**3. Risk factors**

Various risk factors have been postulated to predict the development of chronic post-surgical pain in patients undergoing surgical procedures [9]. These factors are; genetic susceptibility, preceding pain, acute post-operative pain, psychosocial factors, demographic factors and surgical factors. These factors can be classified as patient-related and medical factors or to modifiable and non-modifiable risk factors [6, 10]. Each factor will be discussed separately in the subsequent text (**Figure 2**).

medications will facilitate better understanding of CPSP pathophysiology, and thus it will help to predict a patient's likelihood of developing CPSP even before surgery. In addition, these advances could help in providing effective treatment regimens that will prevent the transition to chronic pain post surgically and help to provide treatment for those who had already developed CPSP. The genetic role is further highlighted by the experimental studies which were done on catecholamine-O-methyltransferase (COMT). In these studies, a correlation was found between the increased COMT activities and the risk of developing chronic temporo-mandibular joint pain [17, 18]. Many investigators have proposed that some clinical disorders such as fibromyalgia, migraine, irritable bowel syndrome, irritable bladder and Raynaud's syndrome could be considered as markers of post-injury chronic pain [23, 24]. In view of the complexity of neuropathic pain, it is very likely that more than one single gene

Is Chronic Post-Surgical Pain Preventable? http://dx.doi.org/10.5772/intechopen.79500 39

Multiple studies looked at the effect of perioperative pain on the development of chronic post-surgical pain [25–34]. The factors mainly studied were the level of pain immediately before the surgery, the presence of previous chronic pain (lasting more than 6 months) before the surgery and acute pain at post-operative period. The first two factors have independently predicted moderate to intense pain in the acute post-operative period [25, 26]. Three studies, which were done on patients who underwent hernia repair and amputation surgeries, reported that the presence of pre-operative pain at the site of the operation or closer to it can

might contribute to the development of CPSP [9].

**Figure 2.** Potential risk factors for CPSP development.

**3.2. Preceding pain and acute post-operative pain**

#### **3.1. Genetic susceptibility**

Different people respond differently to physiological and clinical pain because of the variation in pain sensitivity. This discrepancy in pain sensitivity is a recognised factor for susceptibility to CPSP and response to analgesia [15–19]. There are strong indications that chronic pain and specifically CPSP are heritable traits and that genetic variation accounts for about half of the difference in pain levels. Studies done on rodents pointed to a strong heritable component of susceptibility to develop neuropathic pain, but the responsible genes have not yet been identified [19–21]. Future exploration of pain genetic may lead towards a remarkable improvement in CPSP treatment and to a more specific and personalised pain medicine [22]. Analysis of patients' DNA sequences of pain biomarkers and their analgesic responses to

**Figure 2.** Potential risk factors for CPSP development.

or blocking wind-up. The long-term potentiation is the second-order neurons response which last longer than the initial stimulus. Hyperalgesia results from an amplified response to painful stimuli due to both long-term potentiation and lowering of the pain threshold outside of

Nerve damage is the second major contributor for the development of CPSP. It is very important here to try to explore the mechanisms of differentiation of neuropathic from nonneuropathic pain. In most affected patients, the pain component of CPSP is similar to pain experienced as a result of neuropathic pain [11, 12]. In patients with CPSP, neuropathic pain can occur as a consequence of spontaneous ectopic discharges from damaged nerves and nearby undamaged nerves following nerve injury. Furthermore, disinhibition of pain pathways and facilitation of pain transmission occur due to loss of inhibitory interneurons in the dorsal horn. Hypoesthesia and neuropathic pain are both caused by nerve damage. In addition, the presence of hypoesthesia in CPSP patients confirms the association between nerve damage and CPSP [11, 12]. Thoracotomy is a good example of surgeries which may lead to nerve injury. In thoracotomy, the use of a rib retractor blocks intercostal nerve conduction by 50–100% in segments close to the incision [13]. Moreover, the degree of nerve damage in thoracotomy correlates with the intensity of chronic pain [14]. In conclusion, acute and chronic pain experience is a multifactorial complex process, involving physiological, genetic and psychosocial factors. These factors contribute to the conversion of somatosensory activity into a pain experience, to the amplitude of and reaction to the sensation, and to related

Various risk factors have been postulated to predict the development of chronic post-surgical pain in patients undergoing surgical procedures [9]. These factors are; genetic susceptibility, preceding pain, acute post-operative pain, psychosocial factors, demographic factors and surgical factors. These factors can be classified as patient-related and medical factors or to modifiable and non-modifiable risk factors [6, 10]. Each factor will be discussed separately in

Different people respond differently to physiological and clinical pain because of the variation in pain sensitivity. This discrepancy in pain sensitivity is a recognised factor for susceptibility to CPSP and response to analgesia [15–19]. There are strong indications that chronic pain and specifically CPSP are heritable traits and that genetic variation accounts for about half of the difference in pain levels. Studies done on rodents pointed to a strong heritable component of susceptibility to develop neuropathic pain, but the responsible genes have not yet been identified [19–21]. Future exploration of pain genetic may lead towards a remarkable improvement in CPSP treatment and to a more specific and personalised pain medicine [22]. Analysis of patients' DNA sequences of pain biomarkers and their analgesic responses to

the area of inflammation [10].

38 Pain Management in Special Circumstances

changes in mood and behaviour [9] (**Figure 1**).

**3. Risk factors**

the subsequent text (**Figure 2**).

**3.1. Genetic susceptibility**

medications will facilitate better understanding of CPSP pathophysiology, and thus it will help to predict a patient's likelihood of developing CPSP even before surgery. In addition, these advances could help in providing effective treatment regimens that will prevent the transition to chronic pain post surgically and help to provide treatment for those who had already developed CPSP. The genetic role is further highlighted by the experimental studies which were done on catecholamine-O-methyltransferase (COMT). In these studies, a correlation was found between the increased COMT activities and the risk of developing chronic temporo-mandibular joint pain [17, 18]. Many investigators have proposed that some clinical disorders such as fibromyalgia, migraine, irritable bowel syndrome, irritable bladder and Raynaud's syndrome could be considered as markers of post-injury chronic pain [23, 24]. In view of the complexity of neuropathic pain, it is very likely that more than one single gene might contribute to the development of CPSP [9].

#### **3.2. Preceding pain and acute post-operative pain**

Multiple studies looked at the effect of perioperative pain on the development of chronic post-surgical pain [25–34]. The factors mainly studied were the level of pain immediately before the surgery, the presence of previous chronic pain (lasting more than 6 months) before the surgery and acute pain at post-operative period. The first two factors have independently predicted moderate to intense pain in the acute post-operative period [25, 26]. Three studies, which were done on patients who underwent hernia repair and amputation surgeries, reported that the presence of pre-operative pain at the site of the operation or closer to it can predict chronic pain after the surgery [30, 33, 34]. In addition, the patients who experienced more severe and long lasting pain before the surgery felt more severe pain after the surgery compared to patients who experienced less severe pain before the surgery [29, 30]. Finally, the last factor studied was the correlation between immediate post-operative pain intensity and the development of chronic post-operative pain [31, 32]. Studies found an increase of two- to threefold risk of CPSP development in patients with immediate post-operative pain [34]. In conclusion, these associations indicate the potential for the prevention of CPSP by aggressive control of pain both pre- and post-operatively and by addressing any chronic pain issues well before planning for any surgery.

was independent of the type of surgical procedure and other somatic factors. In addition, research has explored the role of health-related beliefs, including catastrophising, in predicting CPSP. Catastrophising, claimed to be a trait-like characteristic, had mainly been assessed in non-surgical chronic pain populations or within the acute post-operative period [61, 62]. Studies reported that pre-operative catastrophising was the strongest independent predictor of pain ratings 2 years after knee arthroplasty [51, 63]. Also, patients who presented with presurgical anxiety and pre-surgical pain catastrophising before surgery were approximately twice as likely to develop CPSP compared with controls [64]. Furthermore, perceived injustice and sensitivity to pain traumatization might predict CPSP, but only a few studies were done and further research is still needed [52, 55, 56]. On the other hand, high dispositional optimism, high positive affect, low emotional distress, expectation of pain control and expectations about functional recovery before surgery were significantly associated with a lower pain intensity and fewer physical symptoms following surgery and a lower incidence of CPSP at 4 months in women undergoing breast cancer surgery. Taken altogether, these studies indicate that fostering optimism and enhancing self-efficacy and adaptive behaviours in the perioperative period may help patients navigate through their post-surgical recovery period [58, 65]. However, facing an uncertain future with the presence of health problems, and the requirement from the patient to bear significant pain and functional impairment of important daily activities during the recovery stage from major surgery makes it difficult for patients to always maintain an optimistic attitude [66]. Nevertheless, one study found that lower preoperative pain self-efficacy scores, which assess a person's confidence in performing general activities despite pain, to be a significant predictor of greater functional limitations, but not pain, at 1 year after total knee arthroplasty [67]. While another study also done in patients undergoing total knee arthroplasty has shown that patients with a higher pre-surgical score on the Patient Activation Measure (reflecting the propensity to engage in adaptive health behaviours) experienced better pain relief at 6 months [68]. In conclusion, fear of surgery was the most consistent psychological predictor of unfavourable outcome, whereas dispositional optimism was related to a better long-term functional recovery after surgery. Further studies are still needed to develop a better understanding of the interaction between CPSP and

Is Chronic Post-Surgical Pain Preventable? http://dx.doi.org/10.5772/intechopen.79500 41

Multiple surgical factors are related to the development of CPSP. These factors are the duration of the operation, surgical technique (laparoscopy vs. open), incision site and type, the experience of the surgeon and the centre where the intervention is performed [6]. In one study, researchers found that patients who underwent operations lasting more than 3 h had more chronic pain, poor functional outcome and poor global recovery at 6 months post-operatively [60]. Generally, the more serious the medical problem or more complicated, the more complex and longer the surgery [6]. Operations with a longer duration are associated with more surgical trauma, more persistent surgical nociception and sustained peripheral injury which in turn would trigger pathological changes in the central nervous system (CNS) [6, 9, 69, 70]. There is a strong relationship between the technique of surgery and the incidence of CPSP. Evidence showed that the more severe the surgical insult or tissue damage, the greater

psychosocial factors.

**3.5. Surgical factors**

#### **3.3. Demographic factors**

Younger patients are more likely to develop chronic postsurgical pain than older patients [35–40]. Smith et al. [35] found that chronic pain was seen in 65% of the 30–49 years' age group, in 40% of the 50–69 years' age group, and in 26% of patients older than 70 years. Another study showed that the probability of incidence of CPSP decreased by 5% with each 1 year increase in age in women undergoing breast cancer surgery [41]. Similar findings were seen after hernia repair surgery [36]. The explanation for this higher incidence of CPSP in younger age group is not yet known, but it might be related to the reduction in peripheral nociceptive function with increased age [9]. Besides age, gender has also been identified as another demographic factor. Studies showed that women have higher post-operative pain than men [42, 43]. Furthermore, angina patients with a higher body mass index (BMI ≥ 25) pre-operatively or at the time of surgery were more likely to report CPSP [40]. A young obese female has been described as the triad of high risk to develop CPSP in any patient undergoing surgery [6, 9, 42].

#### **3.4. Psychosocial factors**

Previous studies focused on biological factors as predictors for the development of CPSP, but recently, the evidence moved more towards a biopsychosocial model. Multiple pre-operative psychological factors have been studied. These are as follows: negative affective constructs such as anxiety symptoms, depressive symptoms, pain catastrophising, general psychological distress, perceived injustice and sensitivity to pain traumatization [44–57]. Patients with state-trait anxiety are believed to be more hypersensitive and psychologically more reactive to threatening stimuli [44, 57]. Studies showed that pre-operative anxiety and depression are correlated with a higher post-operative anxiety, a higher post-operative pain intensity, higher analgesia requirements and a longer length of hospital stay [44]. Fear of surgery was associated with more pain, poor recovery and a poor quality of life 6 months post-operatively. In one study done on patients who underwent breast cancer surgery, emotional distress like anxiety, depression, illness behaviour and somato-sensory amplification were reported as significant risk factors for higher post-operative acute pain at 1 month, but were not significantly correlated to persistent pain at 3 months post-operatively [58, 59]. On the other hand, a large prospective study with a sample size of 625 patients who had undergone minor, intermediate and major operative procedures found that the fear of the long-term consequences of surgery had predicted an increased level of pain at 6 months post-operatively [60]. This finding was independent of the type of surgical procedure and other somatic factors. In addition, research has explored the role of health-related beliefs, including catastrophising, in predicting CPSP. Catastrophising, claimed to be a trait-like characteristic, had mainly been assessed in non-surgical chronic pain populations or within the acute post-operative period [61, 62]. Studies reported that pre-operative catastrophising was the strongest independent predictor of pain ratings 2 years after knee arthroplasty [51, 63]. Also, patients who presented with presurgical anxiety and pre-surgical pain catastrophising before surgery were approximately twice as likely to develop CPSP compared with controls [64]. Furthermore, perceived injustice and sensitivity to pain traumatization might predict CPSP, but only a few studies were done and further research is still needed [52, 55, 56]. On the other hand, high dispositional optimism, high positive affect, low emotional distress, expectation of pain control and expectations about functional recovery before surgery were significantly associated with a lower pain intensity and fewer physical symptoms following surgery and a lower incidence of CPSP at 4 months in women undergoing breast cancer surgery. Taken altogether, these studies indicate that fostering optimism and enhancing self-efficacy and adaptive behaviours in the perioperative period may help patients navigate through their post-surgical recovery period [58, 65]. However, facing an uncertain future with the presence of health problems, and the requirement from the patient to bear significant pain and functional impairment of important daily activities during the recovery stage from major surgery makes it difficult for patients to always maintain an optimistic attitude [66]. Nevertheless, one study found that lower preoperative pain self-efficacy scores, which assess a person's confidence in performing general activities despite pain, to be a significant predictor of greater functional limitations, but not pain, at 1 year after total knee arthroplasty [67]. While another study also done in patients undergoing total knee arthroplasty has shown that patients with a higher pre-surgical score on the Patient Activation Measure (reflecting the propensity to engage in adaptive health behaviours) experienced better pain relief at 6 months [68]. In conclusion, fear of surgery was the most consistent psychological predictor of unfavourable outcome, whereas dispositional optimism was related to a better long-term functional recovery after surgery. Further studies are still needed to develop a better understanding of the interaction between CPSP and psychosocial factors.

#### **3.5. Surgical factors**

predict chronic pain after the surgery [30, 33, 34]. In addition, the patients who experienced more severe and long lasting pain before the surgery felt more severe pain after the surgery compared to patients who experienced less severe pain before the surgery [29, 30]. Finally, the last factor studied was the correlation between immediate post-operative pain intensity and the development of chronic post-operative pain [31, 32]. Studies found an increase of two- to threefold risk of CPSP development in patients with immediate post-operative pain [34]. In conclusion, these associations indicate the potential for the prevention of CPSP by aggressive control of pain both pre- and post-operatively and by addressing any chronic pain issues well

Younger patients are more likely to develop chronic postsurgical pain than older patients [35–40]. Smith et al. [35] found that chronic pain was seen in 65% of the 30–49 years' age group, in 40% of the 50–69 years' age group, and in 26% of patients older than 70 years. Another study showed that the probability of incidence of CPSP decreased by 5% with each 1 year increase in age in women undergoing breast cancer surgery [41]. Similar findings were seen after hernia repair surgery [36]. The explanation for this higher incidence of CPSP in younger age group is not yet known, but it might be related to the reduction in peripheral nociceptive function with increased age [9]. Besides age, gender has also been identified as another demographic factor. Studies showed that women have higher post-operative pain than men [42, 43]. Furthermore, angina patients with a higher body mass index (BMI ≥ 25) pre-operatively or at the time of surgery were more likely to report CPSP [40]. A young obese female has been described as the

Previous studies focused on biological factors as predictors for the development of CPSP, but recently, the evidence moved more towards a biopsychosocial model. Multiple pre-operative psychological factors have been studied. These are as follows: negative affective constructs such as anxiety symptoms, depressive symptoms, pain catastrophising, general psychological distress, perceived injustice and sensitivity to pain traumatization [44–57]. Patients with state-trait anxiety are believed to be more hypersensitive and psychologically more reactive to threatening stimuli [44, 57]. Studies showed that pre-operative anxiety and depression are correlated with a higher post-operative anxiety, a higher post-operative pain intensity, higher analgesia requirements and a longer length of hospital stay [44]. Fear of surgery was associated with more pain, poor recovery and a poor quality of life 6 months post-operatively. In one study done on patients who underwent breast cancer surgery, emotional distress like anxiety, depression, illness behaviour and somato-sensory amplification were reported as significant risk factors for higher post-operative acute pain at 1 month, but were not significantly correlated to persistent pain at 3 months post-operatively [58, 59]. On the other hand, a large prospective study with a sample size of 625 patients who had undergone minor, intermediate and major operative procedures found that the fear of the long-term consequences of surgery had predicted an increased level of pain at 6 months post-operatively [60]. This finding

triad of high risk to develop CPSP in any patient undergoing surgery [6, 9, 42].

before planning for any surgery.

40 Pain Management in Special Circumstances

**3.3. Demographic factors**

**3.4. Psychosocial factors**

Multiple surgical factors are related to the development of CPSP. These factors are the duration of the operation, surgical technique (laparoscopy vs. open), incision site and type, the experience of the surgeon and the centre where the intervention is performed [6]. In one study, researchers found that patients who underwent operations lasting more than 3 h had more chronic pain, poor functional outcome and poor global recovery at 6 months post-operatively [60]. Generally, the more serious the medical problem or more complicated, the more complex and longer the surgery [6]. Operations with a longer duration are associated with more surgical trauma, more persistent surgical nociception and sustained peripheral injury which in turn would trigger pathological changes in the central nervous system (CNS) [6, 9, 69, 70]. There is a strong relationship between the technique of surgery and the incidence of CPSP. Evidence showed that the more severe the surgical insult or tissue damage, the greater the risk of persistent pain. Significant differences were seen between open and laparoscopic procedures with a higher incidence of CPSP after open surgeries [71–73]. These findings were observed in different types of surgeries (hernia repair, cholecystectomy and hysterectomy) [71–73]. Less tissue handling and less intervention result in a lower incidence of chronic pain development. Wallace et al. [74] reported that the incidence of CPSP varied from 53% for mastectomy with reconstruction by implant, to 31% for mastectomy only, to 22% for breast reduction. Also, nerve protection during cutting and tissue handling in the operation site or in the neighbourhood during the perioperative period may decrease the incidence of CPSP. This is explained by the fact that nerve injury produces acute and lasting changes not only in the damaged nerves but also in the adjacent intact nerves [75]. Such effects would activate the pain pathways in the CNS, and motor and sympathetic systems [75]. The experience of the surgical team and the centre where the intervention took place have an impact on both morbidity and mortality [76]. CPSP was observed more commonly in surgical units with a lower number of cases and limited experience [76].

eight studies, four found that the perioperative administration of gabapentin decreased the incidence of chronic pain more than 2 months after surgery. Six out of the eight studies measured pain 6 months after surgery, and the pooled results demonstrated a moderate to large reduction in the development of CPSP (pooled odds ratio (OR) 0.52; 95% confidence interval (CI), 0.27–0.98; P 0.04) [79]. Two other studies, which investigated the effect of administering 1200 mg of gabapentin before surgery with placebo, reported a reduction in the incidence and severity of CPSP 6 months post -surgery [80, 81]. On the other hand, a systematic review done by Chaparro et al. [82] indicated that the effect of gabapentin was equivalent to placebo in preventing CPSP. Variations were observed in these studies in both the doses of gabapentin which were used (ranged from 300 to 1200 mg per day) and the duration of use (1 h before surgery to 10 days post surgery) [82]. Other variables, which could account for the conflicting evidence for the effectiveness of gabapentin, include diverse surgical procedures and small

Is Chronic Post-Surgical Pain Preventable? http://dx.doi.org/10.5772/intechopen.79500 43

Pregabalin is a structural analogue of c-aminobutyric acid. It binds to the α 2 δ subunit of the voltage-gated calcium channel which subsequently lead to a decrease in the release of neurotransmitters such as glutamate, norepinephrine and substance P, thereby targeting the putative role of these transmitters in central sensitization in a similar way to gabapentin [83]. Chaparro et al. [82] conducted a systematic review in which five pregabalin trials with longterm pain outcomes were included. Two different dosing regimens were used in these clinical trials, either 150 mg 2 h prior to the induction of anaesthesia and 75 mg twice daily for two post-operative days or a 300-mg single dose pre-operatively followed by a 14-day twice-a-day (BID =50–150 mg). The heterogeneity (I2 of 28.5%) of dosing regimens was problematic with respect to comparing long-term outcomes. Two studies demonstrated a significant benefit of pregabalin as compared to placebo [84, 85]. While the pain outcomes differed at 3 months follow-up, an overall significant effect of pregabalin was reported [82]. Moreover, two additional studies showed a significant reduction in the incidence of CPSP 6 months following both total knee arthroplasty and off-pump coronary artery bypass surgery [84–86]. Therefore, despite the heterogeneity between studies, the available literature favours the perioperative use of pregabalin to prevent CPSP; however, the use of a high dose of pregabalin (300 mg) has been associated with serious adverse effects such as visual disturbances, sedation and confusion during the first day after surgery [85, 87, 88]. These adverse effects settled with continued use, but led to an overall recommendation of using lower doses of pregabalin, with the aim of reducing side effects and hence allowing the successful introduction of physiotherapy and

intensive rehabilitation during the immediate post-operative period [85, 87, 88].

Venlafaxine hydrochloride is a selective norepinephrine and serotonin re-uptake inhibitor which is widely used as an antidepressant medication. It has a good safety profile as it does not bind to cholinergic, histamine or alpha 1-adrenergic receptors . The efficacy of Venlafaxine, which was administered perioperatively in patients with acute and chronic postmastectomy

*4.1.3. Selective norepinephrine and serotonin re-uptake inhibitors (SNRIs)*

sample size.

*4.1.2. Pregabalin*
