main topic Wien Med Wochenschr (2014) 164:63–72 DOI 10.1007/s10354-014-0265-1

Pancreatic pain Hana Nechutova · Petr Dite · Marketa Hermanova · Ivo Novotny · Arnost Martinek · Pavel Klvana · Bohumil Kianicka · Miroslav Soucek

Received: 4 September 2013 / Accepted: 27 January 2014 / Published online: 12 March 2014 © Springer-Verlag Wien 2014

Summary  Pain is a common symptom of many diseases. Recently, the pain has been classified and analyzed exactly. Its particular components/types are described to the maximum of their depths and details. That is why each particular pain present in a specific disease (pancreatopathies included) has to be treated according to the presence of the specific type of pain. In diseases of pancreas, there are nociceptive, neuropathic, and inflammatory components of pain participating, frequently.

The first and second named authors participated in this article equally; therefore, either of them represents the first author. H. Nechutova, MD, PhD () · Prof. P. Dite, MD, DSc · B. Kianicka, MD, PhD · Prof. M. Soucek, MD, DSc Second Department of Internal Medicine, St. Anne’s University Hospital Brno, Brno, Czech Republic e-mail: [email protected] Prof. M. Soucek, MD, DSc e-mail: [email protected] H. Nechutova, MD, PhD · Prof. M. Soucek, MD, DSc International Clinical Research Center, St. Anne’s University Hospital Brno, Brno, Czech Republic Prof. M. Hermanova, MD, PhD First Department of Pathological Anatomy, Medical Faculty of Masaryk University and St. Anne’s University Hospital Brno, Brno, Czech Republic I. Novotny, MD, CSc Department of Gastroenterology, Masaryk Memorial Cancer Institute Brno, Brno, Czech Republic Prof. P. Dite, MD, DSc · Ass. Prof. A. Martinek, CSc · P. Klvana, MD Medical Faculty Ostrava, Department of Internal Medicine, University Hospital Ostrava and Academic Center of Gastrooncology, Ostrava, Czech Republic

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Especially long-lasting, not well-controlled pain sets off the process of neuromodulation. The recent pioneering applications/administrations of various neuromodulatory therapeutic approaches represent the promising discoveries for the treatment of long-term, severe, drugresistant pain syndromes, including chronic pancreatitis. In this article, we summarized the characteristics of pain, the therapeutic strategy, and algorithms of analgesic treatment (in general and applied for pancreatopathies), including new therapeutic trends and approaches. Keywords  Pain  · Nociceptive  · Neuropathic and inflammatory pain · Sensitization · Neuroplastic changes · Neuromodulation · Pain in pancreatopathies · Stratification of analgesic treatment

Schmerz bei Pankreaserkrankungen Zusammenfassung  Schmerz ist ein unspezifisches Symptom vieler Erkrankungen. Schmerz kann in seinen Qualitäten und Ursachen näher untersucht und klassifiziert werden. Die spezifischen Schmerzursachen und Schmerzkomponenten können mittlerweile detailliert erfasst werden. Auf Grund dessen muss jede Art von Schmerz bei einer Erkrankung, so auch bei Erkrankungen des Pankreas, spezifisch nach dem jeweiligen Schmerztyp behandelt werden. Bei Pankreaserkrankungen liegen regelmäßig nozizeptive, neuropathische und inflammatorische Schmerzkomponenten vor und spielen zusammen als Schmerzursachen eine Rolle. Langanhaltende und schlecht kontrollierte Schmerzzustände führen zu einer Neuromodulation. Rezente Neuerungen bei der Applikation und im Einsatz von verschiedenen neuromodulatorischen Schmerzmedikamenten stellen neue Therapieansätze dar, die die Hoffnung geben, auch bei schweren, lang anhaltenden und mit konventioneller Schmerztherapie schlecht kontrollierbaren Schmerz-

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syndromen Erfolge zu erzielen, so auch bei der chronischen Pankreatitis. Im vorliegenden Artikel werden die Schmerzkomponenten, die Therapiestrategien sowie die Algorithmen der Schmerztherapie im allgemeinen und speziell für Pankreaserkrankungen dargestellt. Dies beinhaltet auch neue therapeutische Ansätze und Entwicklungen. Schlüsselwörter  Schmerz  · Noziceptive  · Neuropathische  · Inflammatorische Schmerzkomponente  · Schmerzempfindung  · Neuroplastische Veränderungen  · Neuromodulation  · Schmerz bei Pankreaserkrankungen · Stratifikation der Schmerztherapie

Definition of pain Pain is a symptom present in many diseases. It is the most common reason of searching for medical help. Every sixth patient visiting the primary care physician comes because of an acute pain [1], more than half of the patients treated in emergency departments come due to a pain [2], and every third patient visiting a family practice comes due to pain troubles [3]. The data related to the epidemiological counts of a chronic pain vary from country to country (ranging from 12 to 80 %) [4]; in the US population, it represents approximately one-third [5]. According to the International Association for the Study of Pain (IASP) definition, pain is “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” [6]. The presence of a pain in patient’s life influences his or her overall quality of life [7], and in many, its social and economic aspects [8]. Pain is a complex process, serving as the source of the afferent information carried to be processed in the structures of the central nervous system (CNS). As a result of such processing, it also provides the impulses for the actions carried centrifugally by efferent pathways. This simple “action–reaction” loop describes a pain not only as “a signaling body device” (noticing that something somewhere in an organism is not happening well and informing about it to the appropriate nervous system centers) but also as an important active source of patient’s complex response to a painful insult. It means that pain influences patient’s pattern of behavior, through which it could contribute to the removal of the source of the pain (fight or flight reaction) or to modulation of behavior. Pain is responsible for the change in immune responses to an initial nociceptive stimulus, and it modulates inflammation processes, both of them at a systemic and local level. The immune system is responsible for the socalled salutogenic response, which leads to an enhancing of a healing process of particular organ [9]. However, the story, which describes the effect of pain acting on an organism, is not complete yet. Especially long-lasting, not well-controlled pain sets off the process of neuromodulation. Its morphological and functional

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background is represented by peripheral sensitization and neuroplastic changes of the peripheral nervous system and the CNS. The outcomes of such neural transformations are diverse, but the crucial consequence is that the pain is “fixed” within the nervous system. So the existence of pain becomes independent of the presence of peripheral nociceptive stimuli or an inflammation (which perpetuates and enhances the nociceptive stimuli) within an affected organ. It was demonstrated in patients suffering from drug-resistant painful chronic pancreatitis (CP): after total pancreatectomy, in 30 % of cases, pain persisted, unchanged [9]. The importance of pain is recognized also for the future state of an affected organ/whole organism, especially if it acts in neonatal period. The visceral pain (especially not sufficiently managed) present in neonatal period leads to neuromodulatory and neuroplastic changes of the CNS. Besides increased morbidity, mortality, and hyper- or hypo-algesia, there is a negative impact on development. Neuromodulatory changes are responsible for consequent altered functional competency of affected organs in postnatal period [10].

Classification of pain The IASP classified pain according to the specific characteristics: region of the body involved (Fig. 1), system whose dysfunction may be causing the pain, duration and pattern of occurrence, intensity and time since onset, and etiology [11]. For the practical purposes, we distinguish an acute from a chronic (non-malignant/benign and cancer-

Fig. 1  Major sites of pain in 311 patients with painful chronic pancreatitis (according to P. Lankisch).

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related) pain [12]. Another point of view is to define its physical/nociceptive component, the affective or mood component, and the functional component [13].

Pain in pancreatic diseases Almost all patients suffering from pancreatic cancer and CP experience the pain (72–85 % of pancreatic cancer patients [14] and up to 80 % [10] or approximately 95 % [9] of patients with CP). In acute pancreatitis, there is pain radiating through to the patient’s back in approximately 50 % of patients [15].

Etiology of pain in pancreatic diseases In pancreatic diseases, the origin of pain could be divided into three evident etiopathological cascades, which could influence each other, in the end:

Nociceptive pain This is caused by nociceptive stimuli, acting on nociceptors within the pancreas. Due to mechanical activity (e.g., abdominal trauma or injury caused by external source, increased intraductal pressure in an obstructed part of a particular pancreatic duct) or chemical action (e.g., alcohol and other causes of acute pancreatitis) [13], there is a destruction of acinar cells and release of the digestive enzymes (trypsin, chymotrypsin, elastase) into the surroundings [9]. The acinar neighborhood gets inflamed, with increased levels of mediators such as K+ , H+ , ATP [10], histamine, substance P, bradykinin, prostaglandins [9] (thus, medications that inhibit prostaglandins or attenuate inflammatory responses may reduce pain [13]), and norepinephrine (due to ischemia, which may be associated with increased H+ levels and accompanied by increased sympathetic tone) [13]. In the presence of neoplasia, the cells in its vicinity are stimulated to release the mediators (protons, Endothelin 1 (ET-1), tumor necrosis factor (TNF)-α, nerve growth factor (NGF), trypsin, and opioids) [16]. Due to the presence of such substances in their surrounding microenvironment, the nociceptors (the primary sensory neurons) are stimulated through their surface receptors and channels (Transient receptor potential cation channel, subfamily V, member 1 (TRPV1), Transient Receptor Potential Cation Channel, Subfamily A, Member 1 (TRPA1), and Transient receptor potential cation channel, subfamily V, member 4 (TRPV4) [10]) and might modulate their firing thresholds (the so-called sensitization, see “Neuropathic pain” section later in the text). Under normal circumstances, every particular receptor is sensitive to the specific stimulus; e.g., TRPV1 responds to noxious heat, vanilloid compounds (e.g., capsaicin and lipids), and protons [10]. This is an example of the principle—how the electrical threshold originates (transduction) and is conducted along the

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nociceptor axons (finely myelinated A or unmyelinated delta or C fibers) to the cell bodies in dorsal root ganglion (DRG) and then into their central terminals located in the dorsal horn. Visceral pain is carried from the periphery by afferent sympathetic fibers (contained in mixed afferent/efferent sympathetic nerves) to the dorsal horn [13] and by the vagus nerve (which also carries both afferent and efferent signals from/toward the pancreas) [10]. At the dorsal horn, nociceptive fibers synapse with secondary neurons (using neurotransmitters, e.g., neuropeptide substance P), which cross to the contralateral anterior and anterolateral spinothalamic tract and travel to relay centers in the thalamus and midbrain [13]. Then it passes into somatosensory cortical zones, basal ganglia, and limbic system structures. The named areas of the CNS generate the impulses carried along the efferent neural pathways to the peripheral structures (including pancreatic tissues and vessels) and cells (belonging to the immune system), which perform the specific components (inflammatory, immune, and behavior) of the overall response to the nociceptive insult. Visceral pain is often vague, poorly localized, and sometimes referred to the body wall at the same level of innervation (under normal circumstances, the somatosensory and viscerosensory information carried along peripheral nerves does not allow any cross-stimulation). The recognized sensations are aching, burning, and cramping.

Neuropathic pain This is caused by damage of nerve endings within the pancreas, and also as the result of consequent neuroplastic changes in the peripheral nervous system and the CNS, especially when the pain acts over a long period. There are three categories of neuropathic pain [13]: ●● Systemic neuropathy: It is caused by systemic problems that injure nerves (diabetes, alcoholism, vitamin B12 deficiency, or pesticide exposure). Mechanisms of injury may be diverse (e.g., ischemia, toxic nerve injury, micronutrient deprivation, or inflammation) and may involve nociceptors, peripheral nerves, or more central pathways. The pain manifests as aching or burning; it is peripheral and symmetrical. ●● Neuritis/neuroma: After an injury (physical, such as cutting, stretching, contusion of a nerve; or viral inflammation, e.g., due to herpes zoster), most nerves regenerate without complication. However, sometimes (and it is not rare experience), in the course of recovery, the patient experiences painful paresthesias and dysesthesias. These usually resolve with complete regeneration of the nerve. It presents itself as burning and aching and includes extreme sensitivity to touch in the affected area. ●● Deafferentation/phantom pain: Deafferentation is generated in the CNS (at the level of secondary or tertiary neurons—spinal and thalamic levels), after the

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loss of afferent sensory information. The mechanism is not completely understood, but sensitization and neuroplastic changes are probably parts of those actions. When the noxious input is long term/repetitive, it causes peripheral and central changes (sensitization = increase in membrane excitability and synaptic efficacy as well as reduction in inhibition, and neuroplasticity = remarkable morphological and functional changes in the function of neurons and circuits integrated in nociceptive pathways) [17]. The neural remodeling occurs at the level of peripheral nerves, dorsal horns, dorsal columns, and substantia gelatinosa Rolandi of the spinal cord; at the brain stem level—reticular formation (nucleus Raphe magnus); and in the medial thalamus, the limbic system, and somatosensory areas of the neocortex. In viscerosensory processing of acute pain, the structures of the insula, the anterior cingulate cortex, the thalamus, and the basal ganglia are involved. In chronic pain, the prefrontal cortical regions, the basal ganglia, and the amygdala are subsumed. Moreover (and as in nociceptive pain), these zones modulate (through efferent pathways) the autonomic, immune, and inflammatory responses and behaviors (facilitation, protective behaviors, fight or flight reaction, inhibition, analgesia in time of danger, that pain does not compromise function) [18]. The specific type of neuromodulation-induced efferently acting response is the sympathetically maintained pain. Its role is to help and support the healing of an injury (including protection, e.g., against exsanguination). The prototype of this pain is the so-called reflex sympathetic dystrophy. Clinically, these processes of sympathetically maintained pain should be suspected when – in the course of time – the pain (aching or burning) increases rather than decreases; also alterations of surface blood flow, temperature, or skin color are noted; and hypersensitivity to touch is present [13]. Another kind of modulation of pain transmission occurs peripherally (there are afferent non-nociceptive sensory signals such as pressure or touch that may compete for transmission with pain signals) and centrally (serotonergic, noradrenergic, and opioid systems of locus ceruleus and the periaqueductal gray matter; they exert inhibitory influences at the dorsal horn via descending spinal fibers) [13]. Recently, it has been proved that central sensitization contributes to many clinical pain conditions, such as rheumatoid arthritis, osteoarthritis, temporomandibular disorders, fibromyalgia, miscellaneous musculoskeletal disorders, headache, neuropathic pain, complex regional pain syndrome, postsurgical pain, and visceral pain hypersensitivity syndromes in general [18].

Inflammatory pain This is caused by ongoing inflammatory and immune reactions within pancreatic tissues. An injury (induced

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by mechanic, chemical, microbial stimuli) leads to the release of intracellular zymogens from acinar cells, cytokines in the surroundings, local inflammation including inflammatory changes of nociceptors’ nerve endings, and damage of their Schwann sheaths (enabling more aggressive spread of pancreatic cancer along the nerves). Sensitization of nociceptors and plastic changes in sensory neurons (by activating pro-algesic receptors and channels, e.g., tyrosine kinase A and transient receptor potential vanilloid 1 receptor), induced by NGF (released from mast cells), lead to perpetuating pain and chronic inflammation (which is potentiated by efferently carried stimuli from the vagal nerve) [9]. In contrast, inflammation has its proreparative potential, naturally.

General strategy of analgesic therapy Despite all therapeutic approaches in analgesic treatment, the pain is not well controlled. There are many reasons for it, including still existing fears of opioid application. The analgesic therapeutic strategies should be based on presenting causes and types of pain participating in particular diseases. Analgesic therapy consists of the following [13]: 1. Physical treatment (use of therapeutic heat and/or cold treatments, most commonly applied stimulation analgesia—transcutaneous electrical nerve stimulation (TENS), manual treatments—massage etc., the use of orthotic devices—splints and braces) 2. Psychological interventions (introduction of the relaxation response, cognitive restructuring and behavioral interventions, psychotherapy, and treatment of anxiety and depression) 3. Anesthesia block procedures (recent wide use of various epidural infusions (in acute pancreatitis too), regional nerve blocks, etc.) 4. Systemic medications (to directly reduce pain or to manage distressing sequelae and perpetuating factors, e.g., sleep disturbance, anxiety, or depression). Combining adjuvants and analgesics reduces acute pain, enhances diffuse noxious inhibitory control, and reduces central sensitization. Non-steroid antiinflammatory drugs (NSAIDs) are effective analgesics for neuropathic pain. Antidepressants that block norepinephrine uptake are likely to be more effective adjuvant analgesics than those that inhibit serotonin reuptake. Single-dose dexamethasone and gabapentin improve postoperative pain. Dexamethasone may be particularly effective for incident pain after joint replacement. Intrathecal betamethasone reduces lower hemibody pain from cancer. Combinations of tricyclic antidepressants and gabapentin and gabapentinoids plus opioids improve analgesia at lower doses than single analgesics and to a better extent. It is better to add a second drug to moderate doses of an opioid, gabapentin, or tricyclic antidepressants rather than titrate to high and perhaps toxic doses. Flares of

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pain with spinal analgesia unresponsive to intravenous morphine may better respond to sublingual ketamine or spinal levobupivacaine [19]. 5. Non-destructive minimally invasive techniques—to treat refractory pain (electronic stimulations—trying to intervene in the areas of neuroplastic processes and neuromodulation of the CNS, pulsed radiofrequency, and Botox). They do not involve the risk of phenol and alcohol injections or tissue destruction [19].

Certain mediators (protons, ET-1, TNF-α, NGF, trypsin, and opioids) can activate receptors both on the cancer cell (ETBR) and the primary afferent nociceptors (ETAR) and modulate nociception [16]. Cannabinoid receptor (CBr) agonists (reduce cancerinduced nociception) and antagonists act peripherally in the cancer microenvironment (CBr1—on the primary afferent nociceptive free nerve endings, and CBr2—on the carcinoma cells) [16].

Therapeutic approaches in treatment of pancreatic diseases pain

Treatment of pancreatic cancer pain

As it was explained before, the therapeutic strategy has to be based on the type of participating pain (nociceptive, neuropathic, inflammatory) in a particular pancreatic disease. We will focus on the diseases with a pattern of longer-lasting pancreatopathy—pancreatic cancer and CP.

Pancreatic cancer A total of 72–85 % of patients with pancreatic cancer experience the pain, so the prevalence is one of the highest among neoplasms [14]. In general, the pain in cancer is compound. It could have visceral (direct damage of the organ by cancer) and somatic components (e.g., due to metastases within the bones) [20]. According to primarily affected structure, the cancer pain is nociceptive (pressure on, or chemical stimulation of, nociceptors, due to cancer) or neuropathic (caused by damage of nerve fibers themselves). Between 40 and 80 % of patients with cancer pain experience neuropathic pain [14]. The infection of a tumor or its surrounding tissue or the applied treatment (immunotherapy, radiotherapy, chemotherapy, targeted therapies such as rituximab or angiogenesis inhibitors) causes the pain too [14]. The overall local aggressiveness of cancer and its significant impact on generation of pain is due to the following particularities [21]: ●● Cancer cells: crush or infiltrate the tissues around, release the chemicals, e.g., kallikrein (it increases nociceptive mediators, e.g., bradykinin and tryptase, into the cancer microenvironment that makes nociceptors responsive to stimuli that are normally nonpainful—allodynia) [14] ●● Stroma cells and inflammation cells: the mast cells release tryptase and NGF through their stimulation by the cancer [16]. ●● Neural cells: produce neurotrophic factor and autonomic neurotransmitter signaling, which can be proliferative, pro-angiogenetic, and pro-invasive; they release chemoattractive agents and serve as a protective shelter path of tumor dissemination [21].

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Treatment of pancreatic cancer pain uses/applies the general principles and recent options of cancer treatment. It means the application of particular topical and systemic opioids (relatively new is the ultrafast-acting fentanyl effervescent buccal tablets, for breakthrough pain) through the so-called opioid rotation, gene therapy (e.g., genetically engineered viruses, expressing specific neurotrophins; genes, encoding endogenous opioids can be transferred to DRG after inoculation in the related dermatome, thus ensuring continuous release of inhibitory neurotransmitters; proenkephalin-coded genetically modified herpes simplex viruses recently used in rodent models; and vector-mediated enkephalin expression as additives to morphine), TENS therapy for bony metastasis, antidepressants (their use in cancer pain is on the rise; they act on neuropathic pain, but their cost, side effects, and drug interactions are the limitations), and radiotherapy [22]. Neuro-ablation (the physical interruption of pain pathways either surgically, chemically, or thermally, e.g., celiac plexus block—successful pain relief occurs in 85 % of patients with pancreatic cancer [22]; endoscopic ultrasound-guided celiac plexus neurolysis—pain relief in 94 % of unresectable pancreatic carcinoma [22]; superior hypogastric plexus block; ganglion impar block; and presacral neurolytic block for pain relief from pelvic cancer) provides better pain relief when used in early stages of cancer. Percutaneous vertebroplasty is an effective palliative procedure and can be combined with radiotherapy and chemotherapy. Percutaneous cervical cordotomy is intended for terminally ill patients in whom every other modality has been tried already [22]. Neuromodulation is the therapeutic approach recently on the rise. Through stimulation (current) or the administration of drugs (particular transmitters, opioids), intraspinally or intraventricularly, into particular spinal cord and brain structures, it is possible to influence the pain transduction and especially the neuroplastic changes within CNS structures, as the results of long-term effecting pain stimuli (further see “Neuromodulatory approaches in CP pain treatment” section).

Chronic pancreatitis In central Europe, the incidence of CP varies between 6 and 10 of newly diagnosed patients in 100,000 inhabitants

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per year [23, 24]. Approximately 80–95 % of patients experience the pain (the so-called painful disease) [9, 10, 25, 26]. In general, we distinguish two patterns of pain manifestation in CP [9]: ●● Type A—characterized by short episodes of pancreatitis (less than 10 days) separated by long pain-free intervals. ●● Type B—characterized by prolonged periods of intermittent severe pain (more than 1–2 months) and associated with local complications. Mostly, the pain is long term, and occasionally it has the pattern of colic incidence, from mild to severe intensity. So the type B pain pattern predominates, and it might lead to the amplification of brain plastic changes [9]. In CP, the pain is of mixed type, predominantly neuropathic. There are three recently known mechanisms participating in pain for particular CP cases [27] (for further details, see “Etiology of pain in pancreatic diseases” section). Some specificities should be addressed: 1. Nociceptive (peripheral)—direct stimulation of nociceptors within pancreatic tissues: the cause of the acting mechanic force could be located directly within the pancreas—the intrapancreatic reasons (the strictures of the main pancreatic ducts, the stone within the ducts, and the focal/neoplastic glandular processes, including cystoma pressing the duct). Alternatively, the pressure could be induced from the outside—the extrapancreatic reasons (ascites, duodenal stenosis, and bile duct obstruction). The mechanic nociceptive stimuli are caused by the increase in pressure in the main pancreatic ducts and their secondary branches. This induces ischemia. 2. Neuropathic: primarily due to damage of peripheral nerve structures. It is followed by peripheral and central neuromodulation processes.The injury of intrapancreatic nerves causes the damage of their neural coverings (myelin sheaths), enabling the spread of pathological processes along the nerves. The sustained sensitization of damaged pancreatic peripheral nociceptors occurs (by neurotransmitters and neurotrophic factors). This peripheral intrapancreatic neuropathy leads to an increased expression of various surface receptors, e.g., for NGF (neurotrophin family) and other intrapancreatic neuroplastic alterations. It means profound switch in the autonomic innervation of the human pancreas, via “neural remodeling.” These changes induce a hyperexcitability of spinal sensory second-order neurons, so the modulation from the brainstem (via descending facilitation) occurs. Viscerosensory cortical areas react to this too = central sensitization/central neuroplasticity. It means that long-term fixed conseuences take their places [9, 27]. The expression of nestin within nerve fibers in CP and pancreatic ductal adenocarcinoma reflects the pro-

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Fig. 2  Nestin expression in nerve fibers of sporadic chronic pancreatitis tissues (immunohistochemistry; original magnification, 100 ×). (M. Hermanova)

Fig. 3  Nestin expression in nerve fibers, with displayed perineural invasion of the structures of nestin-positive pancreatic ductal adenocarcinoma (immunohistochemistry; original magnification, 200 ×). (M. Hermanova)

cess of neural remodeling responsible for pancreatic neuropathy [28, 29] (Fig. 2, 3). 3. Inflammatory.

Treatment of pain in chronic pancreatitis There are four therapeutic options: 1. dietotherapy, 2. medicamentous/pharmacological treatment, 3. endoscopic approach, and 4. surgical treatment. As the first step of CP pain treatment, it is necessary to evaluate (using endoscopic ultrasound and functional test assessing the exocrine pancreatic functions) the sub-

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type of such illness, from the point of view whether we are dealing with big/main duct disease or small duct/minimal change disease. Main duct disease (major pancreatic duct with luminal diameter 5 mm and more, within pancreatic body) is indicated for the surgical and endoscopic procedures in the first place. Small duct disease is the candidate for the pharmacological intervention [25]. The second step in managing pain is to search for a disease state and disease complications, such as pancreatic cancer in CP, duodenal obstruction, and presence of cystoids [30]. 1. Dietotherapy: In general (and from the long-term point of view), the treatment of CP always starts with the dietary recommendations and restrictions in eating habits, which have to always come as first. It means total prohibition of alcohol, food divided and served in several smaller portions in the course of the day, and the restriction of the animal fat in food. Particularly the abstinence from alcohol has positive impact on the incidence of pancreatic pain relapses [31]. Although presently there is no proof of the effect of cigarette smoking on pancreatic pain, it is recommended not to smoke. Cigarette smoking is considered as an independent etiologic factor for the development of pancreatic fibrosis; thus, it represents the risk for the development of CP. 2. Medicamentous/pharmacological treatment: The medicamentous analgetic treatment is an essential therapeutic step in patients suffering from painful form of CP (Fig. 4). Nowadays, the following drugs are advised to be used in treatment of CP pain: acetaminophen/paracetamol, NSAIDs, opioids, opiates, antidepressants, gabapentin, pregabalin, antioxidants, and pancreatic enzymes. In 1998, the German Society of Gastroenterology has recommended paracetamol as the first-choice treatment because of its good analgetic effect with minimum potential side effects. However, there is a limitation of

Fig. 4  World Health Organization analgesic ladder for cancer pain adapted for pain management in chronic pancreatitis. COX cyclo-oxygenase, NSAIDs non-steroidal anti-inflammatory drugs.

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the analgetic effect of this drug, as the pain in CP has an inflammatory origin and hence an inflammatory component [32]. Tramadol is an effective, frequently recommended drug with a good analgetic effect and a lower frequency of side effects, in comparison with other narcotics [33]. This therapy is effectively extended when selective serotonin reuptake inhibitors, tricyclic antidepressants, norepinephrine reuptake inhibitors, and other receptor inhibitors such as pregabalin and gabapentin are administered, especially for neuropathic pain treatment [19, 34,  35]. Based on the fact that oxidative stress is present in etiopathological processes of CP, there have been many clinical studies with efforts to prove that the integration of antioxidants into the treatment of CP is useful. The use of selenium, methionine, vitamins E and C, and beta-carotene demonstrated also pain attenuation effect of the aforementioned antioxidants in patients with CP [36, 37]. Analgetic effect of perorally administered pancreatic enzymes, mainly with high content of proteases, is a topic full of conflict [38, 39]. The older articles proved the analgetic effect only of the non-enteric-coated pancreatic enzymes due to the blockage of pancreatic secretion, thus decreasing the pressure within the pancreatic duct [40, 41]. More recent studies—testing enteric-coated pancreatic enzymes—did not prove such effect [42], although in 2003, the study by Walkowiak et al. [43] demonstrated the blockage of exocrine pancreatic function by administration of enteric-coated enzymes capsules. The meta-analysis from 2008 did not prove the analgetic effect of pancreatic enzymes. The American Gastroenterological Association (AGA) standards for the treatment of pancreatic pain still state the administration of pancreatic enzymes (together with drugs blocking gastric acid secretion) as one of the possible alternatives in managing pain in small duct disease and in women [30]. NSAIDs have good analgetic effect, and their limitations include side effects such as gastrointestinal symptoms. According to the ESGE guidelines, the endoscopic therapy is recommended as the first-line therapy for painful, uncomplicated CP [44]. The clinical response should be evaluated at 6–8 weeks after the procedure. If the results are not satisfying, the surgical approaches should be considered [45]. The long-term outcomes of endoscopic treatment in CP were evaluated in six studies. The follow-up interval was 44–173 months, and endoscopic therapy was recognized as successful in approximately 60 % of patients with painful CP [46, 47]. In contrast, two randomized control studies have shown better pain control after surgery (in comparison with endoscopic treatment). The first study [48] demonstrated the absence of pain in 15 % of the patients who have undergone endoscopic versus 34 % of those who have undergone surgical approach, after 5 years of follow-up. The study compared the patients with painful

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CP, where extracorporeal shock wave lithotripsy (ESWL) was not used. The second study (included patients with advanced CP) also demonstrated better results in patients treated surgically [49]. However, in this study, the time period during which the stent was inserted was relatively short (the stent was removed as the stricture disappeared on the pancreatogram). 3. Endoscopic approach: According to the European Society of Gastrointestinal Endoscopy (ESGE) guidelines for the therapeutic approach of painful uncomplicated CP (in patients with moderate or marked ductal changes assessed according to the Cambridge classification), the endoscopic treatment is the first-line therapy. For the patients with chronic uncomplicated pancreatitis with presence of radiopaque stones more than 5 mm in diameter (obstructing particularly main pancreatic duct), the ESWL is the first therapeutic step. ESWL alone should be preferred over ESWL combined with Endoscopic Retrograde Cholangiopancreatography (ERCP). The intraductal lithotripsy should be attempted only after the failure of applied ESWL procedure. The ESGE guidelines recommend inserting 10F plastic stent as the first-line treatment for main pancreatic duct stricture. The stent exchange should be performed within 1 year, even in asymptomatic patients. If the ductal stricture persists for more than 12 months, the simultaneous placement of multiple pancreatic intraductal stents is recommended. Pancreatic stenting accounts for 6–39 % of the morbidity (stent migration, stent occlusion). Fully covered self-expanding pancreatic stent is a safe therapeutic approach, with efficacy up to 1 year [44]. The endoscopic therapy is an effective procedure in the drainage of pancreatic pseudocysts. In the small pseudocysts that communicate with pancreatic duct, the transpapillary drainage should be performed. The transmural drainage is indicated in the absence of luminal bulging, and endoscopic ultrasound guidance is important. Endoscopic drainage accounts for an approximately 13 % morbidity, and the mortality is low (0.3 %) [44]. In patients with CP-related biliary stricture, the ESGE recommends the placement of multiple plastic biliary stents, for an interval of 1 year. Pancreatic calcification [50] occurs after the long-term failure of single biliary stenting. The dysfunction rate of using multiple plastic stents is 8–69 %. 4. Surgical treatment: An optimal surgical intervention should manage mainly the pain symptoms. Duodenumpreserving resection of the pancreas combines high safety with high therapeutic efficacy and offers the best short-term outcome. Still, the problem of the optimal timing for the intervention is challenging. At present, simple drainage procedure, resection, or a combination of both is applied [45].

Neuromodulatory approaches in chronic pancreatitis pain treatment As  we already mentioned, the proved presence of multileveled neuroplastic changes of the peripheral and the CNS plays a crucial role in CP pain, not only as the unwanted result of sustained pain stimulation (which becomes fixed and also independent of pancreatic insult, with autonomous pattern of behavior) but also as a desirable, healing promoting trigger [9]. Nevertheless, the therapeutic  interventions target the areas of proved neuromodulatory changes to reduce the pain sensations. Clinically, several studies have shown that the cortical activity modulation by Repetitive transcranial magnetic stimulation (rTMS) (low-frequency rTMS suppresses the activity of the targeted brain region, and high-frequency rTMS tends to promote a facilitation of the targeted area) can be successfully used in the treatment of neuropsychiatric disorders, as well as the treatment of chronic pain. Chronic electrical epidural stimulation of the precentral cortex can improve drug-resistant neurogenic pain, probably due to inhibition of nociceptive neurons at cortical levels through non-noxious fibers from the motor cortex or a secondary modulation of thalamic nuclei. In a 2011 study, a 36-year-old woman with intractable abdominal pain for 5 years (from chronic benign pancreatitis) was reported to have undergone a successful neuromodulatory treatment of the splanchnic nerves (two permanently implanted octopolar leads at the T11/T12 area connected to an implantable pulse generator) [7]. Another non-invasive neuromodulatory method is the transcranial current stimulation: very low-level current is passed between an anode and a cathode attached to the scalp and the patient perceives practically nothing, although a faradizing current is induced in the brain that changes the neuronal membrane potential and can shift the level of brain activity in the targeted brain regions. More invasive tools of neuromodulation include spinal cord stimulation, direct cortical stimulation, and vagus nerve stimulation. Pain stimulation itself can have a modulatory effect on the immune system through the release of humoral substances as well as modulation of peripheral nerves such as the vagus nerve. In contrast, the vagus nerve stimulation might modulate the central activity of the nervous system and also modulate the immune system activity to some extent. Therefore, neuromodulation approaches might be used to modulate not only pain but also the inflammatory process associated with CP [9].

Extended use of neuromodulatory interventions in gastroenterology The brain–gut axis represents a bidirectional interaction, and disturbances at central or peripheral levels will generate gut dysmotility and functional digestive disorders. The neuromodulatory interventions can impact at any

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level of the brain–gut axis, influencing the neural activity, attempting to regain the balance of this system [51]. Neuromodulation can occur pharmacologically (influencing the receptor activity) or by electrical stimulation of the neural circuits (targeting mechanisms related to membrane excitability). The regulation of neuromodulatory processes within the CNS could have positive and promising response in the treatment of various “visceral pain syndromes,” and also in the treatment of particular diseases: gastroesophageal reflux disease, gastroparesis (delayed gastric emptying), pain syndromes (irritable bowel syndrome, visceral pain syndrome, chronic abdominal pain, and chest pain), “long-lasting analgesia (in chronic mesenteric ischemia and abdominal pain associated with familial mediterranean fever).” There has been some success in the improvement of conditions affecting the colon such as refractory constipation, generalized hypomotility of the colon, and/ or pelvic floor dyssynergia and also in the treatment of fecal incontinence produced by trauma at the spinal level with subsequent lost of sphincter control or that generated by different conditions (systemic sclerosis, scleroderma).

Summary Pain is a common symptom of many diseases. Recently, the pain has been classified and analyzed exactly. Its particular components/types are described to the maximum of their depths and details. Their etiopathological cascades are explained well, from the molecular to the organ system level and whole-body consequences. That is why each particular pain present in a specific disease (including pancreatopathies) has to be treated according to the presence of the specific type of pain. In diseases of pancreas, there are nociceptive, neuropathic, and inflammatory components of pain participating, frequently. In CP (and pain in CP too), a long-term dietotherapy is the essential component of usually combined arranged treatment. Although the scale of current endoscopic procedures is broad, in the treatment of CP, the therapeutic horizons that they could offer are within the range of drainage interventions. The “repertoire” of the surgical treatment provides options for drainage and resectional procedures. That is why (according to the subsequent histomorphological changes), the surgery is predetermined to be a more effective choice of treatment, from the long-term point of view. The recent pioneering applications/administrations of various neuromodulatory therapeutic approaches (targeting the areas of the CNS, where the neuroplastic processes have happened) represent the promising discoveries for the treatment of long-term, severe, drugresistant pain syndromes, including pain in CP. The results of the application of currently used analgesic therapeutic techniques and capabilities imply the unquestionable challenge for further improvement of their more effective administration and use, and also searching for new therapeutic approaches.

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Disclosure Supported by European Regional Development Fund— Project FNUSA-ICRC (No.  CZ.1.05/1.1.00/02.0123) and Ministry of Health—grant IGA (NT13434-4/2012). Conflict of interest  The authors declare that there are no actual or potential conflicts of interest in relation to this article.

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