Chronic postsurgical pain and cancer: the catch of ...

CE: Alpana; SPC/120210; Total nos of Pages: 7;

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REVIEW URRENT C OPINION

Chronic postsurgical pain and cancer: the catch of surviving the unsurvivable Stephen R. Humble, Nicolas Varela, Asantha Jayaweera, and Arun Bhaskar

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Purpose of review Chronic postsurgical pain (CPSP) is an important and well recognized cause of much long-term suffering, which in some cases may be preventable and affects many people living with cancer. Unfortunately, general consensus is lacking as to how best reduce the risk of developing CPSP. Recent findings Cancer is now not always a short-lived, fatal disease and is now moving towards a chronic illness. Poorly managed perioperative pain is the greatest risk factor for CPSP. Recent trials have examined preventive strategies for CPSP associated with breast surgery and thoracotomy, two operations used in cancer treatment. Standard antinociceptive drugs, 5% lidocaine patches and ketamine do not prevent CPSP. The evidence for gabapentinoids is conflicting. Intravenous lidocaine and, separately, regional anaesthesia appear beneficial. Summary Well-managed pain, irrespective of technique, reduces the risk of CPSP. The literature is inconclusive regarding an ‘optimal approach.’ Regional anaesthesia, intravenous lidocaine and the aggressive management of perioperative pain using multimodal analgesia including antineuropathic pain agents such as gabapentinoids and certain antidepressants are recommended. Clinicians should not rely on general anaesthesia, opioids, NSAIDs and ketamine to prevent CPSP. A blanket approach using gabapentinoids for all patients undergoing major surgery is not indicated. Instead, the presence of perioperative neuropathic pain should be checked for regularly. Keywords cancer, chronic postsurgical pain, mastectomy, thoracotomy

INTRODUCTION Crombie et al. [1] first described chronic postsurgical pain (CPSP) in 1998 and it is now estimated to account for up to 20% of consultations in some specialist pain clinics [2] as well as having an immense socioeconomic burden [3,4]. The working definition has been refined by other authors [5] and is now ‘essentially pain related to the procedure that persists for more than 2–3 months after surgery, with other causes being excluded’. The relative lack of high-quality randomized controlled trials (RCTs) was previously used by some to justify that CPSP has a certain inevitability in a minority of patients and it is not a significant problem. This led many clinicians to believe that the issue of CPSP was irrelevant to their own perioperative practice and did not consider modifying their practice in order to attempt to reduce the risk of CPSP. However, it is now widely accepted that CPSP is both a significant problem and there are specific, modifiable risk factors [6]. The International Association for

the Study of Pain designated the year 2017 as the Global Year Against Pain After Surgery in order to inform, educate and raise international awareness of this significant issue [7]. More people are now living with CPSP because of increasing number of surgical procedures and improved survival outcomes [8,9]. Certain types of surgery have a higher incidence of CPSP such as breast surgery, thoracotomy, amputation and inguinal hernia repair [10–14], the first three are often performed in cancer patients and are focused on in

Imperial College Healthcare NHS Trust (Dr Humble is also affiliated with Imperial College), Management Clinic, Charing Cross Hospital, London, UK AQ3 Correspondence to Dr Stephen R. Humble, Honorary Senior Lecturer Imperial College, Imperial College Healthcare NHS Trust, Management Clinic, Charing Cross Hospital, Fulham Palace Road, London W6 8RF, UK. Tel: +02033111234; e-mail: [email protected] Curr Opin Support Palliat Care 2018, 12:000–000 DOI:10.1097/SPC.0000000000000341

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KEY POINTS ! As the survivability of cancer itself has improved, a greater number of people living with cancer experience CPSP. ! CPSP occurs more frequently after major surgery such as breast surgery and thoracotomy and the biggest risk factor is poorly managed perioperative pain. ! The combination of general anaesthesia, opioids, NSAIDs and ketamine does not prevent or reduce the risk of CPSP. ! The greatest gains in the prevention of CPSP will likely be through the use of a multimodal management package of care, including regional anaesthesia and antineuropathic pain medications. ! Rather than using gabapentinoids for all patients, perioperative neuropathic pain should be checked for regularly in every patient and managed aggressively when present.

this review. Furthermore, cancer is often associated with significant pain via numerous pathophysiological mechanisms [15 ] and the survivability of cancer itself has improved [8,9]. Separately, it has become increasingly apparent that the management of cancer-related pain requires a multimodal approach that cannot merely rely on strong opioids as recommended by the WHO ladder. This review considers recent incremental developments, with reference to the existing body of literature and attempts to draw conclusions in order to inform clinical practice. &&

EPIDEMIOLOGY AQ4

The IASP estimates that CPSP occurs in approximately 10% of all surgical patients, and the pain may be intolerable (or severe) in roughly one of every 100 operations [7]. A recent meta-analysis of the paediatric demographic identified similar figures in children [16 ]. Certain types of surgery are strongly associated with the development of CPSP viz thoracotomy (30–50%), herniorrhaphy (9– 10%), limb amputation (30–50%), breast surgery (15–25%) and abdominal/pelvic surgery (10–20%) [10–14]. CPSP is less of a problem after laparoscopic surgery, but the incidence is still in the order of 17% [17]. The PAINOUT registry from Europe revealed 11.8% moderate-to-severe CPSP at 12 months and 2.2% of severe pain [18], similar to previous quoted incidences. Numerous studies demonstrated a gradual reduction in the incidence of CPSP with longer &

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follow-up (e.g. 3, 6, 12, 24 months postprocedure) [13]. This is a significant and growing problem given the increasing amount of surgical procedures performed annually. There were 10.9 million operations performed annually in England alone for 2016–2017 [19].

NEUROBIOLOGY The exact mechanisms of postsurgical pain are complex and not fully elucidated. The majority of patients will experience some acute postsurgical pain, but at some point, there is a progression from acute to CPSP [20 ]. This transition is likely secondary to damage and inflammation caused by surgical trauma, leading to peripheral and then central sensitization. A recent review article summarizes the pathophysiology into five hypotheses [20 ] (Table 1). Central sensitization occurs via multiple complex mechanisms and is broadly divided into ascending and descending signal modulation. Surgical trauma activates and sensitizes C and A-d fibres in the periphery (part of the ascending pathway), releasing glutamate (the primary excitatory neurotransmitter in the CNS) and increasing expression of sodium-channels [21]. Glutamate activates both iGlu (ligand-gated ionotropic receptors) and mGlu (G-protein coupled metabotropic receptors), the former has been investigated more in relation to chronic pain (i.e. NMDA receptors). Other mechanisms for the development of neuropathic pain may involve pathophysiological changes related to: long-term potentiation, activated microglial cells and astrocytes [22,23], chemokines (such as CCL2) [24], Toll-like receptor 4 upregulation [25], increased spontaneous impulse discharges, reduced thresholds [21], loss of GABAergic descending modulation [26], protein kinases mediation [27] and expression of CTSG as a pronociceptive mediator in CPSP [28]. &&

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Table 1. Pathophysiology of chronic postsurgical pain Pathophysiology of CPSP 1) Persistent noxious signalling in the periphery 2) Enduring maladaptive neuroplastic changes at the spinal dorsal horn and/or higher central nervous system structures reflecting a multiplicity of factors, including peripherally released neurotrophic factors and interactions between neurons and microglia 3) Compromised inhibitory modulation of noxious signalling in medullary–spinal pathways 4) Descending facilitatory modulation 5) Maladaptive brain remodelling in function, structure and connectivity Data from [20

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Risk factors for chronic postsurgical pain Preoperative pain [29–31] and poorly managed acute perioperative pain [32–34] are the two factors with the strongest correlation for the development of CPSP; they share the same molecular mechanisms, including peripheral and central sensitization [35].

also include posttraumatic stress disorder and psychiatric support [29], recall of perioperative pain [52], emotional function [31] and psychological vulnerability [34]. In addition, a vicious cycle may develop wherein pain increases anxiety and vice-versa [53]. Thus, psychological support should be considered essential in patients at risk of or with CPSP.

Demographics and comorbidities

Surgical technique

The most studied demographic risk factor is age. Younger age has been correlated with higher prevalence of CPSP in different studies [34,36–39]. However, in Leysen et al. review [40 ], the initial metaanalysis could not confirm these results and a moderator analysis withdrawing the weaker methodological studies had to be performed to confirm this finding. BMI has also been proposed as a risk factor in several studies [4,29,31,39,36,41] with an increased risk of CPSP in patients with BMI more than 30. There is also a consistent and significant higher rate of CPSP in patients with lower education level [4,29,30,36] with the cut-off point for this difference being 12–13 years of education. It has been postulated that marriage, full- time employment, alcohol consumption and cigarette smoking may all have protective influences, but the real effect of these factors remains unclear [4,36].

Thoracotomy, breast surgery, amputation and hernia repair all have significant associations with CPSP [10–14,54,55]. Differences in surgical technique such as open thoracotomy versus video-assisted thoracic surgery may also affect the risk of CPSP [56]; however, definitive data are lacking at present. Similarly, aggressive or conservative breast surgery may result in different incidences of chronic pain, but a recent meta-analysis could not find significant differences [40 ] except when comparing sentinel lymph node biopsy versus axillary lymph node dissection.

Genetics

Predictive models of chronic postsurgical pain

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Preclinical work has suggested that different genetic morphologies can produce differences in the incidence of neuropathic pain [42]. Genetic variations have also been described in human population, whether linked to drug metabolism pathways [43–45] or neurological pain pathways [45]. The largest study in this area reported 42 gene polymorphisms associated with CPSP [46]. Monozygotic twins only manifest partial concordance in the development of inflammation and pain [47], and genes may contribute to less than a third of the relevant risk factors [39]. Therefore, epigenetics may also have a role in the development of CPSP, that is the way genes are expressed, without modification of the genetic code itself [38].

Psychological Engel’s biopsychosocial model [48] is relevant not only to chronic pain in general, but also in cancer pain [49]. There is an increased risk of CPSP in patients with anxiety or depression as well as in fear-avoidance and catastrophizing situations [50], and these factors are independent predictors of CPSP regardless of the surgical model [51]. Other psychological risk factors

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Chemotherapy and radiotherapy The addition of chemotherapy and/or radiotherapy appears to be a clear risk factor for CPSP [36,53,54]. This is unsurprising given the inherent neurotoxicity associated with these therapeutic modalities.

Knowledge of risk factors is the first step towards realization of predictive models which can become useful tools to assess an individual patient’s risk of developing CPSP. Several predictive models have been published which allocate different weights to each of the risk factors [51,57,58]; however, statistical significance does not always equate with clinical significance, or clinical utility and these models have high specificity but low sensitivity, thus failing to identify a significant proportion of patients who are likely to develop CPSP.

PREVENTION OF CHRONIC POSTSURGICAL PAIN There have been numerous RCTs examining potential approaches for the prevention of CPSP in recent years. Cancer survivorship has also improved significantly with improved treatment options. This is particularly relevant to breast surgery, thoracotomy and amputations, which are associated with a high risk of CPSP. A recent systematic review on these particular procedures recommended a pragmatic approach when interpreting the evidence rather



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than waiting for a ‘magic bullet intervention’ [6], which is highly unlikely to materialize given the complex pathophysiology [15 ]. On the basis of the trials analysed, Humble et al. [6] postulated that regional anaesthesia and certain antineuropathic pain medications had the potential to reduce the severity of both acute and chronic pain after surgery. Intravenous lidocaine, gabapentinoids and antidepressants, as part of a multimodal analgesic approach showed promise, but the dosage and duration needed to be optimized (which is often not the case in the published trials as well as in clinical practice). Ketamine and intercostal cryoanalgesia were ineffective in reducing CPSP. Total intravenous anaesthesia using propofol and remifentanil rather than standard inhalational anaesthesia has the potential to be beneficial, but the effects of opioids are uncertain. There has been considerable debate both in the literature and at clinical meetings around this topic with a wide range of opinions [6]. &&

Prevention of chronic postsurgical pain after breast surgery There have been several recent trials and reviews related to the prevention of CPSP after breast surgery. Trials of opioids and NSAIDs have revealed clinically significant benefits for acute pain, but these have not had a clear impact on CPSP [59– 62]. In contrast, recent trials of perioperative intravenous lidocaine infusions (1.5 mg/kg) have reported small reductions in CPSP [63 ,64,65]. A meta-analysis of perioperative gabapentinoids found that although these agents could be effective for acute pain as part of a multimodal approach, there was no evidence of benefit at 3 months after breast surgery [66 ]. However, the authors concluded that the available evidence should be rated as low to very low quality and that further studies are required to provide clarity [66 ]. &

pregabalin to patients in the postoperative period after they complained of moderate-to-severe pain not relieved with standard antinociceptive drugs. Yoshimura et al. [69] reported that more patients had no neuropathic pain in the pregabalin group than in the control group at 3 months (88 vs. 48%; P ¼ 0.001). A trial using 5% lidocaine patches found little benefit for either acute pain or CPSP in patients undergoing robotic cardiac surgery [70]. A recent systematic review of perioperative ketamine (intravenous and/or epidural) [71] concluded that while the drug is effective for acute pain, it does not prevent CPSP, similar to previous findings [6].

Prevention of chronic postsurgical pain after other surgical procedures There have been few other recent trials exploring ways to prevent CPSP in relation to other surgical procedures. A meta-analysis of perineural local anaesthetic catheters in patients undergoing major lower limb amputation reported halving of opioid consumption, but a significant impact on acute or chronic pain was not observed [72]; the authors themselves stated that the quality of evidence included in the analysis was low. The few recent trials published related to inguinal hernia repair had methodological flaws. Of relevance, Crompton et al. [73] reported that perineural infiltration of the ilioinguinal, iliohypogastric and genitofemoral nerves reduced the incidence of CPSP at 3 months after open inguinal hernia repair. Arora et al. [74] reported that transversus abdominis plane block for laparoscopic inguinal hernia repair reduced acute pain, but did not appear to reduce CPSP.

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Prevention of chronic postsurgical pain after thoracic surgery Recent trials related to CPSP after thoracic surgery have focused on two main areas; reducing the risk of CPSP by using minimally invasive surgical techniques or via the use of anaesthetic interventions. The benefits of minimally invasive surgical techniques are promising, but as yet, unproven in reducing CPSP. There were three recent trials examining the potential ability of pregabalin to reduce CPSP after thoracic surgery; all studies were underpowered and had underdosing other methodological flaws. Two studies found no benefit with pregabalin [67,68] and the third trial [69] only administered 4


DISCUSSION Cancer is no longer always a short-lived, fatal disease and is now moving towards a chronic illness. Cancer and major surgery were often ‘unsurvivable’ prior to the 20th century, which saw great advances in anaesthesia and the treatment of sepsis; hence, it could be postulated that the nervous system is not ‘calibrated’ to survive these events. Chronic pain related to both of these is a relatively recent phenomenon and may be considered as the catch or the cost of surviving the unsurvivable. Although cancer survival rates have improved dramatically, there is still a long way to go with regard to the prevention or reduction of CPSP. The epidemiology combined with the ageing populations and growing disease burdens in many countries necessitates better perioperative care for this challenging cohort. How can we take a pragmatic approach to this significant problem? It is better understood that Volume 12 ! Number 00 ! Month 2018


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poorly managed severe perioperative pain is the most important risk factor for the development of CPSP particularly with breast surgery and thoracotomy. There is increasing evidence that well-managed pain irrespective of techniques reduces the risk of CPSP; however, the literature is inconclusive regarding an ‘optimal approach.’ The incidence of CPSP in several recent trials was lower overall compared to previous literature. The authors conclude that this may be partly because of routine use of regional anaesthesia such as thoracic epidurals and paravertebral blocks and the use of antineuropathic agents. In the light of recent trials and clinical discussion, the focus of preemptive anaesthetic and analgesic techniques appears to have shifted towards the inclusion of regional anaesthesia and multimodal analgesia.

CONCLUSION Key recommendations include the aggressive management of perioperative pain using multimodal analgesia, which may involve regional anaesthesia, intravenous lidocaine and antineuropathic pain agents such as gabapentinoids and certain antidepressants. Clinicians should not rely on general anaesthesia, opioids and ketamine to prevent CPSP. It would appear that a blanket approach using gabapentinoids for all patients undergoing major surgery is not indicated and that individualized care would be more appropriate. Indeed, the presence of perioperative neuropathic pain should be checked for regularly in every patient and managed appropriately. Further trials would also do well to adopt this selective approach as it is likely that the greatest gains in the prevention of CPSP will be through the use of a multimodal management package of care. Acknowledgements None. Financial support and sponsorship None. Conflicts of interest There are no conflicts of interest.

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