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 Table of Contents  
REVIEW ARTICLE
Year : 2022  |  Volume : 4  |  Issue : 1  |  Page : 9

Pain and its Management in Severe Acute Pancreatitis


Department of Critical Care Medicine, Chongqing University Cancer Hospital, Chongqing, China

Date of Submission07-Nov-2021
Date of Acceptance30-Mar-2022
Date of Web Publication22-Apr-2022

Correspondence Address:
Dr. Zhengying Jiang
Department of Critical Care Medicine, Chongqing University Cancer Hospital, Chongqing 400030
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JTCCM-D-21-00026

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  Abstract 


Pain is common in severe acute pancreatitis (SAP) and is associated with the disease severity and outcomes. The management of pain in SAP may not only relieve pain but also improve outcomes. However, pancreatic pain in SAP involves several complicated mechanisms. Poor understanding about the pain mechanism in SAP and lack of enough high-quality data on pharmacological and nonpharmacological intervention lead to a limited analgesia strategy in patients with SAP mainly managed using nonsteroidal anti-inflammatory drugs and opioids. This makes pain management in SAP challenging and may cause potential harm. This article reviewed the current management of pain in SAP by combining pain mechanisms with animal or clinical studies and proposed an analgesic ladder based on available evidence to improve pain management in patients with SAP.

Keywords: Management, mechanism, pain, severe acute pancreatitis


How to cite this article:
Long Y, Jiang Z, Wu G. Pain and its Management in Severe Acute Pancreatitis. J Transl Crit Care Med 2022;4:9

How to cite this URL:
Long Y, Jiang Z, Wu G. Pain and its Management in Severe Acute Pancreatitis. J Transl Crit Care Med [serial online] 2022 [cited 2022 Sep 27];4:9. Available from: http://www.tccmjournal.com/text.asp?2022/4/1/9/343745




  Introduction Top


Acute pancreatitis (AP) is a disease of variable severity caused by the premature activation of pancreatic enzymes.[1] The global incidence of AP in 2019 is about 34.8/100,000, decreased by 8.4% compared with that in 1990, yet it is still high and continues to increase in some countries.[2] Severe AP (SAP) accounts for about 25% of the AP cases, and the mortality is still as high as 15%–30% despite the advancement of the management.[3],[4] Pain is the most common clinical manifestation in AP and plays an important role in diagnosis and prognosis. Patients with SAP experience more severe pain than those with mild and moderate AP. Nowadays, pain management has drawn increasing concern as a part of comprehensive treatment measures in both AP and SAP.[5],[6],[7] However, the reality is that we have a poor understanding of the pain mechanism, and pain in SAP is mainly managed by nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. This study reviewed the knowledge about pain and its management in AP and SAP intending to improve pain management in SAP. Two points are important here. First, pain in patients with SAP may be caused by a variety of factors, such as inflammatory damage to the pancreas, surgical procedures, and mechanical ventilation. This review only focused on abdominal pain caused by SAP itself. Second, the studies on pain in SAP are limited. Given the high similarity in the etiology and pathogenesis of AP and SAP, it seems acceptable to use some studies on AP to illustrate the pain and its management in SAP.


  Role of Pain in Severe Acute Pancreatitis Top


Abdominal pain is the earliest and most common symptom and is considered a hallmark of AP. The features of abdominal pain in AP have been well described in the literature.[5],[8] According to the modified Atlanta consensus guidelines, the hallmark abdominal pain is one of the diagnostic criteria for AP.[9] Resent studies suggested that the severity of pain correlated with the severity of AP, and the interval between onset of pain and hospitalization was also a prognostic factor for estimating the severity of AP.[10],[11] Patients with SAP experienced more severe abdominal pain and required more opioids for pain relief.[8],[12],[13],[14] The severity of pain may be impacted by the underlying causes, biliary AP may cause more severe pain compared with alcoholic AP and autoimmune pancreatitis.[15],[16],[17],[18]

Pain may lead to adverse outcomes such as impaired tissue perfusion, catabolic hypermetabolism, and immunosuppression. It is associated with prolonged mechanical ventilation duration and increased morbidity and mortality in critically ill patients.[19],[20],[21],[22] As mentioned earlier, more severe pain is associated with more severe disease severity and worse outcomes. However, it is difficult to assess the impact of pain itself on the disease severity and outcomes in SAP. Clinical practice and several animal experiments showed that analgesic treatment not only relieved pain but also reduced damage to the pancreas and extrapancreatic organs and alleviated inflammation (described below), suggesting that pain might exacerbate disease progression. Consequently, pain management, fluid resuscitation, nutritional support, and organ support are considered the mainstays of treatment in SAP.[6],[7],[23]


  Pancreatic Pain Mechanisms Top


Providing appropriate analgesic therapy for patients with SAP is challenging, partly due to a poor understanding of the mechanisms of pancreatic pain. Since AP and SAP may share the same pain mechanism, we used AP as an example to illustrate the pain mechanism of SAP. Pain is defined as an unpleasant sensation that has an organic and a psychogenic component. Based on the underlying mechanism, pain is classified into three types: nociceptive (mediated by the activation of normal pain pathways), neuropathic (abnormal response to pain stimuli), and psychogenic (psychological/mental-driven pain). All three are involved in pancreatic pain, but the first two are the main causes of pancreatic pain. In AP, nociceptive pain plays the most important role.[24] A better understanding about the mechanism of pancreatic pain may help improve pain management. The pain mechanisms and potential therapeutics in SAP are summarized in [Table 1].
Table 1: Mechanisms of pancreatic pain and potential therapeutics in severe acute pancreatitis

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  Sensory Mechanism of the Pancreas to Nociceptive Stimulation Top


The afferent nerve endings (receptive fields) are located in the pancreas with their cell bodies in the nodose ganglia and dorsal root ganglia (DRG) for the vagal and spinal afferent (splanchnic) nerves, respectively. Nonpainful stimuli are primarily conducted through the vagus nerve, while painful stimuli are conducted by the splanchnic nerves. The cell bodies of pancreatic afferent nerves in DRG of the rodents are located at T5–L2, mainly at T10–T11, and project to the spinal cord.[25] These afferent nerves are activated during the onset and progression of AP.[26] The nerve endings can be activated by mechanical stimuli (such as stretch of the pancreas capsule caused by pancreatic edema owing to AP or dilatation of the bile duct caused by bile duct obstruction owing to the gallstones) and some chemical stimuli (such as cholecystokinin, histamine, and bradykinin).

A variety of receptors and ion channels are involved in the activation of nerve endings and are described in detail in the literature.[27] Some afferent nerves may be silent under normal physiological conditions and become excited only after tissue injury or inflammation; the excitability of afferent nerves can be altered by numerous factors in the neuronal environment (such as inflammatory mediators).[28] The activation of nerve endings leads to the generation and propagation of afferent nerve action potentials. The sympathetic nerve is the main afferent nerve for nociceptive stimulation of the pancreas. Visceral pain and somatic pain are conducted through C fibers and Aδ fibers, respectively.[29] Once the pancreatic afferent neurons are activated, neurotransmitters such as calcitonin gene-related peptide and substance P (SP) were released to activate second-order neurons in the dorsal horn of the spinal cord.[30] The nociceptive stimuli are projected through the primary pancreatic afferent neurons in DRG and the dorsal horn of the spinal cord to the neurons in the prefrontal cortex, the dorsal motor nucleus of the vagus nerve, and the nucleus tractus solitarius to form pain sensation.[31],[32] The neurons that innervate the nociceptive stimulation to the pancreas may also innervate somatosensory, somatic, and visceral afferent nerves, which may integrate and interact in the spinal cord. One consequence is that visceral pain may cause pain in the somatic structure near or far from the origin of the visceral pain, also termed as referred pain. Meanwhile, simultaneous cutaneous and visceral stimuli evoke a larger response than the response evolved by either stimulus on its own.[33],[34] The sensory mechanism of the pancreas to nociceptive stimulation is shown in [Figure 1].
Figure 1: Sensory mechanism of the pancreas to nociceptive stimulation. The nociceptive stimuli to the pancreas activate the nerve endings of the primary afferent nerve to generate electrical and chemical signals, which are transmitted through dorsal root ganglia and spinal dorsal horn to the brain to form pain sensations

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  Neuropathic Pain in Severe Acute Pancreatitis Top


Neuropathic pain is important pathogenesis in chronic pancreatitis.[24],[27] Despite lacking direct evidence, neuropathic pain may be associated with the development of pain in AP. Neuropathic pain is defined as the pain after a lesion or disease of the peripheral or central nervous system.[35] The damage to the endings of peripheral nerves can generate neuropathic pain states.[36] Thus, it is reasonable to hypothesize that the damage to the pancreatic afferent nerve endings and the sensitization of pancreatic afferent nerves by inflammation in SAP may cause neuropathic pain.[37] The stimulus-evoked pain types are classified as dysesthetic, hyperalgesic, or allodynic according to the dynamic or static characteristic of the stimulus.[38] The mechanism of neuropathic pain involves peripheral and central sensitization, which are discussed in the following text

The molecular and cellular changes at the level of the uninjured primary afferent nociceptor after a nerve lesion may lead to sensitization and ectopic spontaneous activity of primary afferent nociceptors. The changes in the expression of voltage-gated sodium channels, transmembrane proteins such as vanilloid receptors and temperature-sensitive excitatory ion channels, and adrenoreceptors on the uninjured primary afferent nerves (DRG) may be involved in peripheral sensitization.[39],[40],[41],[42] Nerve growth factors (NGF) released by the injured nerves may be associated with the aforementioned changes in the uninjured nerve receptors. It has been suggested that NGF not only plays an important role in the onset and progression of AP but also leads to sensitization in the afferent neurons.[43],[44],[45] Pro-inflammatory cytokines such as tumor necrosis factor-alpha and interleukin 6 (IL-6) released after nerve lesions may induce ectopic activity in both injured and adjacent uninjured primary afferent nociceptors at the lesion site also involved in the peripheral sensitization.[46] Furthermore, oral small-molecule IL-6 receptor inhibitor may reduce abdominal hyperalgesia during AP.[47]

The central sensitization in neuropathic pain includes sensitization in the spinal cord and brain. The current research mainly focuses on sensitization in the spinal cord. The first mechanism of sensitization in the spinal cord is the increased excitability of the multi-receptive spinal cord neurons (wide-dynamic-range neurons with multiple synaptic inputs from the nociceptive and non-nociceptive system multisensory neurons) in the dorsal horn. Research shows that glutamate and neuropeptide SP are released by C fibers, and the expression of sodium channels (Nav1.3) in second-order dorsal horn neurons is changed after peripheral nerve injury. Those changes increase the excitability of the multi-receptive spinal cord neurons. The consequence is increased neuronal activity in response to noxious stimuli, expansion of neuronal receptive fields, and spread hyperexcitability of the spinal cord to other segments.[48] Another mechanism of spinal cord sensitization is disinhibition. In rodents, peripheral nerve injury promotes selective apoptosis of inhibitory interneurons that release γ-aminobutyric acid in the superficial dorsal horn of the spinal cord, which may weaken the inhibition of spinal dorsal horn neurons.[49] The dorsal horn neurons of the spinal cord receive descending modulating control from supraspinal brainstem centers; the loss of function in descending inhibitory serotonergic and noradrenergic pathways may be involved in the central sensitization.[50] Finally, nonneural glial cells are also involved in the sensitization of the spinal cord. Excitatory neurotransmitters such as pro-inflammatory cytokines and glutamate released by nonneural glial cells, which are activated by injury to the peripheral nerves, may lead to spinal sensitization.[51] Animal studies and brain function studies have shown that the brain is also involved in central sensitization.[52],[53]


  Analgesics for Severe Acute Pancreatitis Top


Since pain in SAP involves multiple mechanisms, various analgesics may be available for its management. However, due to limited evidence, it is not possible for guidelines to make specific recommendations for analgesics. Analgesics used in SAP are listed in [Table 2] and described in the following text.
Table 2: Analgesics used in severe acute pancreatitis

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  Opioids Top


Opioids are one of the commonly used analgesics for patients with SAP that work through binding to opioid receptors. Opioid receptors are of three types: μ, δ, and κ receptors, with a total of seven subtypes (μ1 and μ2; δ1 and δ2; κ1, κ2, and κ3). These receptors are mainly located in the central nervous system, whereas the μ receptors are also located in the gastrointestinal tract. The pharmacological effects of opioids vary according to the activated opioid receptors, the ability to bind to different opioid receptors, and the pharmacokinetics of opioids; therefore, the time of onset, effect, duration, and side effects of opioids may vary among individuals.[69],[70] Many kinds of opioids used for the analgesia in AP include pethidine, morphine, buprenorphine, fentanyl, remifentanil, and pentazocine.[54],[55],[71],[72] A few randomized controlled studies and systematic reviews compared the effects and safety of opioids for analgesia in AP. The aforementioned researches confirmed the analgesia effect of opioids in AP; buprenorphine and pentazocine seem to be more favorite options due to their better effects and safety. However, another meta-analysis showed no difference in adverse reactions and mortality between different opioids for pain management in AP.[56] Due to the limited number of studies and heterogeneity of study quality and methodology, we may not conclude the optimal opioid for analgesia in SAP.[55],[56],[73] Opioids also showed other effects besides analgesia in AP. Rat AP animal model experiments showed that sufentanil combined with midazolam might reduce inflammation and pancreatic damage.[74] Fentanyl reduced myocardial injury in SAP in a rat model by regulating the NF-κB signaling pathway.[75]

However, opioids may cause potential harm. They may lead to the contraction of the Oddi sphincter and increased pressure of the bile duct, which may induce or exacerbate AP, especially when several case reports of opioid-induced AP exist; this effect of opioids may be related to the effect of μ-receptors.[76],[77],[78],[79],[80] Morphine has the strongest effect on the Oddi sphincter, whereas low-dose fentanyl results in a lower incidence of the spasm of the Oddi sphincter.[81],[82] In the AP animal model induced by caerulein, L-arginine, and ethanol-palmitoleic acid, the administration of morphine increased neutrophil infiltration and necrosis of pancreatic tissue, leading to the exacerbation of pancreatitis. The pathways activated during pancreatic regeneration, such as sonic hedgehog, and activation of embryonic transcription factors, including pdx-1 and ptf-1, are downregulated after the administration of morphine, indicating that the recovery of pancreatitis is inhibited. Gut permeabilization and bacteremia caused by AP were exacerbated by morphine, and these effects seemed to be mediated by μ-receptors.[57] A recent retrospective nested case–control study of a commercial claims database for patients who underwent cholecystectomy showed that codeine increased the incidence of AP in patients after cholecystectomy.[83] The multiple logistic regression analysis of 93 patients with AP showed that opioid analgesic treatment in AP was associated with severity, complications, and mortality.[84] Besides potential damage to the pancreas, opioids might cause side effects such as ileus and immunosuppression, exacerbating the preexisting multiple-organ dysfunction syndrome in patients with SAP.[85],[86] A prospective cohort study in the surgical intensive care unit (ICU) demonstrated that adverse drug reactions were mainly caused by opioids, each adverse drug reaction was associated with an increase in ICU length of stay by 3.39 days, and the length of ICU stay increased by 2.31 days (increased by 53.2%) even when confounding variables were eliminated.[87] Therefore, opioids are a double-edged sword in AP and should be individualized according to the patient's condition and the pharmacokinetics/pharmacodynamics of the drugs.[70] Despite the lack of data from patients with SAP, data from ICU patients suggested the adjuvant use of non-opioids to minimize opioid-related adverse effects.[86]


  Nonopioids Top


Nonsteroidal anti-inflammatory drugs

NSAIDs are commonly used anti-inflammatory and analgesic drugs. Since AP involves inflammation and pain, theoretically, it is a suitable option. Indeed, the analgesic effect of NSAIDs in AP has been confirmed. Besides analgesia, patients with SAP may receive other benefits from NASAID treatment. A retrospective study including 324 patients with AP in 2 large teaching hospitals in the UK showed that compared with patients who did not receive NSAIDs, patients who received NSAIDs for other complications had a lower rate of pancreatic necrosis and pseudocysts and a lower level of CRP ≥ 150 mg/L on the 2nd day, but no difference in the length of hospital stay, need for ICU admission, and mortality.[88] Some animal experiments also suggested that some NSAIDs might play a role in preventing or treating AP, although some research results are still controversial. However, current studies mainly focus on AP rather than on SAP. The most often used NSAIDs in AP are indomethacin and diclofenac.

Indomethacin

Lankisch used indomethacin in an AP animal model in 1978. The results showed no difference in serum enzymology and pancreatic tissue damage, but the mortality rate in the indomethacin group decreased.[89] Another acute hemorrhage pancreatitis animal experiment showed that adding indomethacin to drinking water might improve pancreatic tissue damage. However, 10 and 20 mg/L indomethacin in drinking water might worsen liver tissue damage; the overall result was that the 5 mg/L group revealed the highest survival rate.[90] A SAP mouse model found that indomethacin might protect pancreatic acinar cells from damage by inhibiting the NLRP3 pathway and reducing the severity of SAP, which might be a potential pancreatic protective mechanism of indomethacin.[91] However, another mouse pancreatitis animal model experiment suggested that indomethacin worsened pancreatic damage and death, while the subcutaneous injection of prostaglandin showed a better outcome.[92] Animal experiments evaluating the effect of indomethacin on hemodynamics showed that indomethacin might increase blood pressure in an animal model of acute hemorrhagic pancreatitis; the effect on cardiac output is controversial, but indomethacin might reduce pancreatic blood flow.[93],[94] Different results of animal experiments might be related to the different methodologies of the animal experiment.

A controlled double-blind trial conducted in 1985 evaluated indomethacin treatment in AP. The indomethacin group had a shorter time of pain and a lower opioid consumption, but no differences were found in serum amylase level, blood calcium level, and gastrointestinal bleeding.[95] Five clinical studies evaluated the use of indomethacin in preventing or treating AP after endoscopic retrograde cholangiopancreatography (ERCP); of these, two were randomized controlled trials (RCTs) and three were cohort studies (two of which were retrospective studies and one was prospective study). Among these, one RCT and two cohort studies (one prospective and one retrospective) showed that indomethacin might reduce the incidence and severity of pancreatitis after ERCP (PEP).[58],[59],[60] However, one RCT and one retrospective cohort study showed that indomethacin might not reduce the incidence of PEP.[96],[97]

Diclofenac

Diclofenac is another NSAID used for treating pain in AP. Two studies evaluated the analgesic effect of diclofenac in AP. The results showed that diclofenac 1 mg/kg two times per day had a similar analgesic effect as tramadol 1 mg/kg two times per day, while diclofenac 75 mg three times per day had a weaker analgesic effect than pentazocine 30 mg three times per day.[55],[98] Besides its analgesic effects, diclofenac may also prevent and treat AP and related complications. Two AP animal model studies suggested that diclofenac might reduce pancreatic injury, pulmonary edema, and damage to tissues besides the pancreas when combined with other drugs.[99],[100],[101]

Two RCTs suggested that diclofenac reduced the incidence of PEP. The European Society of Gastrointestinal Endoscopy suggested rectal administration of diclofenac or indomethacin before ERCP to prevent PEP.[61],[62],[63] However, a recently published RCT suggested that diclofenac might not lower the incidence and severity of PEP in patients with primary biliary cirrhosis. This might be related to the higher incidence of PEP associated with the special disease state in this patient group.[98]

Other nonsteroidal anti-inflammatory drugs

Two animal studies assessed the role of aspirin in preventing and treating AP. The results suggested that aspirin pretreatment might prevent and/or improve cerulein-induced AP, aspirin prevented the necrosis of the acinar cells of the mouse SAP model, and no gastrointestinal side effects were observed.[102],[103] However, no clinical studies evaluated the analgesic effect of aspirin in patients with AP, especially those with SAP.

Animal studies suggested that celecoxib might reduce the serum IL-6 levels and the injury to the pancreas, lung, and kidney of rats with acute necrotizing pancreatitis. However, case–control studies suggested that the use of celecoxib was associated with an increased risk of AP.[104],[105],[106] The use of parecoxib was also evaluated in treating AP. The results suggest that the early use of parecoxib might improve the incidence of complications of moderate AP. However, parecoxib did not relieve pain in patients with AP.[107]

Acetaminophen

Acetaminophen is a commonly used analgesic suggested as an adjuvant to opioids by the guidelines because research suggests that acetaminophen may reduce the consumption of opioids in patients after cardiac and abdominal surgery.[86],[108],[109] To date, no clinical research has evaluated the role of acetaminophen in SAP. However, the potential side effects such as hypotension caused by acetaminophen may worsen shock and MODS in patients with SAP.[85],[110] Moreover, acetaminophen may be associated with the onset of AP. Several case reports of acetaminophen-induced AP exist.[111] A population-based retrospective cohort study suggested that, compared with patients without acetaminophen poisoning, the risk of AP in patients with acetaminophen poisoning increased by 2.4 times.[64] Therefore, the efficacy and safety of acetaminophen for analgesia in patients with SAP require further research.

Ketamine

Ketamine is an N-methyl-D-aspartate (NMDA) receptor inhibitor, which contains two optical isomers (S-ketamine and R-ketamine), with anesthetic, analgesic, antidepressant, and anti-inflammatory activities. It has been used for general anesthesia, but its use has gradually decreased due to side effects such as dissociative anesthesia, hallucinations, and potential drug abuse. A much lower dose of ketamine may be sufficient for analgesia (plasma concentration: 70–160 ng/mL vs. 1200–2400 ng/mL).[112] The side effects of ketamine are usually dose-dependent and temporary; a low dose of ketamine has little impact on the incidence of psychotomimetic effects and cognitive impairment.[113],[114],[115] Several results suggested that low-dose ketamine, as an adjuvant to opioids, might reduce opioid consumption and improve outcomes.[115],[116] Nevertheless, a randomized, controlled, double-blind study, including 162 mechanically ventilated patients in the ICU, demonstrated that the adjuvant low dose of ketamine to opioids did not reduce the consumption of opioids, but might lower the incidence of delirium.[117] A recent published systematic review and meta-analysis performed by Atm et al. included 3 RCTs and 12 observational studies involving 892 mechanically ventilated patients; it concluded that the adjuvant ketamine to opioids did not reduce the consumption of opioids. However, due to some limitations in terms of both quantity and methodological quality in the included studies, more high-quality studies are needed to verify the conclusion.[118] Based on the data from other critically ill populations and the animal experiment suggesting that NMDA receptors were associated with pancreatic pain, ketamine may serve as an appropriate option for analgesia in SAP. Future research should be conducted to evaluate the role of ketamine for analgesia in patients with SAP.

Other analgesics

Nefopam exerts analgesic effects by inhibiting the reuptake of dopamine, norepinephrine, and serotonin in the spine and supraspinal space but has no impact on hemodynamics, liver function, and gastrointestinal function. A clinical study evaluated the role of nefopam in patient-controlled analgesia in the ICU after cardiac surgery. The results suggested that nefopam might reduce opioid consumption and opioid-related adverse effects.[119] Although no clinical studies have evaluated the role of nefopam in pain management in SAP, it is considered a potential drug that can be used in this condition.

The PADIS guideline recommended that neuropathic pain medications (e.g., gabapentin, carbamazepine, and pregabalin) should be used as an adjunct to opioids for managing neuropathic pain in critically ill adults.[86] Neuropathic pain is involved in the onset of pain in SAP. An AP animal model experiment suggested that the intrathecal injection of gabapentin might enhance the analgesic effect of subtherapeutic doses of morphine.[120] However, to date, no clinical research has evaluated the role of neuropathic pain medication in SAP. Evidence to help speculate whether neuropathic pain medication can be used for pain management in SAP is insufficient.

Procaine intravenous infusion has been used to treat pain in AP. However, an RCT suggested that the intravenous infusion of procaine 2 g per day did not improve pain in AP compared with the intravenous infusion of placebo (normal saline).[65] In another RCT, patients with AP were divided into two groups; one group received a continuous intravenous infusion of procaine 2 g/day, while the other group received intravenous bolus of pentazocine 30 mg every 6. Pentazocine was used as a supplement when needed. Both the groups showed no difference in the consumption of pentazocine, while the procaine group had a higher pain score.[66] Although animal experiments suggested that the intra-arterial lidocaine infusion might reduce pancreatic damage in cerulein-induced AP, no clinical research evaluated the role of lidocaine in SAP.[67] A randomized, controlled, double-blind study in patients who needed to be admitted to the ICU after cardiac surgery showed that lidocaine had no impact on pain intensity, postoperative consumption of fentanyl and sedative, time to extubation, length of ICU stay, and hospital stay compared with placebo.[68] Considering the safety concerns of lidocaine intravenous infusion, the routine use of lidocaine as an adjuvant to opioids in ICU patients is not recommended. This general principle is also valid for patients with SAP. The aforementioned research results showed that the intravenous infusion of local anesthetics should not be used for the analgesic treatment of SAP.


  Epidural Analgesia and Other Analgesia Measures Top


Although analgesics (especially opioids) are the mainstay for pain management in AP and SAP, direct interruption of afferent nociceptive visceral stimulation is thought to be a more effective approach. Clinically, epidural analgesia and celiac plexus block are currently available analgesia measures.

Epidural analgesia was reported as early as 1950 for pain relief in AP. SAP and AP animal model studies showed that thoracic epidural analgesia might increase the perfusion of viscera and pancreas, improve the microcirculation of the pancreas, alleviate liver damage, and significantly reduce mortality.[121] However, the clinical applications of epidural analgesia in AP or SAP are limited.[122] A multicenter retrospective cohort study included 1300 patients with AP in 17 ICUs in France and Belgium. The propensity score matching analysis found that the risk of all-cause 30-day mortality in patients with AP who received epidural analgesia was significantly lower than that in matched patients who did not receive epidural analgesia (2% vs. 17%; P = 0.01).[123] A multicenter randomized controlled study is underway to evaluate the role of epidural analgesia in SAP.[124] EA is an invasive treatment, the implementation of EA in patients with SAP has potential risks, and patient and intervention timing are important. EA may be undertaken in some experienced centers with special concern on the potential risks and side effects.[125] Although epidural analgesia has shown advantages in terms of both pain relief and clinical outcomes in AP, some patients may have a poor response to epidural analgesia. For such patients, intermittent or continuous celiac plexus block may offer an effective alternative treatment for pain in SAP.[126] However, celiac plexus block is more commonly used for analgesia in chronic pancreatitis and pancreatic cancer rather than in AP. Furthermore, case reports of using the radiofrequency ablation of the splanchnic nerve to manage pain in acute and chronic pancreatitis exist.[127],[128] These sporadic case reports or case sequences showed that the radiofrequency ablation of splanchnic nerves achieved a good response in pain management in AP. However, given the requirements for special equipment and technology and potential risks, some barriers are encountered in clinical use.


  Management of Pain in Severe Acute Pancreatitis Top


Pain management in SAP includes pharmaceutical interventions (such as NSAIDs, opioids, and other auxiliary analgesics) and nonpharmaceutical interventions (such as epidural analgesia). Clinically, pain is typically managed with NSAIDs and intravenous opioids. This may result from the poor understanding of the complex pain mechanism in AP and SAP and the lack of enough high-quality clinical research in this specific population.

The treatment of pain should be initiated and titrated based on accurate pain assessment to achieve a balance between the benefits and the potential adverse effects of analgesics. It is definite that 0–10 numeric rating scale should be adopted for critically ill patients who are able to self-report pain, and the behavioral pain scale and critical care pain observation tool should be adopted for critically ill patients who are unable to self-report pain.[86]

Despite the lack of recommended proposal in pharmaceutical pain management in SAP, some generally accepted principles are available for reference. The World Health Organization (WHO) developed a useful algorithm on pain management, suggesting that pain should be treated according to the degrees of severity, which is termed as “analgesic ladder.” Although it has only been validated in cancer pain, it has also been extended to managing noncancerous pain. Due to the extensive potential side effects of opioids, the adjuvant use of multiple drugs to opioids (i.e., multimodal analgesia) is recommended to lower the consumption of opioids.[86] Based on the WHO analgesic ladder and the aforementioned evidence, we provide a practical analgesic ladder for pain management in SAP [Figure 2].
Figure 2: A practical analgesic ladder for pain management in severe acute pancreatitis

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The responses to noxious stimuli, pain mechanisms, and pharmacokinetics and pharmacodynamics of analgesics vary among individuals, which may be related to the heritability of nociception and polymorphisms of the endogenous opioid system.[129],[130] Therefore, “one model fit all” may have potential drawbacks. However, it is difficult to formulate precise analgesic treatment measures for specific patients due to the huge individual differences and current knowledge gaps. Thankfully, interdisciplinary collaborations such as pain counseling may help improve pain management in SAP.[131] It has been supposed that a new strategy based on the analysis of different underlying pain mechanisms, rather than the traditional strategy based on lesion topography and underlying pathology, may achieve a better treatment outcome in neuropathic pain.[132],[133],[134] Mechanism-based therapy assumes that a specific symptom predicts a specific underlying mechanism, while clinical experimental studies indicate that a specific symptom may be generated by several entirely different underlying pathophysiological mechanisms. Therefore, a specific symptom profile rather than a single symptom may be required to predict the underlying mechanism. In 2002, Germany established the Neuropathic Pain Research Network; a standardized quantitative somatosensory phenotype protocol was introduced to establish a link between clinical manifestations and underlying mechanisms. An optimal comprehensive treatment and individual drug combination that target based on a specific mechanism may be formed using this information.[135] It is reasonable to hypothesize that this method may be used in pharmaceutical pain management in AP and SAP in the future.


  Conclusion and Future Directions Top


Unlike other studies, this study reviewed the current pain management in SAP by combining the pain mechanisms with animal or clinical studies. We also proposed an analgesia ladder based on current evidence. Overall, although pain management is the mainstay of SAP treatment, our understanding of pancreatic pain in AP is limited and the research on pain management in patients with SAP is severely under-researched. Future research should focus on gaining insight into and differentiating the pain mechanisms in AP, besides developing new drugs targeting these mechanisms. Meanwhile, evaluating the impact of the currently available drugs and different management strategies of pain on the outcomes of patients with SAP may fill gaps in current knowledge and improve the outcomes of this specific population. This may lead to precise analgesia treatments and improved outcomes for patients with SAP in the future.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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  In this article
Abstract
Introduction
Role of Pain in ...
Pancreatic Pain ...
Sensory Mechanis...
Neuropathic Pain...
Analgesics for S...
Opioids
Nonopioids
Epidural Analges...
Management of Pa...
Conclusion and F...
References
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