LEADING ARTICLE

Risk Factors and Early Pharmacological Interventions to PreventChronic Postsurgical Pain Following Cardiac Surgery

Kari Hanne Gjeilo • Roar Stenseth •

Pal Klepstad

� Springer International Publishing Switzerland 2014

Abstract Chronic postsurgical pain (CPSP) after cardiac

surgery represents a significant clinical problem. The preva-

lence of CPSP varies widely between studies, but severe CPSP

is present in less than 10 % of the patients. Important differ-

ential diagnoses for CPSP after cardiac surgery are myocardial

ischemia, sternal instability and mediastinitis. CPSP after

cardiac surgery may be thoracic pain present at the site of the

sternotomy or leg pain due to vein-graft harvesting. The CPSP

can be neuropathic pain, visceral pain, somatic pain or mixed

pain. Potential risk factors for CPSP are young age, female

gender, overweight, psychological factors, preoperative pain,

surgery-related factors and severe postoperative pain. In

addition to standard postoperative analgesics, the use of N-

methyl-D-aspartate (NMDA) antagonists, alpha-2 agonists,

local anesthetics, gabapentinoids, and corticosteroids are all

proposed to reduce the risk for CPSP after cardiac surgery.

Still, no specific pharmacological therapy, cognitive therapy

or physical therapy is established to protect against CPSP. The

only convincing prevention of CSPS is adequate treatment of

acute postoperative pain irrespective of method. Hence,

interventions against acute pain, preferably in a step-wise

approach titrating the interventions for each patient’s indi-

vidual needs, are essential concerning prevention of CPSP

after cardiac surgery. It is also important that surgeons con-

sider the risk for CPSP as a part of the basis for decision-

making around performing a surgical procedure and that

patients are informed of this risk.

Key Points

Up to one tenth of cardiac surgery patients develop

severe chronic postsurgical pain.

No specific therapy is established to protect against

chronic postsurgical pain.

Adequate treatment of acute postoperative pain may

minimize the risk for chronic postsurgical pain.

1 Introduction

Chronic postsurgical pain (CPSP) is a common complica-

tion after most surgical procedures [1, 2], cardiac surgery

K. H. Gjeilo (&)

Department of Cardiothoracic Surgery, St. Olavs Hospital,

Trondheim University Hospital, Trondheim, Norway

e-mail: kari.hanne.gjeilo@stolav.no

K. H. Gjeilo

Department of Cardiology, St. Olavs Hospital, Trondheim

University Hospital, Trondheim, Norway

K. H. Gjeilo

National Competence Centre for Complex Symptom Disorders,

St. Olavs Hospital, Trondheim University Hospital, Trondheim,

Norway

K. H. Gjeilo � R. Stenseth � P. Klepstad

Department of Circulation and Medical Imaging, Faculty of

Medicine, Norwegian University of Science and Technology,

Trondheim, Norway

R. Stenseth

Department of Cardiothoracic Anaesthesiology, St. Olavs

Hospital, Trondheim University Hospital, Trondheim, Norway

P. Klepstad

Department of Anaesthesiology and Intensive Care Medicine, St.

Olavs Hospital, Trondheim University Hospital, Trondheim,

Norway

Am J Cardiovasc Drugs

DOI 10.1007/s40256-014-0083-2

included [1, 3]. CPSP after cardiac surgery disturbs daily

life and interferes with sleep, mood and health-related

quality of life (HRQOL) [4–8]. Thus, pain that persists

after the surgical wound has healed is a major clinical

problem [1]. Despite this, CPSP, both in general and after

cardiac surgery, is often not diagnosed or treated [9, 10].

Given the large number of patients who undergo cardiac

surgery, even a 10 % risk of persistent pain has a major

epidemiological significance. Therefore, identifying risk

factors for and potential treatment of CPSP is important

[10]. The aim of the current paper was to review risk

factors and prevention of CPSP after cardiac surgery

through sternotomy.

2 Prevalence, Mechanisms and Risk Factors

2.1 Prevalence

The prevalence of CPSP after cardiac surgery varies widely

in different populations, with observed numbers from 11 to

56 % [5, 7, 11–13]. However, the number of patients

reporting severe, disabling pain is quite consistently about

2–10 % [4–6, 12]. The prevalence of CPSP has generally

been reported to decrease over time after surgery [14–17].

This is also exemplified in a study by Choiniere et al. [13],

who found CPSP prevalence to be 40.1 % at 3 months,

22.1 % at 6 months, 16.5 % at 12 months and 9.5 % at

24 months after cardiac surgery.

The prevalence depends on the patient population, the

assessment method, retrospective or prospective design,

and the definition of CPSP. The following criteria,

originally proposed by Macrae [3], are widely used to

define CPSP [6, 11, 18, 19]: (1) the pain developed after

a surgical procedure; (2) other causes for pain have been

excluded; (3) the possibility that pain is continuing from

a pre-existing problem has been explored and excluded;

and (4) the pain is of at least 2 months duration. How-

ever, most studies follow the established definition of

chronic pain by the International Association for the

Study of Pain (IASP), which includes a duration of

3 months or more [5, 20, 21].

The prevalence may also depend on the location of

pain. Studies on CPSP after cardiac surgery have often

focused on pain related to the sternotomy [7, 11,

22, 23]. However, CPSP may also be related to leg

pain due to vein-graft harvesting for coronary artery

bypass grafting (CABG) [4, 5, 12]. Some studies have

found that patients with pain both at the leg and ster-

num site have more intense pain [4, 6]. Pain from

other sites such as the head, neck, back and upper

extremities is also reported to appear frequently after

cardiac surgery [6, 24].

2.2 Mechanisms and Risk Factors

CPSP develops through complex mechanisms. The devel-

opment of chronic pain may be due to both peripheral and

central sensitization caused by the acute pain and by

changes caused by direct neuronal damage during surgery

[25, 26]. The resulting pain may both be somatic, visceral

or neuropathic [27, 28]. Whether the biological changes are

a result of the surgical trauma, neuroplastic changes

induced by the operation, a lack of adequate analgesia, or

preoperative predisposing factors has not been clarified [1].

Even if the role of acute pain in the development of chronic

pain is unknown, acute pain may be viewed as an initial

phase of pain responses that has the potential to progress to

chronic pain [1, 29]. The multiple biological systems with a

potential to be involved in the pathophysiology of CPSP

have been recently reviewed by Deumens et al. [30].

Despite the fact that the mechanisms of CPSP are not

clear, a number of risk factors for CPSP in general have

been identified [1–3, 31]. Preoperative pain, psychological

vulnerability, repeat surgery, nerve damage and acute

postoperative pain are all factors suggested to contribute to

CPSP. Psychological factors that heighten pain sensitivity

are also predictors of chronic pain. Furthermore, genetic

predisposition is in some studies shown to be associated

with an increased frequency or intensity of chronic pain [1,

31–33]. The most studied genes involved are the catechol-

O-methyltransferase (COMT) gene and the GTP cyclohy-

drolase 1 gene [34]. However, no studies have assessed if

such genetic risk factors also are relevant specifically for

CPSP after cardiac surgery.

Risk factors for CPSP after cardiac surgery are not well

established. However, potential risk factors are illustrated

in Fig. 1. Studies have found patient-related factors such as

younger age [4, 6, 8, 12], increased body mass index [4]

and female gender [8, 13, 24] predict CPSP. Furthermore,

psychological factors are believed to be important. High

levels of preoperative anxiety, depression and catastro-

phizing, which is a tendency to magnify the threat value of

pain and to feel helpless in the context of pain, are asso-

ciated with higher rates of CPSP [35–37].

Presence of preoperative pain is also found to be a risk

factor for the development of CPSP after cardiac surgery

[8]. Studies on CABG patients have found that patients

who developed CPSP had more presurgery coronary-rela-

ted pain than those without [27]. In a prospective study of

CPSP, we found that patients with CPSP reported higher

pain scores and also lower HRQOL before surgery, sug-

gesting that patients likely to develop CPSP after cardiac

surgery are a subset of a vulnerable group of patients [6].

Furthermore, Choiniere et al. [13] found that patients with

nonanginal pain before surgery were at significantly

increased risk of CPSP.

K. H. Gjeilo et al.

Surgery-related factors such as emergency surgery, type

of cardiac surgery (e.g., CABG, heart valve surgery or

combined surgery), re-sternotomy during hospital admis-

sion, surgical technique and duration of surgery [8], and

previous cardiac surgery are all suggested as risk factors

for the development of CPSP after cardiac surgery. How-

ever, the present evidence related to the role of these fac-

tors remains inconclusive [13]. The immediate

postoperative course may also have implications for the

development of chronic pain. More pain and higher

requirements for analgesics during the first postoperative

days after cardiac surgery have been associated with

increased risk of CPSP [5, 8] as well as pain in the first

weeks after surgery [12, 23]. Whether this observation

simply reflects that more complex surgery results in both

more postoperative pain and a higher risk for CPSP, or

whether inadequately treated postoperative pain in itself

increases the risk for CPSP, is not known. Thus, whether

the relationships between acute pain and CPSP are asso-

ciative or causal is unclear and part of an ongoing debate

[13, 31].

Intraoperative use of remifentanil has been associated

with acute hyperalgesia, but conflicting results have been

reported [38–40]. Higher intraoperative doses of remifen-

tanil were associated with CPSP 1 year after cardiac sur-

gery [41]. However, the role of remifentanil as a trigger of

CPSP is still under debate.

3 Pharmacological Approaches to Prevent CPSP

3.1 Acute Pain

The most common source of acute postoperative pain, in

addition to pain from the surgical incision, is pain from the

chest wall. Sternal retraction results in a trauma to muscles,

bones, tendons and ligaments. A local inflammatory com-

ponent will usually follow a surgical insult, in addition to a

general inflammatory response due to cardiopulmonary

bypass (CPB) [1]. If nerves are injured during surgery, a

neuropathic component of the pain might develop imme-

diately and then persist in the absence of any peripheral

noxious stimulus or ongoing peripheral inflammation [1].

Opioids have been the cornerstone in the treatment of

acute pain after cardiac surgery for decades. There are

several alternative opioid agents, each with unique

Femalegender

CPSP

Youngerage

Acute post-

operative pain

Preoperative pain

Surgical factors

REDOsurgery

Psychological vulnerability

Over-weight

Geneticpredisposition

Fig. 1 Potential risk factors for

chronic postsurgical pain

(CPSP) following cardiac

surgery. REDO Repeat Cardiac

Surgery

Risk Factors and Prevention of Chronic Pain Following Cardiac Surgery

pharmacological characteristics, which give differences in

time of onset and duration of action. Among the most

commonly used opioids for postoperative pain relief are

morphine, fentanyl, and oxycodone [42]. In addition, a

number of other opioids with specific indications (i.e.,

alfentanil and remifentanil, which are mainly used during

surgery) and those only used in some countries (i.e., ke-

tobemidone in Scandinavia) are available. There is no

convincing evidence that one opioid is universally better

than another [43], but for an individual patient, one opioid

can have a better effect versus adverse effect profile than

others. The opioids can be given by several routes. Usually

intravenous administration is used in the acute care setting

and for unstable pain, while oral opioids are preferred for

more stable long-standing pain.

In addition to opioids, non-opioid analgesia with para-

cetamol or non-steroidal anti-inflammatory drugs (NSA-

IDs) is frequently used. Paracetamol reduces the dose of

opioid required [44]. Reduction in the overall dose of

opioid can reduce opioid-induced adverse effects.

Absorption of paracetamol after oral or rectal administra-

tion is unpredictable, and intravenous administration may

be preferred for the first 24 h after surgery [45]. NSAIDs,

with a documented opioid sparing effect, are popular after

non-cardiac surgery, as part of a multimodal analgesic

regimen, but are less frequently used in cardiac surgery

[46, 47]. Cardiac surgery patients regularly receive platelet

inhibitors until the day of surgery. An increased risk for

postoperative bleeding in such patients after CPB can cause

some reluctance to administer NSAIDs [48]. These drugs

may also increase the risk for renal insufficiency in sus-

ceptible cardiac surgery patients [48]. However, NSAIDs

are potent analgesics, in particular with regard to myofas-

cial pain and pain from mediastinal drains. Therefore,

NSAIDs may be used for short periods in selected patients

who have a normal preoperative renal function and are not

bleeding after surgery [49].

In addition to standard therapy with opioid and non-

opioid treatment, a number of other medications have been

added either to improve postoperative analgesia or to

reduce sensitization and the risk of chronic pain. These

medications include drugs from several classes.

1. The N-methyl-D-aspartate (NMDA) blocker ketamine,

a noncompetitive NMDA receptor antagonist, may

prevent opioid-induced analgesic tolerance and hyper-

algesia [50]. In some studies, it has also been shown to

reduce acute postoperative pain and opioid require-

ments [51]. Because of its psychotomimetic side

effects, the use of ketamine in large doses is generally

restricted to the intraoperative period, or, alternatively,

it may be given in sub-anesthetic doses

postoperatively.

2. The alpha-2 agonists clonidine and dexmedetomidin

will provide both analgesia and sedation in addition to

sympatholysis, which may be beneficial in cardiac

surgery. However, sedation is less favorable, as

modern fast-track cardiac surgery will include early

mobilization and activation [30, 52].

3. Intravenous infusion of local anesthetics, most often

lidocaine, has in numerous clinical studies been shown

to reduce postoperative pain and morphine require-

ments [30, 53–55]. This reduction of pain may be

caused by an antihyperalgesic action [30].

4. The gabapentinoids gabapentin and pregabalin may

prevent the establishment of surgery-induced central

sensitization and have in some studies been shown to

be effective in the treatment of acute postoperative

pain [56, 57].

5. Pre-incisional use of methylprednisolone has been

used to reduce postoperative pain after surgery [58].

Corticosteroid therapy, whether used in high or low

doses, attenuates the inflammatory responses to cardiac

surgery and CPB. One smaller study suggests a

beneficial effect of reduced doses of steroids on pain

after cardiac surgery [59]. However, the use of steroids

in cardiac surgery patients remains controversial [59–

61]. Corticosteroids have multiple potential adverse

effects, and the cost–benefit analyses of corticosteroid

must be assessed for each particular group of patients.

6. Regional techniques like intercostal, paravertebral and

spinal or epidural local anesthetic blocks have been

recommended as useful analgesic techniques after

cardiac surgery [62–64]. However, cardiac surgery

patients regularly receive antithrombotic and antiplate-

let drugs before surgery, during surgery they are on

CPB with full heparinization, and they receive anti-

thrombotic and antiplatelet drugs after surgery. There-

fore, because of the risk of bleeding, regional

techniques are used sparingly [65, 66].

3.2 Effect of Treatment of Acute Pain on Development

of CPSP

There is no substantial evidence that the use of specific

drug agents, opioid or non-opioid analgesics, co-analgesics

or regional anesthesia reduces the risk of CPSP [30, 31,

67]. However, some promising results are reported, for

example, for gabapentin and pregabalin in non-cardiac

surgery [57, 68]. More likely it is the reduction of acute

pain that may reduce the risk for CPSP. Therefore, the

current advice is to use the analgesics needed to provide

optimal postoperative pain relief. The choice of analgesics

may be based upon individual considerations and local

hospital routines. Irrespective of the choice of medications,

K. H. Gjeilo et al.

pain should be adequately monitored in all patients and a

step-wise approach with increasing doses or additional

medications used to decrease severe postoperative pain.

Evidence to support the protective effect of an analgesic

regimen in cardiac surgery is either lacking or limited [13,

69]. The few studies suggesting some effect on the risk for

developing CPSP include the use of epidural analgesia

[70], pregabalin [71] and gabapentin [56]. The evidence

from these studies is not sufficient to change clinical

practice. The lack of convincing evidence related to the

effect of specific drugs on the development of CPSP after

cardiac surgery may be due to small study samples and the

relatively low prevalence of severe CPSP. In addition, the

underlying mechanisms are complex, and to believe that

one single treatment is effective may be an unrealistic

oversimplification.

4 Non-pharmacological Approaches to Prevent CPSP

Studies of non-pharmacological approaches to prevent

CPSP after cardiac surgery are scarce. As CPSP may be

related to the nerve injury and tissue trauma, nerve-sparing

techniques and less extensive surgery may prevent both

acute pain and CPSP. Studies on the impact of performing

surgery through ‘‘mini’’ sternotomy have mixed results

concerning postoperative pain, and are inconclusive. Still,

alternative minimally invasive surgically techniques may

also provide a pain benefit for cardiac patients [69].

Patient education may play an important role in the

prevention of CPSP. Patients undergoing cardiac surgery

might not be aware of the risk of chronic pain and its

potential detrimental effects on their well-being. Several

barriers to adequate pain management after cardiac sur-

gery have been identified [72]. Patients may not use

adequate analgesics for postoperative pain, because of

fear of addiction and adverse effects. They may also

hold beliefs about being a ‘‘good’’ patient and therefore

not complain about pain. Some patients also believe that

pain medication should be saved in case the pain

worsens [67, 72]. Lee at el. [73] found that patients with

a negative belief in opioid use had more CPSP 3 months

after cardiac surgery. The development of fast-track

cardiac surgery has reduced the duration of the hospital

stay. Shorter in-hospital stay obviously gives a shorter

period where analgesics are administered by health care

workers and less time for patient education [74, 75].

This may reduce patient adherence to pain medication

regimens after discharge [75]. The subsequent subacute

period, when the patient is responsible for pain man-

agement, may be more important than previously thought

in preventing CPSP.

4.1 Evaluation and Treatment of Chronic Pain

Myocardial ischemia, sternal instability and mediastinitis

should be ruled out in every cardiac surgery patient pre-

senting with chest pain, and the appropriate non-surgical or

surgical therapy should be initiated. Also, sternal wire

removal may be considered, as it is an effective treatment

for pain in a subgroup of cardiac surgery patients [76, 77].

If these specific causes of pain are not present, referral to a

chronic pain management specialist is recommended. A

pain clinic will evaluate the pain through an interdisci-

plinary approach and initiate physical, cognitive and

pharmacological treatment. The principles for evaluation

and treatment of CPSP are similar to those used for other

chronic pain diagnoses.

5 Conclusion

The potential development of CPSP after cardiac surgery

is an important clinical challenge and should be dis-

cussed in preoperative counseling of patients as a part of

the decision-making and informed consent for surgery

[78]. Patient education and decision-making must be

reliable and up to date. Hence, older and retrospective

studies should not be the foundation for decision-making.

A prevalence of about 50–60 % in these older studies

may be an overestimation of the problem [1]. Current

prospective studies report an overall prevalence from 9.5

to 35 % and numbers below 10 % for severe pain [6, 8,

11, 13]. The lower prevalence of CPSP in current studies

may, in addition to better methodology, reflect an

improvement in treatment and care along the pain tra-

jectory of cardiac surgery patients.

Pharmacological studies of specific interventions to

protect against the development of CPSP have been dis-

appointing. However, there is an association between the

intensity of acute postoperative pain and CPSP. Hence,

interventions to decrease acute pain should be considered

important in the prevention of CPSP after cardiac surgery.

Acute postoperative pain after cardiac surgery is usually

treated with a combination of opioids and paracetamol, but

a number of other agents may be used. Irrespective of the

choices made regarding opioids, route and co-analgesics,

the patient should receive the medications needed to pro-

vide optimal pain relief. CPSP is a serious and important

complication after cardiac surgery that may interfere with

daily activities and HRQOL. Therefore, not only treatment,

but also prevention of CPSP is essential.

Acknowledgments K.H. Gjeilo, R. Stenseth and P. Klepstad have

no conflicts of interest to declare related to the content of this article.

No funding was received for the preparation of the manuscript.

Risk Factors and Prevention of Chronic Pain Following Cardiac Surgery

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