it is a potential burden for the healthcare systems that until recently has been an unrecognized complication of surgery. What we can do to prevent patients from developing chronic pain postsurgery is now considered one of the most important research priorities in anesthesia and perioperative medicine.[16]

The major objective of this review is to provide both a conceptual view of the transition from acute pain to persistent postoperative pain from a neurobiological perspective and an updated pragmatic review of the pharmacologic strategies that can be used to prevent the development of persistent postoperative pain. Here we describe both the basic science mechanisms of acute pain and the critical factors that may be responsible for transition from acute pain to persistent postoperative pain. In the second part, we provide the various pharmacologic strategies for limiting the risk of pain chronification postsurgery. Our research focused mainly on published clinical studies and meta-analyses evaluating the effects of clinically available drugs that can demonstrate preventative effects on the development of persistent postoperative pain. We also considered drugs commonly used by anesthesiologists that may be of interest in preventing persistent postoperative pain due to their mechanism of action even without or with small reported clinical evidence.