**3. Pain control**

Acute abdominal pain is the commonest presenting symptom of AP and the leading reason for hospital admission. It was already identified as the most popular finding by the board of International Symposium on Acute Pancreatitis of 1992 and still represents one of the three diagnostic criteria of the revised Atlanta Classification [15].

Pain consistent with AP is localized in the epigastric region and radiates like a belt around the trunk into the back. It is usually constant and described as deep and penetrating, due probably to retroperitoneal localization of pancreas. Pain may be exacerbated by eating, drinking, or lying supine and is often associated with nausea and vomiting [16, 17].

Its pathogenesis is complex and multifactorial: pancreatic acinar cell injury triggers the synthesis and release of pro-inflammatory cytokines and chemokines such as leukotrienes, bradykinin and arachidonic acid metabolites, and pancreatic proteases such as trypsin stimulate sensory neurons, which release substance P and calcitoningene-related peptide. This sophisticated signal net tends to self-amplify and involve the immune system with leukocytes activation too [18].

Whereas for almost all patients with AP experience pain, its relief is a clinical priority. Patients must receive satisfactory analgesia after hospital admission and until they need, tailored on subjective perception and modulated according with dayby-day pain variation, in order not to compromise their quality of life. Providing good analgesia is associated with enhanced lung function and reduced deep vein thrombosis: if pain is well controlled, patients can breathe deeply, sitting on chair and walking around. All these activities reduce length of stay and improve outcome.

Unfortunately, no guidelines provide sufficient details regarding analgesia administration in AP, and best current recommendation is to adhere to the acute pain management in the perioperative setting.

Several randomized controlled trials (RCTs) analyze the feasibility of a specific strategy or compare safety and efficacy of different analgesics, but clinicians who daily work in surgery or emergency wards probably do not find it very useful [19].

This is the reason why we revise the most recent literature and provide some simple indications about type, dose, route, and frequency of analgesia administration, in accordance with the current evidence.

### **3.1 Multimodal analgesia**

Numerous studies have focused on comparing the efficacy of different classes of intravenous analgesic, in order to choose only one of these to manage AP pain, but a more modern approach is growing.

There is consistent evidence that multimodal analgesic approach should be used when treating postoperative pain, and it is possible to extend this concept to the management of acute pain in general, because it means achieve better pain control minimizing side effects. Combined different classes of analgesics such as nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol, and opioids, which act through several mechanisms and bind different receptors, enable to reach a satisfying analgesic plain, using a lower dose of each one [20].

NSAIDs inhibit prostaglandins production acting on phospholipase A2 and cyclooxygenases (COXs) and thus relieve pain by reduction of pro-inflammatory cytokines cascade. NSAIDs have been shown a protective effect against AP in elective contest such as endoscopic retrograde cholangiopancreatography (ERCP), probably because COX-1 and COX-2 inhibition downregulates local inflammation and mediators spread [21, 22].

Paracetamol is the most popular analgesic and antipyretic drug in the world and has the well-known advantage of being used even in patients at increased risk of bleeding, but its mechanism of action is still unclear. It has a central effect, when given as a rapid intravenous bolus over 15 minutes, which is mediated by serotoninergic descending pathway, inhibits cyclooxygenases (especially COX-3 isoenzyme), and acts via the endocannabinoid system. Therefore, its analgesic effect comes from a quite different process respect of NSAIDs and justifies their association [23].

Opioids are the most frequently prescribed analgesics for pain relief of patients with AP. All opioids used in clinical practice today exert their action on μ receptors, with some having additional activity on κ and δ. Opioid receptors are distributed throughout the central nervous system (CNS) and in the dorsal horn. They have two main effects: block incoming nociceptive afferents (medulla and brainstem) and increase the inhibitory activity of the descending pathways (periaqueductal gray). They act on multiple sites of the CNS, also lowering negative affective connotation of pain [24].

They are the most powerful analgesics available and beyond relieving pain they have the advantageous property of making patients feel relaxed and promote sleep. People who are sick in fact are often distressed, anxious, insomnious because of discomfort, and sometimes oppositive to treatment.

Despite old beliefs about the risk of the Oddi's sphincter spasms after systemic administration, several studies have clarified that opioids do not negatively impact on the course of AP and could be safely administered, and their use may decrease the need for supplementary analgesia [25, 26].

It is known that opioids expose to a greater risk of nausea, vomiting, and stypsis and that is why the association with non-opioids helps to reduce the total amount of their administration but allowing to obtain an analgesia level that would be unthinkable with paracetamol alone.

No evidence or recommendation about any restriction in pain medication is available. Of course, NSAIDs should be avoided in patients with acute or chronic kidney injury.

Ensuring proper analgesia avoids the chronicization of pain and therefore the long-lasting intake of anti-inflammatory drugs or even worse opioids addiction.

Furthermore, pain is a potentially treatable cause of delirium, a condition that frequently affects elderly or multipathological patients admitted to hospital especially in the case of prolonged hospitalizations, as the case for AP in general. Delirium is an acute and fluctuating disturbance of consciousness with reduced ability to focus, maintain, or shift attention, accompanied by change in cognition. It includes psychomotor disturbances, disorder of the sleep–wake cycle, and emotional instability. It also causes poor patient cooperation, complicating medical and nursing care.

It is of clinical interest because it correlates with length of hospitalization, longterm cognitive dysfunction, and mortality; therefore, it is a costly health condition and significantly impacts on outcome and patient performance.

Delirium has multifactorial causes, but there is convincing evidence that sleep deprivation is a risk factor for the development and in our patients, insomnia is frequently pain-related [27].

### *3.1.1 A practical approach*

Good pain management is providing timely coverage during all day. Both surgical and oncologic pain are controlled by prescription of one medication, or a combination of medications, that is given at regularly intervals through the day, for maximum control of baseline pain. This is the around-the-clock medication (ATC), and we could agree that a patient with AP deserve to receive at least paracetamol 1 g every 6 hours and one NSAIDs, for example, ketorolac 30 mg or ketoprofen 100 mg, every 8 hours (**Figure 2**) [28, 29].

In addition, we should also include a rescue therapy, to cover breakthrough pain that is not adequately covered by ATC and morphine 3 mg could be a good option because it's easily managed in the surgery ward and nursing staff are confident with. It is possible to administer again the same dosage after 30 minutes, which is the time for morphine to achieve maximum effect and the recommended dose is 10–15 mg within 24 hours, depending on the patient's age and kidney function. In fact, morphine has a long half-life and produces some active metabolites, and its elimination is dependent on kidney excretion, so it can easily accumulate in subjects with impaired renal function and cause undesirable effects such as respiratory depression. Old people are more sensitive to pharmacodynamic effect of opioids, and clinicians must be aware of this and pay more attention with their prescription [30].

**Figure 2.**

*An example of multimodal analgesia schematic approach.*

Knowing that AP is an overly complex pathology and associated pain can range from mild to severe, it would be advisable to contact the anesthesiologist if the administered morphine exceeds 10 mg, because it might be reasonable to upgrade the analgesia strategy. A multidisciplinary approach to patient care is the key for a more comprehensive assessment and his greater satisfaction.

### **3.2 Patient-controlled analgesia**

A patient-controlled analgesia (PCA) pump is a computerized machine that gives a programmed amount of analgesic, usually an opioid, when the patient presses a button (bolus or demand dose). The drug might be delivered only as a bolus, or also with a continuous background infusion (basal rate) depending on the pharmacokinetic and dynamic of the drug itself, the entity of pain, and the patient performance.

Anesthesiologist presets the dosage in order to make the infusion absolutely safe [31].

PCA is a widespread technique already used to treat acute and chronic pain, in postoperative setting and emergency department. It has proven to be more effective than non-patient opioid injections because patients can self-administer small dose of analgesic, this results in better pain control and higher satisfaction, moreover with a net reduction in opioid consumption [32].

It is universally recognized that undertreatment of pain has important impact, including hemodynamic fluctuation with tachycardia and hypertension, peripheral vasoconstriction, which can cause poor peripheral perfusion, activation of the stress response with increased cortisol production and hyperglycemia, and not least patient discomfort.

One of the problems with pain management is time from patient complain and drug administration. Unfortunately, sometimes it takes a lot because of department organization, and there is strong evidence that poorly controlled pain is much harder to relieve than and indeed increases the incidence of chronic pain.

PCA therapy increases patient satisfaction, decreases pain scores, and reduces opioid consumption [33, 34].

### *3.2.1 PCA with morphine*

Morphine is used for the management of moderate to severe pain. It is metabolized in the liver with formation of several metabolites, among which morphine-6-glucuronide is actually responsible for the observed response. It is predominantly excreted

*The Anesthesiologist Contribution to Management of Acute Pancreatitis DOI: http://dx.doi.org/10.5772/intechopen.105821*


**Table 1.**

*Schematic morphine PCA administration.*

in the urine, and its half-life elimination is about 2–4 hours, partly still under active metabolites. It is a drug with a high interindividual variability both as regards the pain reduction and side effects such as respiratory depression, constipation, nausea, and itching. Also for this it is important to choose an adequate administration protocol (**Table 1**) [35].

The bolus is the dose of morphine delivered each time the patient presses the button, and it might range from 1 to 3 mg depending on patient's physical characteristics: we will prefer lower dosages in elderly and frailty subjects. Morphine has an onset time of 15 minutes, but a slower peak effect, and it needs at least 30 minutes to exert its action. This is why the lockout interval, or time after a bolus in which another one is not allowed even if patient presses the button, is 20 minutes to permit the analgesic effect and prevent overdosing. Because of its long context-sensitive half time, after an adequate loading dose, the demand dose alone might be enough without background infusion, to reach satisfactory analgesia.

The 4-hour limit defines the maximum allowed amount of medication to be administered within that period, is usually less than the dose given if the patient presses the button every time, and acts as a safety mechanism.

The loading dose is a starting bolus that you can administer with the pump or manually with the aim to achieve more rapidly the patient well-being and having adequate stable concentration.

### *3.2.2 PCA with sufentanil*

Among opioids, sufentanil has the highest therapeutic index, hence the safest to use. It is enormously powerful; therefore, it ensures excellent analgesia, but at the same time, it benefits from a much lower incidence of respiratory depression.

Is a highly lipophilic opioid and has a small volume of distribution. It has a time to peak effect after bolus of approximately 6–8 minutes, thus the patient will be able to manage in a satisfactory and punctual way his own analgesia, profiting from a rapid achievement of the effect.

It does not produce active metabolites and its excretion is not conditioned by renal function, as is the case for morphine, so it has a higher safety profile in elderly or patients with renal failure.

Its high therapeutic index and predictable pharmacokinetics make it the ideal candidate for administration via PCA pump as schematized in **Table 2** [36].

Sufentanil has a faster half-life of elimination than morphine and a sensitive context half-life that is too short, this is the reason why it is advisable to couple with a background infusion of about 2–5 μg/h to reach a stable concentration and maintain the analgesic effect between boluses. The continuous infusion will administer 72–120 μg in 24 hours, which represents a reasonable and harmless amount.

In most cases it may be enough to set a low infusion (2 μg/hour) and instead prefer a more consistent bolus (5 μg).


**Table 2.**

*Schematic of sufentanil PCA administration.*

The lockout may be shorter than what we usually set for morphine, because the sufentanil reaches peak effect more quickly, therefore 10–15 minutes are enough to ensure the effect perception, avoiding excessive self-administering.

It is preferable to give a loading dose before starting PCA infusion to immediately relieve patient's condition and maybe observe the effectiveness of it [37].

### *3.2.3 Ketamine*

Ketamine is an old hypnotic that is back in vogue because at low concentration acts as a fantastically painkiller and has safe profile because it does not impact on respiratory drive.

It inhibits N-methyl-D-aspartate receptor (NMDA-R) of glutamate, which is the main excitatory neurotransmitter: blocks nociceptive peripheral afferents into posterior dorsal horn, propagation through spinal cord, brainstem. and then higher centers projections.

Ketamina acts synergistically with opioids and hence has an opioid-sparing effect. Blocking the NMDA receptor prevents the calcium channel opening and its entry into the cell, which would lead to a lowering of the pain threshold and a lack of pain control with opioids.

Adding a little amount of ketamine, for example, 40–50 mg, to the PCA pump could be an excellent way to improve the patient's analgesic management, reducing side effects and above all avoiding the need to increase morphine or sufentanil dosages. It also appears that this drug has the pleasant effect of mood improving, which can represent an added value to our therapy.

This approach significantly enhances activity of both morphine and sufentanil, improves their efficacy, and reduces tolerance to opioids [38–40].

### **3.3 Thoracic epidural analgesia**

AP causes severe pain, which sometimes is difficult to adequately control with intravenous analgesics, therefore epidural analgesia becomes a good treatment option. Epidural analgesia is an essential component of perioperative medicine because it guarantees an excellent pain control, reduces opioid consumption, and improves recovery especially after major surgery. It is currently used for labor pain management in the delivery room because it allows to modulate analgesia according to the various stages of labor, with great mothers' satisfaction. It is also employed in ICU after severe chest trauma.

There is recent evidence from both preclinical and clinical trials supporting beneficial effects of epidural analgesia in AP. These studies suggest that epidural analgesia increases arterial perfusion of pancreas and redistribution of blood flow to nonperfused pancreatic regions [41, 42].

AP resulting from an inappropriate activation of trypsinogen leads to local injury and inflammation with increased capillary permeability, edema, augmented

### *The Anesthesiologist Contribution to Management of Acute Pancreatitis DOI: http://dx.doi.org/10.5772/intechopen.105821*

leukocyte adhesion, free radical production, and enhanced coagulation activity. This inflammatory vicious circle releases proinflammatory cytokines (IL-1, IL-6, IL-8) and systemic mediators (TNF-α) that discharge into the circulatory stream triggering a systemic inflammatory state.

Pancreatic tissue has been shown to be extremely sensitive to hypoxemia and ischemia, conditions that can lead to tissue necrosis and which strictly depend on microcirculation. Inadequate microvascular perfusion and hypoxia may play a significant role in early disease progression.

Thoracic epidural analgesia (TEA) induces a selective segmental sympathetic block, which, in addition of pain removal, increases splanchnic perfusion and reduces ischemic damage. TEA was found to improve gut mucosal perfusion and liver injury in sepsis too. It reduces pro-inflammatory state and improve outcome [43–45].

Significant complications related to the use of TEA are epidural hematoma, infection, and nerve damage. In spite of most of the research being done on patients admitted to ICU and thus with critical conditions, epidural has proved to be a safe technique [46]. This suggests that it can be used safely even in subjects with mild to moderate AP who are admitted to emergency or surgical department, if needed, for example, in obese or pneumopatic patients for whom we prefer to avoid opioids.

One of the reasons that creates reticence in the use of TEA is the fear of its hypotensive effect but, as for obstetrical analgesia, is possible to use low local anesthetics' concentrations with none or minimal hemodynamic impact.

### *3.3.1 Practical tips*

Pancreas sympathetic afferent innervations originate from both thoracic and lumbar spinal cord (T6–L2 metamers). The epidural catheter might be placed at the thoracic level (indicatively between T8 and T10) and analgesia can be driven with an elastomeric continuous infusion or with a patient-controlled epidural analgesia (PCEA) with only mandatory bolus or demand dose.

In any case, the use of low anesthetic concentrations is recommended, for example, ropivacaine 0.05%–0.075% administered with bolus of 5–7 ml, to minimize the block extension regarding the risk of hypotension. If it is not enough to meet patient satisfaction, is possible to increase this concentration to 0.1%–0.125%. The association of an opioid is always indicated, and sufentanil 0.2–0.5 μg/ml may be a desirable choice because of is lipophilicity.

Combination with an opioid results in better analgesia with smaller dose of anesthestic [43].

### **3.4 Pain evaluation**

A successful strategy of pain management starts with measuring the patient's pain. The numeric rating scale (NRS) consists of a numeric version of the visual analog scale and is one of the most commonly used to assess pain severity (**Figure 3**). It helps healthcare professionals in quantifying a very subjective condition such as pain, in order to modulate analgesic administration and understand if current therapy works. On the other hand, it encourages patients to become active participants in pain assessment and management, and this is reflected on a well perception of care during hospital staying [47].

Scores also help in sharing information between different health professionals, speak the same language, and easily reassess patient's response.

### **Figure 4.** *Step up pain control.*

**Figure 3.**

NRS starts with zero that means no pain and well-being, numbers from 1 to 3 correspond to mild pain, from 4 to 6 moderate pain and above severe pain. Number 10 identifies worst possible pain.
