DÄ internationalArchive15/2019Chronified Pain Following Operative Procedures

Review article

Chronified Pain Following Operative Procedures

The place of locoregional and systemic local anesthetics

Dtsch Arztebl Int 2019; 116(15): 261-6; DOI: 10.3238/arztebl.2019.0261

Geil, D; Thomas, C; Zimmer, A; Meißner, W

Background: Over 18 million operative procedures are performed each year in Germany alone. Approximately 10% of surgical patients develop moderate to severe chronic post-surgical pain (CPSP), which can severely impair their quality of life. The pain must persist for at least three months to be called chronic; pain that arises after a symptom-free interval is not excluded. The perioperative use of local anesthetic agents may lessen the incidence of CPSP.

Methods: We selectively reviewed the pertinent literature, including two current Cochrane Reviews. Local and regional anesthetic techniques are discussed, as is the intravenous administration of lidocaine.

Results: The main risk factors for CPSP are pre-existing (preoperative) chronic pain, opioid intake, a pain-related catastrophizing tendency, intraoperative nerve injury, and severe acute postoperative pain. CPSP is reported to be especially common after thoracic surgery, breast surgery, amputations, and orthopedic procedures. Local and regional anesthetic techniques have been shown to significantly lower the incidence of CPSP after thoracotomy (number needed to treat for an additional beneficial outcome [NNTB] = 7), breast cancer surgery (NNTB = 7), and cesarean section (NNTB = 19). Intravenous lidocaine also lowers the incidence of CPSP after various types of procedures.

Conclusion: Local and regional anesthetic techniques and intravenous lidocaine lower the incidence of CPSP after certain types of operative procedures. The intravenous administration of lidocaine to prevent CPSP is off label and requires the patient’s informed consent. The evidence for the measures presented here is of low to medium quality.

LNSLNS

Postoperative pain resolves rapidly in most patients who undergo surgery, but some complain weeks or months afterward of persistent pain in the area of the procedure. Since the first description of chronic post-surgical pain (CPSP) (1), many publications have appeared on its incidence, risk factors, and potential preventive measures. The reported incidence and severity of CPSP after various types of procedure varies markedly depending on the relevant definitions and designations, making comparisons across studies difficult. It is nonetheless clear, in view of the large and growing number of surgical procedures that are now performed—more than 18 million per year in Germany alone (2), and more than 312 million per year worldwide (3)—that this phenomenon is a matter of the first importance not only in clinical medicine, but also in health policy and economics (4).

We use the designation “chronic post-surgical pain” (CPSP) rather than the alternative, “persistent postoperative pain” [PPP], because it has been found that chronification does not always consist of the prolongation and persistence of the acute pain that was present after surgery. Rather, in some cases, CPSP arises after a pain-free interval (5). The modified criteria of Werner and Kongsgaard (6) (Box) serve as a basis for the inclusion of CPSP in the new edition of the International Classification of Diseases, the ICD-11 (7). These criteria, however, were not uniformly applied in the sources we evaluated in preparing the current review.

Definition*
Definition*
Box
Definition*

In this article, we describe the frequency and mechanisms of CPSP and the potential utility of local and regional anesthetic techniques to prevent the post-surgical chronification of pain.

Method

We qualitatively searched the literature for relevant publications on the frequency, risk factors, and mechanisms of chronic postoperative pain. To determine the preventive effect, if any, of regional anesthetic techniques, we made use of two current Cochrane Reviews (8, 9), which included publications up to the years 2015 and 2016, respectively. For more recent literature, we selective searched medical databases using a search strategy similar to those of the Cochrane Reviews, in order to cover the period up to mid-2018. One Cochrane review (9) included studies on intravenous lidocaine administration. We therefore decided to discuss this technique as well in our review, even though it is a systemic rather than local or regional anesthetic technique.

Frequency

The reported frequencies of CPSP vary widely depending on the patient collective studied, the type of operation performed, the time elapsed since surgery, the definition of CPSP, and the method of analysis (5, 10, 11). In a survey (part of the PAIN OUT project) of 1 044 patients who had undergone various types of surgery, 13.1% said they had persistent pain of intensity 3–5 on the Numerical Rating Scale (NRS) in the area of the procedure six months later, and 2.9% reported pain of intensity 6 or more (0 = no pain, 10 = the most intense pain imaginable). By one year after surgery, these figures declined to 9.6% and 2.2%, respectively (12).

CPSP is reportedly especially common after thoracic surgery, breast surgery, amputations, and orthopedic procedures (11, 12). 15–50% of patients with CPSP report that their pain has a neuropathic component (11). Neuropathic manifestations are associated with higher pain intensity, marked functional impairment, and poorer quality of life (12).

The incidence of CPSP after outpatient surgical procedures has been estimated at 15.3% (13). In children, the reported incidence of CPSP is 11% (14). In principle, CPSP can arise after any kind of surgical procedure.

Risk factors

Preoperative risk factors

Preoperatively existing chronic pain, either in the region to be operated on or elsewhere, is a risk factor for the development of CPSP (15, 16). Preoperative opioid use in women about to undergo gynecological surgery is associated with a markedly higher postoperative incidence of CPSP (17). Psychological risk factors are currently controversial, but it seems that a catastrophizing tendency, thought focusing, a feeling of being under excessive stress, and an anxious tendency are linked to a higher risk of CPSP, particularly when these features are associated with pain (18). In contrast to these clinical factors, it has not yet been possible to identify any genetic, histological, or biochemical biomarker that is associated with the development of CPSP (19). An association of altered cutaneous sensitivity, as revealed by a preoperative Quantitative Sensory Test (QST), with CPSP has been observed in only a few cases and seems to be of little predictive value (20).

Intraoperative risk factors

Certain specific types of operation seem to elevate the risk of CPSP, and the nature, extent, and invasiveness of operative trauma may elevate it as well (e.g., axillary dissection in breast cancer surgery, video-assisted thoracoscopy vs. open thoracotomy [21]). Intraoperative nerve injury is considered an important pathophysiological risk factor of chronification mechanisms (22).

Postoperative risk factors

Nearly all studies have revealed a very close association between (acute) postoperative pain on the one hand and CPSP on the other. Aside from the absolute intensity of the pain, the duration of severe pain (e.g., the first 24 hours after surgery) is a risk factor (16). It is unclear, however, whether the relation between intense acute pain and chronic pain is one of cause and effect, for both may be epiphenomena that reflect a common pathogenetic mechanism. Postoperative neuropathic pain is likewise a risk factor for CPSP (23). Moreover, similar psychological factors seem to be at work before and after surgery. The role played by post-surgical complications (e.g., wound infection) is controversial. Twelve months after discharge from the intensive care unit, 16% of patients report chronic pain of intensity 4 or more (NRS) that was not present before admission (24).

Mechanisms

Unlike the mechanisms underlying acute postoperative pain (25), those underlying CPSP have received little scientific attention to date.

For detailed discussions, we refer the reader to the publications of Richebé et al. (26) and Chapman et al. (27). The latter postulates five mechanisms that can contribute to the development of CPSP, either alone or in combination:

  • peripheral sensitization via inflammation and/or nerve injury.
  • maladaptive central neural plasticity at spinal and higher levels (central sensitization), caused by opioids (particularly when given preoperatively), stress, and other factors.
  • compromised descending nociceptive inhibition: among other factors, it has been hypothesized that the excessive administration of exogenous opioids can impair the functioning of this system via negative feedback.
  • pathological descending nociceptive facilitation: among other factors, cognitive factors such as expectations, anxiety, and a catastrophizing tendency can apparently influence the systems that inhibit and facilitate pain, yielding both placebo and nocebo effects.
  • alterations of brain function, connectivity, and structure (cerebral plasticity), for example, in phantom pain. Changes in the representative zones of the sensory cortex can be associated with the generation and disappearance of phantom pain and other types of pain.

In general, however, these proposed mechanisms have not been studied with reference to a CPSP model, and not at all in human beings. They also only partly integrate the potential role of some of the risk factors listed above, e.g., psychosocial variables. They do, however, provide a useful framework of hypotheses that can motivate future research in the field.

Prevention of CPSP with local and regional anesthetic techniques

An overview of the relevant study findings with respect to surgery other than orthopedic surgery is given in the Table.

Findings of the Cochrane analysis concerning CPSP after non-orthopedic surgery*1
Findings of the Cochrane analysis concerning CPSP after non-orthopedic surgery*1
Table
Findings of the Cochrane analysis concerning CPSP after non-orthopedic surgery*1

Thoracotomy

A meta-analysis of randomized, controlled trials, by Weinstein et al. (9), revealed a reduction of the risk of CPSP after thoracotomy by the intraoperative use of regional anesthesia in addition to general anesthesia (Table). Seven patients need to be so treated to prevent one case of CPSP, i.e., the number needed to treat for an additional beneficial outcome (NNTB) is 7. A larger benefit was found when only the five studies of epidural anesthesia were considered (NNTB = 5).

Breast cancer surgery

A Cochrane analysis of 18 studies, which included a total of 1297 patients, revealed a reduction of the risk of chronic pain after breast cancer surgery through the intraoperative use of regional analgesia (RA) in addition to general anesthesia (NNTB = 7) (Figure). A larger benefit was found when only the studies of intravenous lidocaine were considered (NNTB = 4) (9).

Wound-edge infiltration with ropivacaine after surgery on the right breast for cancer.
Wound-edge infiltration with ropivacaine after surgery on the right breast for cancer.
Figure
Wound-edge infiltration with ropivacaine after surgery on the right breast for cancer.

Two further publications on the use of intravenous lidocaine (28, 29) and four randomized, controlled trials (RCTs) on the use of paravertebral blockade after breast cancer surgery also indicate a preventive effect on CPSP. Multilevel paravertebral blockade seems to be particularly effective (30).

Cesarean section

Four RCTs on CPSP after cesarean section, including a total of 551 patients, were studied in the meta-analysis by Weinstein et al. (9). It was concluded that the use of RA in addition to spinal anesthesia lowers the risk of CPSP (NNTB = 19) (9). A tranversus abdominis plane block was used in two of these trials, while infiltration of the wound edges and peritoneal instillation of a local anesthetic were used in one trial each.

Iliac crest bone harvesting

Weinstein et al. also reported evidence of a preventive effect of intraoperative local anesthesia on CPSP after iliac crest bone harvesting, but the individual studies included in the analysis employed different endpoints and were thus hard to compare with each other (9).

Further surgical procedures

Studies have shown that the use of regional anesthetic in prostatectomy, hysterectomy, or amputations has no effect on CPSP. There is as yet inadequate evidence to judge the possible effect of RA after cardiac surgery, laparotomy, herniotomy, spinal surgery, and thyroidectomy (9). Two RCTs (31, 32) showed a preventive effect of intravenous lidocaine and of wound-edge infiltration (respectively) after nephrectomy, but the postoperative follow-up interval in one of these trials was only one month (31).

Knee replacement surgery

In a Cochrane review concerning joint surgery, in which only RCTs were included in the analysis, the outcome parameters in the various trials were so different that data from only three trials could be pooled. The range of knee movement was the primary endpoint, serving as a surrogate parameter for joint function (8). Regional analgesia was not found to have any statistically significant effect on the frequency of CPSP three months after surgery.

A randomized, controlled trial published in 2015 showed the superiority of a continuous femoral nerve block over patient-controlled analgesia (PCA) with intravenous opioids, not only with respect to the incidence of CPSP, but also with respect to joint function three and six months after knee replacement (33). Comparisons of different RA techniques in randomized, controlled trials did not reveal any differences with respect to the incidence of CPSP:

  • femoral nerve vs. adductor block (34)
  • epidural anesthesia vs. local infiltrational anesthesia (LIA) (35)
  • single-shot vs. continuous LIA (36)
  • LIA vs. systemic analgesia (37).

Hip surgery

Three trials on the use of RA to prevent CPSP after hip surgery (LIA vs. systemic analgesia [37], single-shot LIA vs. repeated local anesthetic (LA) boli [38], and LIA vs. systemic analgesia [39]) yielded inconsistent results.

Discussion

The best evidence concerning the prevention of CPSP is for the perioperative use of epidural analgesia in thoracotomy, and of paravertebral blockade or intravenous lidocaine administration in breast cancer surgery. In each of these situations, four to seven patients must be treated for a single clinically relevant case of CPSP to be prevented. In view of these findings, we suggest that these preventive measures should always be applied unless there is a valid reason for not applying them; all the more so because they also markedly lessen the pain intensity and analgesic requirement in the early postoperative phase (40).

The use of regional or local analgesia in addition to spinal anesthesia has been shown to lower the incidence of CPSP after caesarean section. Marked chronic post-surgical pain is rarer after cesarean section than after chest surgery or breast cancer surgery (e1) (and the NNTB is correspondingly higher), but cesarean section is one of the most common operations (232 505 of them were performed in Germany in a single year [e2]). The available studies have not shown any particular RA technique to be superior to the others for this purpose.

In the Cochrane analysis concerning iliac crest graft harvesting (9), the inclusion criteria of the individual studies under analysis (with dichotomization of the CPSP endpoint) led to the exclusion of one out of four studies. As a result, no significant preventive effect of local analgesia was demonstrable. The use of this technique should nonetheless be considered, as it can be performed easily and with practically no risk.

The interpretation of the protective effect of RA in nephrectomy, as revealed by two studies, is hampered by the fact that one of these studies, though otherwise methodologically sound, included only one month of postoperative follow-up (31). The evidence is, therefore, limited, and nephrectomy is not a very common procedure. It is, however, one of the most acutely painful urological operations (e3), and this alone would seem to justify the use of RA.

Which methods of analgesia have been found to be especially effective? In the thoracotomy studies, regional analgesic techniques were most commonly used. In breast cancer surgery, paravertebral blockade, local infiltration, and intravenous lidocaine administration were used; the odds ratios for the benefit of the latter two techniques were more favorable than that of paravertebral blockade (Table). If one also considers the ease of application and the potential complications, then wound-edge infiltration and systemic lidocaine are the main techniques to be recommended for CPSP prophylaxis in breast cancer surgery.

There have been many studies on the use of intravenous lidocaine to prevent CPSP after various surgical procedures. Two relevant meta-analyses have been published, one on breast cancer surgery (three underlying studies [e4]) and one on a mix of surgical procedures (six underlying studies [e5]). The authors of both analyses conclude that intravenous lidocaine can lower the incidence of CPSP. The mechanism of action of systemic lidocaine is not fully understood. The benefit of local and regional analgesic techniques may, in fact, be partly due to the systemic effects of the local anesthetic drugs used: whenever regional analgesia is performed, some of the local anesthetic is resorbed into the systemic circulation.

It is thus recommended for clinical practice that intravenous lidocaine should always be given when an indicated, or planned regional analgesia cannot be performed—particularly in view of the fact that intravenous lidocaine is also recommended for the treatment of acute pain (40). In the authors’ institution, a lidocaine bolus of 1.5 mg/kg body weight is given as a rapid infusion, followed by a continuous infusion of 1.5 mg/kg×hr until ca. 30 minutes before the patient’s transfer out of a monitored area (recovery room, intensive care unit, or intermediate care unit) (e6).

As this use of lidocaine is off label, the patient must be informed specifically, and in advance, of its benefits, risks, and side effects, and must give informed consent. As long as the dosages mentioned above are adhered to, complications such as cardiac arrhythmia or epileptic seizures are extremely rare.

Conclusion

Chronic pain after operative procedures is a clinically relevant problem whose frequency should not be underestimated. Tissue damage, inflammation, nerve injury, and pre-existing and postoperative pain, in addition to psychological factors, can alter the nociceptive signaling pathways on multiple levels. As a result, pain can persist for months or years after an operation, or can re-emerge after a pain-free interval. After some types of surgery, local or regional analgesic techniques seem to be able to lessen such chronification processes or prevent them entirely. This is particularly true of epidural anesthesia in thoracotomy and of local infiltration with LA or systemic lidocaine administration in breast cancer surgery.

It would be desirable for future interventional trials in pain therapy to contain not just documentation of the patients’ acute postoperative pain, but also long-term observation for the better assessment of the effects of RA and LA on chronic post-surgical pain.

Conflict of interest statement

Prof. Meissner has received lecture honoraria from the BioQ Pharma, TAD Pharma, Mundipharma International Limited, Grünenthal, and Menarini companies and has served as a paid advisor to Grünenthal and Sanofi. He has also received third-party research support from the European Society of Anaesthesiology (ESA).
Dr. Geil has received reimbursement of scientific meeting participation fees and travel expenses from the German Society for Anesthesiology and Intensive Care Medicine (Deutsche Gesellschaft für Anästhesiologie und Intensivmedizin).

The other authors state that they have no conflict of interest.

Manuscript submitted on 20 November 2018, revised version accepted on 18 February 2019.

Translated from the original German by Ethan Taub, M.D.

Corresponding author
Dr. med. Dominik Geil

Klinik für Anästhesiologie und Intensivmedizin

Universitätsklinikum Jena

Am Klinikum 1

07740 Jena, Germany

Dominik.Geil@med.uni-jena.de

Supplementary material
For eReferences please refer to:
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Department of Anesthesiology and Intensive Care Medicine, Jena University Hospital:
Dr. med. Dominik Geil, Dr. med. Claudia Thomas, Dr. med. Annette Zimmer,
Apl. Prof. Dr. med. Winfried Meißner
Definition*
Definition*
Box
Definition*
Wound-edge infiltration with ropivacaine after surgery on the right breast for cancer.
Wound-edge infiltration with ropivacaine after surgery on the right breast for cancer.
Figure
Wound-edge infiltration with ropivacaine after surgery on the right breast for cancer.
Key messages
Findings of the Cochrane analysis concerning CPSP after non-orthopedic surgery*1
Findings of the Cochrane analysis concerning CPSP after non-orthopedic surgery*1
Table
Findings of the Cochrane analysis concerning CPSP after non-orthopedic surgery*1
1.Crombie IK, Davies HT, Macrae WA: Cut and thrust: antecedent surgery and trauma among patients attending a chronic pain clinic. Pain 1998; 76: 167–71 CrossRef
2.Gesundheitsberichterstattung des Bundes: Operationen der vollstationären und ambulanten Patientinnen und Patienten. Daten von 2017: www.gbe-bund.de/gbe10/I?I=662:36191304D und www.gbe-bund.de/gbe10/I?I=606:36191324D. (last accessed on 12 March 2019).
3.Weiser TG, Haynes AB, Molina G, et al.: Estimate of the global volume of surgery in 2012: an assessment supporting improved health outcomes. Lancet 2015; 385 (Suppl 2): S11 CrossRef
4.Guertin PM, Tarride JE, Talbot D, Watt-Watson J, Choinière M: Just how much does it cost? A cost study of chronic pain following cardiac surgery. J Pain Res 2018; 11: 2741–59 CrossRef MEDLINE PubMed Central
5.Lavand‘homme P: ‘Why me?‘ The problem of chronic pain after surgery. Br J Pain 2017; 11: 162–5 CrossRef MEDLINE PubMed Central
6.Werner MU, Kongsgaard UE: I. Defining persistent post-surgical pain: is an update required? Br J Anaesth 2014; 113: 1–4 CrossRef MEDLINE
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