Introductory Chapter: Understanding Postoperative Pain

*Victor M. Whizar-Lugo, Guillermo Domínguez-Cherit, Marissa Minutti-Palacios and Analucía Domínguez-Franco*

#### **1. Introduction**

Postoperative pain (POP) is the result of the aggression of the surgical scalpel and sometimes of some anesthetic procedures. Both factors trigger a number of side effects including inflammation and nerve injury as a result of different pathophysiological mechanisms. This symptom can be devastating and does not have a useful biological function, which is why it is mandatory to prevent it, diagnose it, and treat it with a multimodal approach and thus reduce or avoid its multiple deleterious effects and, of course, reduce or evade the possibility of chronic postoperative pain (CPOP) [1, 2]. Despite advances in the comprehensive management of POP, its incidence could reach 86% of people who undergo surgery and suffer from moderate or severe POP on the first postoperative day [3]. Fortunately, physicians are now more interested in the proper management of POP and we have multiple resources to prevent and treat it more effectively and safely.

There are recognized factors for developing POP, such as age, pain prior to surgery, general anesthesia, long-term surgery, and some types of surgery, such as mastectomy, cesarean section, amputation, etc. [4].

Proper management of POP includes drugs, anesthesia techniques, enhanced recovery pathways in surgery and anesthesia, as well as non-pharmacological modalities. At present, multimodal analgesia combines all these management modalities and it has been shown that the postoperative evolution is better and with a clear decrease in the consumption of opioids [5], which is essential in this critical period of legal and illegal use of narcotic drugs.

The crisis of using illegal fentanyl mixed with other narcotics is a factor that should interest us in relation to a more rational management of opioids in the perioperative period. Although fentanyl and morphine have a prominent place in the management of POP, patients taking opioids prior to surgery have been found to be at high risk of continuing this habit even after they have recovered from their surgery.

The objective of this introductory chapter to our book on topics in postsurgical pain is the understanding of POP, its management, and repercussions on the evolution of patients.

#### **2. Anatomy and physiology**

Surgical tissue trauma leads to nociceptive activation and sensitization. POP is caused by surgical incision, inflammation, and nerve injury as a result of different pathophysiological mechanisms. Acute POP is described as nociceptive pain that is well localized and characterized as sharp, aching, and throbbing, triggered by myelinated A-delta and slow conducting unmyelinated C-fiber nociceptors that are sensitized by an incision [6] and this is better known as nociceptive pain [7]. Nociceptive input from A-delta and C fibers enters the spinal cord via the dorsal horn and synapses with second-order neurons at A-delta at laminae II and V, and C and laminae II. From here, pain signals cross to ascending spinothalamic and spinoreticular pathways to ultimately reach higher brain centers. The spinothalamic tract is considered the main pain pathway and originates from the neurons in laminae I and V–VII. This tract synapses with third-order neurons in the thalamus. The spinoreticular pathway synapses in the brainstem with projections to the thalamus, hypothalamus, and cortex and this is the pathway that is involved in the emotional and psychological experience of pain [6].

Inflammatory responses are involved in acute POP. This response is induced by a surgical tissue injury that originates a cascade of events that result in an expression of mediators including prostaglandins, interleukins, cytokines, and neurotrophin-like nerve growth factor (NGF), glial-derived neurotrophic factor (GDNF), neurotrophin-3 (NT-3) and neurotrophin-5 (NT-5), and brain-derived neurotrophic factor (BDNF) [7, 8]. These mediators lead to a reduction in the threshold that innervates the injured tissues and explains peripheral sensitization [8–10]. The prostanoid production at the site of surgical injury results from the generation of arachidonic acid from membrane phospholipids by phospholipase A2. Cyclooxygenase-2 (COX-2) converts arachidonic acid into prostaglandin H, which is converted into specific prostanoid species, such as prostaglandin E2, by prostaglandin synthases. The prostanoid prostaglandin E2 and NGF bind to G-protein-coupled prostaglandin E and tyrosine kinase A receptors, respectively, to modify the sensitivity of the terminal without emitting direct nociceptor activation [10]. Central sensitization is a form of synaptic plasticity in the neurons from the dorsal horn of the spinal cord or in the spinal nucleus of the trigeminal nerve. This type of sensitization describes the phenomenon of amplifying pain signaling and it requires concise but intense nociceptor activity to be initiated, like a surgical incision. The repeated low-frequency activation of C fibers and the glutamate-activated N-methyl-D-aspartate (NMDA) receptor are closely involved in this sensitization pathway. The descending noradrenergic pathways are inhibitory and modulate nociceptive transmission and spinal sensitization. The rostroventromedial medulla (RVM) and adjacent areas though the dorsal horn of the spinal cord transmit in a descending way the pathways originated in the cortex and thalamus. These areas of the brainstem also receive afferent input from the superficial dorsal horn, periaqueductal gray (PAG), nucleus tractus solitarius (NTS), and parabrachial nucleus [11]. The descending and inhibitory pathways minimize the nociceptive transmission via noradrenaline, stimulating alpha 2 (a2)-adrenoceptors and serotonin [12].

#### **3. Evaluating POP**

The assessment of POP is of paramount importance in the comprehensive management of surgical patients. Pain intensity assessment should be done with a pain


#### **Table 1.**

*Scales to measure pain.*

scale. POP is most often measured using unidimensional pain scales. While there are many different pain scales available, the visual analog scale (VAS) is the most commonly used scale. This scale involves the use of a metric line marked from 0 to 10 with verbal descriptions of pain at either end of the scale, with 0 representing "no pain" and 10 representing "worst possible pain." Since the original description of VAS [13], various measurement tools have been described and validated to assess acute and chronic pain as observed in **Table 1** [14–16]. In adults, the VAS, verbal rating scale (VRS), and numerical rating scale (NRS) are the most used due to their ease and veracity of the data obtained. When adult patients have some cognitive deficiency, it is prudent to use other scales such as those used with emoji faces as described by Li et al. [17] for patients to assess their pain on mobile devices and found that this form of assessment was reliable and valid compared with traditional pain scales in adult surgery patients. Analgesic management that delivers a change of 10 for the 100 mm pain VAS signifies a clinically important improvement or deterioration, and a VAS of 33 or less signifies satisfactory POP control [15].

In pediatrics, it is mandatory to assess pain with special scales designed for different ages; neonates, children, or adolescents [18–20]. In children with cognitive deficiency, the nonverbal expressions of pain should be used. The Non-Communicating Children's Pain Checklist-Postoperative Version (NCCPC-PV) and the Face, Legs, Activity, Cry, and Consolability (FLACC) scales have proven to be reliable [21].

#### **4. Preventing acute postoperative pain**

As we mentioned, inadequate pain management after surgery increases the risk of postoperative complications and may predispose for chronic postsurgical pain. The original idea of preventing pain is attributed to George W. Crile who in 1912 described what he called anoci-nociception; before starting the surgery, he injected parenteral morphine and local cocaine to block the transmission of painful stimulation [22–24]. Years later, Woolf [25, 26], Dickenson [27], and Wall [28] evidenced that administration of opioids or local anesthetics before noxious stimulus can prevent the development of injured-spinal hyperexcitability and pain-related behavior. The first clinical investigation on preemptive analgesia was published by Tverskoy in 1990 [29]. Since then, the prevention and management of POP has evolved based on these facts and its solid evolution is founded on advances in pharmacology and the various techniques of anesthesia, surgical and non-pharmacological approaches, as described


**Figure 1.**

*Pre-emptive analgesia is accomplished with analgesics, local anesthetics and adjuvants drugs given before surgery begins. Preventive analgesia refers to drugs given before, during and after surgery [24].*

in the chapters of this book. **Figure 1** shows Crile's original idea as it is used today. As seen in **Table 2**, there are several drugs that are used in the preemptive and preventive management of POP.

The side effects mentioned in **Table 2** are infrequent, sometimes dose-dependent, and should not be a limitation in the prescription of these drugs, except when there is any formal contraindication or history of adverse reactions, including known allergies [29–36].



#### **Table 2.**

*Most used analgesic and adjuvant pre-emptive and preventive drugs.*

## **5. Postsurgical pain management**

The prevention and management of POP requires a complete knowledge of the anatomy, physiology, and pharmacology of the elements involved: from molecular receptors to psychological aspects in such a way that we can structure a perioperative multimodal analgesic plan [5, 8, 9, 11, 34]. The American Society of Anesthesiologists (ASA) and other similar societies have published various guidelines for the multidisciplinary management of POP [37–39].

The timely identification of risk factors [1, 3, 4] for patients to develop severe or difficult-to-manage POP is of vital importance to plan a preemptive and preventive pain management. For example, prolonged surgeries with extensive tissue damage, potential for neural injury, multiple simultaneous operative sites, oncologic and orthopedic procedures, and breast surgery produce POP more frequently. In a study of 11,510 patients from 26 countries, it was found that POP decreases with increasing age, although this decrease in pain is of questionable clinical importance [3].

In this clinical setting, it is accepted that the combination of various therapeutic approaches—multimodal analgesia—is currently the most effective and safe treatment, reduces the consumption of opioids, as well as decreases postoperative nausea and vomiting [5]. **Table 3** mentions the most common management approaches.

Recently, some countries are experiencing a severe opioid consumption crisis in which the legal prescription and the unlawful use of these drugs are determining factors in the alarming increase in mortality related to the use of opioids, particularly fentanyl [40]. A multicenter study of 1093 major surgery cases found that the most important variable in opioid use 3 months after surgery was preoperative opioid use [41]. The current trend is to reduce opioids during and after surgery whenever possible with the goal of curbing opioid-related morbidity and mortality and engaging in the safe and rational management of POP [42]. Opioid-free anesthesia is a strong proposition in the midst of this global opioid consumption crisis [43–46]. However, the reduction of opioids in the perioperative period, especially in the management of POP, requires more aggressive programs among anesthesiologists, surgeons, and nurses.

There is a recent advance in the pharmacological management of POP; the new drug oliceridine is an innovative mu-opioid receptor agonist that is part of a new group of biased ligands that selectively activate G-protein signaling and downregulate


#### **Table 3.**

*Drugs, and procedures used in the comprehensive management of POP.*

β-arrestin recruitment. Since G-protein signaling has been associated with analgesia while β-arrestin recruitment has been related to opioid adverse events, there is potential for a wider therapeutic window, including postoperative analgesia. It has been approved by the Food and Drug Administration (FDA) for the treatment of moderate-to-severe postoperative acute pain. Its analgesic efficacy has been found to be similar to that of morphine, with a profile of fewer side effects. More clinical studies are required to determine its role in the management of POP [47–50].

Obese and opioid use disorder patients are a challenge in opioid administration for POP. Regional anesthesia techniques and trying to avoid opioids are preferred analgesic approaches, with multimodal analgesia being the technique of choice.

Comprehensive management of POP should include the non-pharmacological approaches listed in **Table 3**. Some perioperative psychological techniques can decrease the intensity of POP and thereby reduce the use of opioids in POP [51].

#### **6. Acute complications of POP**

Inadequate postoperative analgesia induces adverse consequences in the immediate postoperative period and favors CPOP. Nowadays, literature suggests that severe acute


#### **Table 4.**

*Complications related to inadequate POP management.*

POP is common, though most of the time it is underestimated and often inadequately treated (**Table 4**). Ineffective postoperative acute pain control is associated with poor outcomes including increased length-of-stay, sleep disturbance, prolonged time to first mobilization, and increased opioid use. Furthermore, poor postoperative pain control has been associated with delirium in the elderly, cardiopulmonary and thromboembolic complications [52]. POP not only affects patient health, but it may also increase the risk of developing chronic pain and its consequences. Fletcher et al. [53] reported that every 10% increase in the time spent in severe postoperative pain was associated with a 30% increase in chronic pain 12 months after surgery. Tissue injury generates an allostatic response that involves nervous, endocrine, and immune processes. Initially, the physiologic response to acute pain is adaptive, as it facilitates an immediate response via the sympathetic nervous system and the neuroendocrine system [54]. As the autonomic nervous system may be activated during an acute painful event, different changes in vital signs like the elevation of systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), and pulse rate (PR) are recorded. These changes could be suggestive of the presence of discomfort or pain like how some studies show in the intensive care unit (ICU) population [55]. Willingham et al. [56] analyzed a cohort that included 11,986 adult postsurgical patients, and the most common type of postoperative complication was wound infection (3.6%), followed by respiratory (3.0%), neural (2.8%), cardiac (2.5%), thrombotic (2.5%), and renal/gastrointestinal (2.0%). Patients with severe pain experienced an overall complication rate of 15.9% versus that of 12.4% in those patients without. Its key factor not only focuses on controlling PAP, but is also necessary to systematically identify significant preoperative predictors of poorly controlled acute postoperative pain and to quantify the associated risks. It has been hypothesized that adequate pain control represents a reduction in the surgical stress responses (endocrine, metabolic, and inflammatory), therefore improving analgesia will lead to a reduced incidence of postoperative organ dysfunction and result in a better outcome.

#### **7. Conclusions**

Management of acute postoperative pain is a major challenge for clinicians, with more than 80% of patients reporting pain after surgery and 75% reporting pain that is moderate, severe, or even extreme, although these figures vary according to factors, such as the age and sex of the patient, certain preoperative factors, biopsychosocial factors, the type and duration of surgery, the analgesic/anesthetic intervention used, and the time elapsed after surgery. This may favor CPOP. It is vitally important to identify the risk factors for POP and establish perioperative management plans using the techniques described, multimodal analgesia being the most effective procedure. Emphasizing a multimodal analgesic approach and an individualized plan for the management of POP significantly reduces the demand for opioids while optimizing pain relief and speedy recovery of patients.
