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Expert Review of Clinical Pharmacology

ISSN: 1751-2433 (Print) 1751-2441 (Online) Journal homepage: https://www.tandfonline.com/loi/ierj20

Mechanism-based pain management in chronicpancreatitis - is it time for a paradigm shift?

Louise Kuhlmann, Søren S. Olesen, Anne E Olesen, Lars Arendt-Nielsen &Asbjørn M. Drewes

To cite this article: Louise Kuhlmann, Søren S. Olesen, Anne E Olesen, Lars Arendt-Nielsen & Asbjørn M. Drewes (2019): Mechanism-based pain management in chronicpancreatitis - is it time for a paradigm shift?, Expert Review of Clinical Pharmacology, DOI:10.1080/17512433.2019.1571409

To link to this article: https://doi.org/10.1080/17512433.2019.1571409

Accepted author version posted online: 21Jan 2019.

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Publisher: Taylor & Francis

Journal: Expert Review of Clinical Pharmacology

DOI: 10.1080/17512433.2019.1571409

Review

Mechanism-based pain management in chronic pancreatitis - is it time for a paradigm shift?

Louise Kuhlmann1,2,3, Søren S. Olesen1,3, Anne E Olesen1,3 Lars Arendt-Nielsen4 & Asbjørn M. Drewes1,3

1. Centre for Pancreatic Diseases and Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark

2. Department of Internal Medicine, North Denmark Regional Hospital, Hjørring, Denmark

3. Department of Clinical Medicine, Aalborg University, Aalborg, Denmark

4. Center for Sensory-Motor Interaction, School of Medicine, Aalborg University, Aalborg, Denmark

Corresponding author:

Asbjørn Mohr Drewes

Mech-Sense & Centre for Pancreatic Diseases, Department of Gastroenterology and Hepatology,

Clinical Institute, Aalborg University Hospital, Mølleparkvej 4, 9000 Aalborg, Denmark

Telephone: +45 97663562, Fax: +45 97666507

E-mail: amd@rn.dk

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Abstract

Introduction

Pain is the most common symptom in chronic pancreatitis and treatment remains a challenge.

Management of visceral pain in general, is only sparsely documented, and treatment in the clinic is

typically based on empirical knowledge from somatic pain conditions. This may be problematic, as

many aspects of the neurobiology differ significantly from somatic pain, and organs such as the gut

and liver play a major role in tolerability to analgesics. On the other hand, clinical awareness and new

methods for quantitative assessment of pain mechanisms, will likely increase our understanding of

the visceral pain system and guide more individualized pain management.

Areas covered

This review includes an overview of known pain mechanisms in chronic pancreatitis and how to

characterize them using quantitative sensory testing. The aim is to provide a mechanism-oriented

approach to analgesic treatment, including treatment of psychological factors affecting pain

perception and consideration of side effects in the management plan.

Expert opinion

A mechanism-based examination and profiling of pain in chronic pancreatitis will enable investigators

to provide a well-substantiated approach to effective management. This mechanisms-based,

individualized regime will pave the road to better pain relief and spare the patient from unnecessary

trial-and-error approaches and unwanted side effects.

Keywords: Chronic pancreatitis; Chronic Pain; Pain Management; Pain Measurements;

Neurophysiology; Analgesics; Symptom Assessment

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1. Introduction

Chronic pancreatitis (CP) is a fibro-inflammatory disease where the pancreatic parenchyma is

progressively replaced by fibrous connective tissue, potentially leading to exocrine and endocrine

pancreatic insufficiency. The most common symptom in CP is abdominal pain which is present in

about 70% of the patients. The typical description of the pain is a constant dull ache in the

epigastrium with referral to the back (including referred muscle hyperalgesia) that often increases

with food intake, but it can manifest in a variety of ways, ranging from patients with limited,

intermittent pain to those with constant, intense, and severe pain [1]. Previously it was believed that

pancreatic pain would “burn-out” as the disease process evolved with destruction of the pancreatic

tissue [2]. Today the “burn-out” theory is regarded obsolete as evidence against it has been provided

in large retrospective studies [3,4]. Thus, it is not advisable with a “wait-and-see” approach to

patients with on-going pain. Unfortunately, management of pancreatic pain remains a considerable

therapeutic challenge [5]. It is known from other chronic pain conditions that the longer the pain

persists and the stronger it is, the more effect pain has on the central sensitization processes and the

more difficult is to treat [6].

Different management regimes for visceral pain are only sparsely documented as compared with its

somatic counterpart. As a consequence, the approach used in treatment of somatic pain is typically

used as framework for visceral pain management, with analgesic use based on the World Health

Organization (WHO) ladder [7,8]. Although visceral, somatic, neuropathic and inflammatory chronic

pain conditions share common mechanistic features, visceral and somatic pain has several important

differences that should be considered when initiating analgesic treatment [6]. Hence, visceral pain is

more diffuse and difficult to localize. This can lead to malpractice, as failing to localize the origin of the

pain can hinder for example surgical treatment. It is also accompanied by symptoms arising from the

autonomic and enteric nervous system that may need specific management, including nausea and

gastrointestinal disturbances [9]. Chronic visceral pain also induce peripheral and central sensitization

more frequent than in somatic pain conditions [10]. Finally, when drug absorption and metabolism is

considered, the gut and liver are of major importance, but they are often malfunctioning in CP due to

steatorrhea, bile duct stenosis, duodenal stenosis and comorbidities including alcoholic liver disease

[11]. These organs are also the main targets to side effects.

As a new dimension, characterization of the pain mechanisms underlying painful CP can theoretically

facilitate individualized treatment targeting the involved mechanism, and thereby enable

personalized pharmacological treatment, improve patient outcome, and reduce unwanted side

effects. Therefore, the aim of this paper is to review the involved pain mechanisms in chronic

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pancreatic pain and discuss the future of mechanism-based analgesic treatment. This will be done by

evaluating studies that have used quantitative sensory testing (QST) to phenotype/profile patients

and evaluate treatment response.

2. Pain mechanisms and quantitative sensory testing

There are several reasons for chronic pain in patients with chronic pancreatitis, for review see [5]. The

pain can be nociceptive, inflammatory and/or neuropathic and thereby arise from an actual or

threatened damage to the tissues. This can occur due to a number of complications to CP, and many

of them are treatable. The initial step in treating pancreatic pain is to examine whether any of these

complications are present and treat appropriately. If there are no anatomical complications, or if

treatment of these complications does not relieve the patient’s symptoms, the pain could be of

predominantly neuropathic origin and a different approach must be taken. In case of no obvious

organic identifiable reasons but the patients show hyperalgesic reactions, the new descriptor

neuroplastic pain may be used [12]. Like all other kinds of chronic pain, pancreatic pain can affect the

peripheral and central nervous system leading to neuropathy and sensitization. For example,

exposure to several chemical agents released following cellular damage in the pancreas, including H+,

K+, inflammatory molecules and trypsin, lead to increased spontaneous activity and excitability

manifested as peripheral sensitization. These peripheral changes result in an ongoing and vigorous

nociceptive input to the spinal cord that may result in an altered function of the central pain

pathways due to neuroplasticity (central sensitization) [13,14].

***Figure 1 near here***

Sensitization is characterized by hyperalgesia, where pain detection threshold is decreased compared

to that in patients without chronic pain. The hyperalgesia can be detected either locally as seen in

peripheral sensitization or generalized as seen in central widespread sensitization. General

sensitization can also induce allodynia, where even stimuli that normally does not induce pain, can

feel painful. This is obviously difficult to assess from structures as the pancreas but often those

chronic visceral pain conditions manifest somatic hyperalgesia and allodynia in the referred somatic

areas [15]. Although hypothetical, symptoms such as postprandial pain may be a manifestation of

allodynia [16].

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In central pain processing, there is a closely regulated balance between descending excitatory and

inhibitory drives. In chronic pain patients It has been suggested that an imbalance between inhibitory

and facilitatory descending pain modulatory systems can occur, favoring increased gain of incoming

nociceptive signals [17]. Multiple studies have shown, that the balance between descending pain

inhibition and facilitation is disturbed in patients with chronic pain and it has been proposed as a

significant factor in the chronification of pain [18–21]. Similar modulatory pathways can perhaps also

play a role in “temporal summation” of pain. Temporal summation is the perception of increased pain

as a response to repetitive nociceptive stimulations with the same intensity due to a wind-up effect in

the spinal dorsal horn [22]. A train of stimuli with a frequency of 0.33 Hz or higher induces cumulative

depolarizations of the post-synaptic membrane thus resulting in wind-up of action potentials [23,24].

Temporal summation is facilitated in case of central sensitization [25]. Central sensitization can in

some cases be detected without the presence of enhanced temporal summation, which shows that

the interaction between the two is a complex interplay [26].

The function of pain processing and some of the underlying mechanisms can be characterized using

QST. QST is comprised of a variety of stimulation modalities, at specific anatomical structures and

using various evaluation methods. Well defined stimulations of skin and muscle are widely used, as

the structures are easily accessible. Modalities may include mechanical stimulation (including touch,

pinprick, and pressure) as well as thermal and electrical stimulation. In contrast, visceral QST, with

stimulation of the gastrointestinal tract or other internal organs are unpleasant to the patient due to

the invasive nature of the stimulus and more comprehensive and time consuming to conduct [27].

Rectal distension with an electric “Barostat” is occasionally used clinically in patients with e.g.,

irritable bowel syndrome, but beyond this visceral QST has mainly been limited to research settings

[28,29].

On the other hand, central pain processing is the same whether the pain is visceral or somatic of

origin. Hence, convergence between somatic and visceral nerves makes it possible to use somatic QST

as a proxy of central referred pain mechanisms in the context of visceral pain [30]. The QST protocol

we use for patients with CP is shown in figure 1. There is a static part that determines pain detection

and pain tolerance thresholds to accurately calibrated phasic and tonic stimuli, and a dynamic part

that determines the function of e.g. descending pain modulation and temporal summation. It has

been shown to be sensitive for quantifying sensory abnormalities on an individual patient level and be

predictive for outcome of management [31–33]. The dynamic parts of the QST paradigm is designed

to evaluate changes in pain perception due to descending modulation and temporal summation. The

descending modulation can be studied by the conditioned pain modulation (CPM) paradigm, where a

painful conditioning stimulus at a remote area, attenuates pain responses to a test pain stimulus.

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***Figure 1 near here***

Figure 1 shows the involved pain mechanisms that can be evaluated in a QST examination for CP

patients and Table 1 shows an overview of the different QST parameters:

- Segmental and generalized hyperalgesia. Sensitization of the nervous system can be explored

by examining pressure pain detection and tolerance thresholds and comparing data with data

from age and gender matched healthy volunteers. The pain detection threshold shall be

assessed from several anatomical locations, including the pancreatic dermatome (Th10) and

control dermatomes (e.g. C5, L4 etc.). Figure 2 shows an example of pressure pain detection

thresholds in a patient with generalized hyperalgesia compared to a healthy control

population [34].

- CPM. This can be assessed by applying a painful conditioning stimulus in between two

identical test pain stimuli and the difference in the result of the two stimuli would then be a

measure of the CPM efficacy [35]. The CPM effect can be expressed both as a relative and an

absolute value. The conditioning stimulus can for example be the cold pressor test, where the

extremity is exposed to cold water as used in our protocol. Ischemic pain, chemically induced

pain, heat, and electrical induced pain can also be used. The test pain stimuli can for example

be mechanical pressure, electrical stimulation, heat stimulation, and cold stimulation. There is

currently no consensus how CPM should be assessed and unfortunately CMP seems to vary

between repeated assessments and between patients/volunteers [36].

- Temporal summation is evoked by a series of e.g. 5 painful stimuli delivered by one per

second [37]. Temporal summation magnitude is the difference between the sensory rating of

the first and last stimuli. The stimulation can e.g. be heat, cold, mechanical pressure or

electrical stimulation. Again, there is no golden standard how to assess temporal summation.

***Table 1 and Figure 2 near here***

3. Mechanism-oriented pain treatment

3.1. Initial approach

When treating a patient with painful CP, the primary focus should be on treating the causality of pain

in a mechanistic way. Patients with CP can have several complications that cause pain, including

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pancreatic pseudocysts, peptic ulcers, pancreatic cancer, duodenal stenosis, and duct obstruction due

to stones or stenosis [38,39]. Nutrition should be optimized, as high fat foods can provoke pancreatic

pain in lack of pancreatic enzymes, and patients should be advised against smoking and drinking [1].

Whether pancreatic enzymes works as an analgesic is debatable, please see the appendix in Drewes

2017 for clarification [5]. Alcohol is a risk factor for CP, and cessation of alcohol consumption has

been shown to be protective against developing pancreatic dysfunction as well as recurrent

pancreatitis [40]. Smoking is an independent risk factor for CP and more than 80% of patients with

chronic pancreatitis are smokers [41]. Tobacco can potentiate alcohol toxicity in a dose-dependent

way, and a recent study has shown that smoking cessation increases the chance of successful

outcome of pain relieving surgery [5,41,42].

Although treatment of the aforementioned complications along with successful smoking and alcohol

cessation may result in pain relief in a proportion of patients, many patients will require additional

pain management [43]. The patients could at this point possibly benefit from a mechanism-oriented

pharmacological treatment of malfunctions in the pain processing pathways. If this approach fails to

provide sufficient analgesia, a multidisciplinary approach adding alternative treatments including e.g.,

spinal cord stimulation and acupuncture may be useful.

Although not validated, an example of a mechanism-based treatment algorithm is presented in figure

3, and the rationale explained below.

***Figure 3 near here***

3.2. Neurophysiological evaluation of the response to analgesics

3.2.1. Sensitization Sensitization is an important factor in the chronification of pain and a study has shown that treatment

can be guided from this feature. N-methyl-D-aspartate (NMDA)-receptor antagonists, tricyclic

antidepressant agents (TCA) and gabapentinoids have often been used to treat patients with

sensitization and their potential use in patients with chronic pancreatic pain with sensitization will be

reviewed here. Gabapentinoids is a group of anticonvulsant agents that acts by binding to the α2-δ

unit of voltage-gated calcium channels in the central neural pathways, whereby it reduces the release

of excitatory neurotransmitters [44]. The group includes gabapentin and pregabalin.

Olesen et al. examined the effect of pregabalin on painful CP and found that lower electrical pain

detection threshold at the abdominal pancreatic area had high accuracy to separate responders from

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non-responders [45]. The classification accuracy was 80.6%, which is significantly above the effect of

random selection. From the same study, Bouwense et al. reported that treatment with pregabalin in

patients with CP leads to a greater increase in electrical pain thresholds at the C5 dermatome than

placebo treatment, but not in the pancreatic “viscerotome” (dorsal and ventral T10 dermatome)

suggesting a possible prevention on spreading hyperalgesia to higher segmental levels [46].

Pregabalin did also increase pain detection threshold and tolerance threshold in rectal stimulation

[47]. This supports findings in previous studies where pregabalin reduces visceral hyperalgesia

[48,49].

Many studies have examined the effect of ketamine on different types of pain. Ketamine is a NMDA

receptor antagonist and thereby a possible treatment modality for central sensitization. Arendt-

Nielsen et al. likewise found that ketamine increased the temporal summation pain threshold in

healthy volunteers compared to placebo [50]. Several studies have tried to unravel the long-term

effect of different administration forms of ketamine in patients suffering from various pain

syndromes, but with inconsistent results. Currently large studies are ongoing in Australia examining

the effects of low dose ketamine in managing and preventing chronic pain [51]. Generally the studies

showed that infusion of ketamine provides immediate analgesic effect, which attenuates over time

[52,53]. In CP, Bouwense et al. found that ketamine increases the sum of pressure pain detection

threshold immediately after infusion, but the effect was not significant one hour after infusion [54].

TCA probably relieves pain through multimodal mechanisms of action, involving inhibition of

serotonin and noradrenaline reuptake, blockage of sodium channels as well as blocking of the NMDA-

receptors. The effects on pain thresholds are therefore likely to attenuate central sensitization.

Enggaard et al. examined TCA’s effect on QST results in healthy volunteers and found that it increased

pressure pain thresholds and decreased temporal summation [55]. It has also been examined in

patients with painful polyneuropathy by Holbech et al., who found that pain intensity decreased

significantly and that it improved both temporal summation by mechanical repetitive stimuli as well

as cold pain [56]. TCA has not been tested in CP patients, but as the affected pain mechanisms of CP

resembles those affected by other chronic pain conditions, it makes sense to use findings in other

conditions when knowledge is limited in CP.

3.2.2. Impaired descending pain inhibition

Descending pain inhibition is an important pain processing pathway and it is decreased in many

chronic pain conditions [57]. Olesen et al. has shown that conditioned pain modulation function is

reduced in patients with painful CP compared to healthy volunteers [21]. Treatment targeted this pain

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mechanisms could therefore be used to manage pancreatic pain. Bouwense et al. has looked at the

effect of pregabalin compared with placebo on CPM function in CP patients [58]. They found that

pregabalin responders (patients with a decrease of more than 30% on their average daily pain

intensity after 3 weeks of pregabalin treatment) had a significant increase in CPM function from

baseline measures. This indicates that pregabalin could have a direct anti-facilitatory effect on CPM or

an indirect reduction of the transmission in the ascending pain pathways [58]. Even though this was a

posthoc analysis, data are supported from preclinical studies, studies in healthy volunteers and from

different patient categories than CP. From these studies, we can be inspired to find other treatments

that could be helpful when treating pancreatic pain. As serotonin, noradrenaline, and opioid peptides

are important neurotransmitters in relation to descending pain inhibition, many studies have

examined the effect of serotonin and norepinephrine reuptake inhibitors (SNRI), TCA, and opioids in

relation to defective pain modulation.

In two rat studies, TCA and low dose of opioids, respectively, have been shown to enhance

endogenous pain modulation [59,60]. The noradrenergic system plays an important role in

endogenous pain modulation and is influenced by TCA [60]. The authors of the opioid study

speculated that opioids target supraspinal structures such as the periaqueductal grey and

ventromedial medulla and thereby enhance descending modulation [59]. In humans, studies of

opioids effects on descending modulation are more contradictory [61–64]. Olesen et al. examined

morphine’s effect on different experimental pain models in healthy volunteers and did not find that

morphine increased CPM effect [65]. Arendt-Nielsen et al. found that buprenorphine and fentanyl

both increased the CPM function significantly compared to placebo in healthy volunteers after 72

hours treatment [63]. Hermans et al. found that morphine had no effect on CPM in patients with

either rheumatoid arthritis or fibromyalgia combined with evidence of central sensitization [66].

However, the study only consisted of a single subcutaneous injection of morphine and does not tell us

anything about the long-term effects of morphine treatment. Tapentadol, which has a dual effect on

opioid receptors and noradrenalin reuptake, was examined in healthy volunteers in two studies, and it

was shown not to affect CPM or experimentally induced heat, cold or mechanical hyperalgesia

[61,64]. On the other hand, in patients with diabetic neuropathy where the pain system had

undergone pathological changes, Niesters et al. found that tapentadol increased CPM function after 4

weeks of treatment [62]. Tapentadol both activates the µ-opioid receptor as well as inhibits neuronal

norepinephrine reuptake. It therefore makes sense also to examine whether norepinephrine reuptake

inhibitors also increase CPM function in patients. This has been done by Yarnitsky et al. who has found

that CPM function predicts treatment effect of duloxetine [67].

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3.2.3. Temporal summation

Chronic pain can induce enhanced temporal summation. The NMDA receptor is also believed to play a

key role in this mechanism through a release of both peptides and glutamate that may lead to hyper

excitability of spinothalamic tract neurons, and this characterizes central sensitization [23,68].

Different opioids have shown to inhibit temporal summation, including codeine and morphine

[55,69]. Anticonvulsants drugs including the gabapentinoids and carbamazepine have also been

shown to inhibit temporal summation in healthy subjects [50,70,71]. Amitriptyline (TCA) is thought to

block the NMDA receptor, and this would theoretically lead to a decrease in temporal summation.

However, a study surprisingly found that it significantly increased temporal summation, and

speculates that this probably is caused by amitriptyline’s augmentation of glutamate release, making

it less effective as a NMDA receptor antagonist [70].

As expected from a pathophysiological level, other NMDA antagonists are found to inhibit temporal

summation. Ketamine was found to decrease temporal summation in healthy volunteers [50]. In

another study, the effect of dextromethorphan on temporal summation was examined in patients

suffering from abdominal pain due to irritable bowel syndrome. Here, the drug decreased temporal

summation from a pathological baseline limit [72]. The authors did not report the effect of

dextromethorphan on the patients’ pain ratings, and one could question whether the effect was

clinically relevant.

3.2.4. Choosing analgesic treatment

In the clinic, many patients with severe pain will have several malfunctions when evaluating their QST

results. An example from our clinic is that there is a substantial overlap of between abnormal

mechanisms in 56% of the patients. This can be a challenge, because several treatments could

potentially be beneficial. In preliminary results from our pain clinic, 57% of the patients have deficient

CPM, 52% have segmental hyperalgesia and 43% of the patients have temporal summation. In this

case, we suggest to treat the most deviant mechanism first and if management is insufficient to retest

the algorithm on treatment and add supplementary therapies depending on the new findings.

However, the algorithm can also be a supportive tool in the management strategy, and treatment

shall always be based on the patients and doctors’ preferences, side-effect profile etc.

If the results of the QST examination is conflicting, it may make sense to use a more traditional

analgesic strategy instead of the QST-guided regimen.

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We are not able to say whether this method for choosing analgesic treatment is more cost-effective

than using the WHO treatment ladder, as this will require a large number of treatments in different

combinations. However, analgesic treatment costs only represent less than 1% of the socio-economic

burden of chronic pain, and a small increase or decrease of the treatment cost will therefore seldomly

have a significant impact on the total chronic pain related cost [73].

3.3. Psychological evaluation

The patients’ mental condition has great influence on the experience of pain as well as treatment

outcomes [74]. Pain catastrophizing is when a patient describes the pain in exaggerated terms,

ruminates on it and feels increasingly helpless about the situation. Several studies have shown that

high pain catastrophizing predicts poorer treatment outcome in various chronic pain conditions

[75,76]. At this stage, it is not clear which of the individual factors composing the manifestation of

catastrophizing can be modulated by analgesics and e.g., cognitive therapy.

Depression is closely related to pain symptoms and studies have found that it has a significant

influence on quality of life in patients with chronic pain [77]. The response to pharmacological pain

treatment is also closely linked to the presence of depression [78,79]. Psychological interventions as

mindfulness and cognitive-behavioral therapy can have a positive influence on catastrophizing scores

and can raise the patients’ quality of life [80–82]. Pharmacological antidepressant treatments can also

decrease pain intensity, however it is not clear whether this effect is based on the improvement of

mental health rather than direct effects on malfunctioning pain system as discussed above [83].

3.4. Complementary treatment

Besides pharmacological management, many other pain treatment modalities exist. Acupuncture has

been used to alleviate pain for many years, although the scientific results have been inconsistent [84–

86]. It is difficult to examine the result of acupuncture in a randomized placebo-controlled study, as

sham treatments are difficult to control. Hence, sham acupuncture needles are only different from

actual acupuncture needles by the fact that it does not puncture the skin, but the tactile stimulation is

still present and can possibly induce some of the effects from acupuncture [87]. However, in a sham

controlled study examining the analgesic effect of acupuncture on painful CP, an effect on pain

intensity was seen, although a short lasting response limits its clinical use [84].

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Different kinds of neuromodulation have also been evaluated. Spinal cord stimulation has shown

promising results in different types of chronic pain including CP [88,89], but as numbness during

stimulation can be felt, no real sham controlled studies have been done. The mechanisms involved

remains unclear, but several effects including blockage of nerve conduction, release of inhibitory

neuromodulators, and direct stimulation on the dorsal column pathways has been proposed [89]. A

study examining transcranial magnetic stimulation on the secondary somatosensory cortex in patients

with CP found a significant decline in pain ratings after treatment. The effect was correlated to an

increase in glutamate and N-acetyl-aspartate levels in the somatosensory cortices, and low baseline

glutamate level was predictive for a positive treatment outcome [90]. This field is current under

development as high frequency stimulators have been proposed to exert more specific effects [91].

Vagal nerve stimulation has been examined for a number of conditions with chronic visceral pain

often with good results [92,93]. No clearly defined mechanism has been discovered, but theories

point to anti-inflammatory effects in conjunction with pain modulatory effects [94]. Juel et al. has

examined acute accentuation of vagal tone on the auricular vagal branch in CP patients, but found no

effect on experimental pain thresholds. [95]. This may relate to the short stimulation period, as only

60 minutes stimulation was performed. It could also be because the analgesic potency of this type of

stimulation was not powerful enough to induce measurable effects. Further studies are needed

where longer stimulation periods with multiple stimulations are performed, and perhaps the

stimulation should be in closer relation to the vagal nerve than just the auricular branch.

At this level, complementary treatment cannot be used in a mechanism-based treatment, as the

effect on different pain processing mechanisms is unknown and the effects are not validated.

3.5. Gastrointestinal side effects of analgesics

No treatment with analgesics is without risks, and due to changes in exocrine pancreatic function,

motility and gut blood supply, patients with CP are especially prone to develop gastrointestinal

adverse effects, for details see [96]. Acetaminophen is generally well tolerated, but its treatment

carries a risk of acute liver failure if the instructed dosages are not complied. Furthermore long term

use of acetaminophen may cause medicine overuse headache [97]. NSAIDs is linked to non-variceal

upper gastrointestinal bleeding, lower gastrointestinal bleeding, gut perforation and strictures, and

protein-losing enteropathy. There are several risk factors for developing gastrointestinal side effects

to NSAID use including high age, female sex, smoking, former peptic ulcer, and concurrent use of

steroids, anticoagulants, or selective serotonin reuptake inhibitors, and in these cases NSAID

treatment should be avoided [98]. The risk of peptic ulcer seems to be especially high in CP patients

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likely due to compromised blood supply of the stomach after attacks of acute pancreatitis as well as

increased infection rates with H Pylory [99].

Opioids, both weak and strong, have a potent pain-relieving effect, but are associated with addiction

and major side effects where the gastrointestinal includes anorexia, nausea, vomiting and

constipation [100,101]. In this context, new drugs such as peripherally-acting µ-opioid receptor

antagonists have proven valuable in the treatment of opioid-induced bowel dysfunction as they block

the µ-opioid receptors locally in the gut without affecting the central analgesic effect. [102].

Although long-term use of opioids may be necessary in CP and can provide potent pain control, it can

also lead to opioid-induced hyperalgesia, which is characterized by a paradox of increased perception

of pain, without a progression in the disease or opioid withdrawal [103].

Adjuvant analgesics such as antidepressants and anticonvulsants, are all known for having a long list

of potential gastrointestinal side effects, some more severe than others. These include abdominal

pain, diarrhea, constipation, dyspepsia, nausea, vomiting, hepatitis, and liver failure. They should

typically be started in a low dose and titrated up, to find an optimal balance between beneficial

effects and side effects [104]. Therefore, the risks of potential side effects shall be considered in the

algorithm proposed in figure 3, and often this limits dosing and optimized pain control.

4. Conclusion

Pain management in CP remains a significant challenge, and no single analgesic is the best match for

every patient. To achieve optimal pain management, quantitative assessment of affected pain

mechanisms provides a platform for individualized and multimodal pain management, which may lead

to a more rational and precise use of analgesics. This is exemplified in figure 3 where a suggestion for

a mechanism-based approach for pain management is illustrated. The flowchart is based on proposed

mechanisms mainly found in basic cross-sectional studies. Although different treatment studies in CP

and other painful conditions have confirmed the value of the different steps in the algorithm, it needs

to be tested further as an overall concept in clinical practice, preferably in a randomized fashion. This

will hopefully give data from mechanistic clinical studies, where analgesic treatments are supported

by the different steps in the algorithm, allowing us to adapt it to the results. Other features such as

genetic profiling, drug kinetics and assessment of the autonomic response may be important as well,

but the suggested tests can be used bedside with minimal costs."

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5. Expert opinion

Pain treatment in CP has for years mainly been based on knowledge of somatic pain. Although the

mechanisms (and hence the effect of analgesics) are to some degree similar, there are also

differences. An increasing number of mechanism-based studies on pain treatment has elucidated a

number of relevant mechanisms that can be treated with specific analgesics. Our knowledge is

expanding, but there are still significant gaps that need to be explored. Quantitative sensory testing

can be used to characterize pain processing and delineate relevant pain mechanisms on an individual

patient basis, but many QST protocols used in clinical studies are quite extensive and not easily

transferred to the clinic. There is therefore a need for a simple and feasible QST examination protocol

with appropriate reference material. The QST protocol should include examinations providing

information on the presence of segmental and widespread hyperalgesia, temporal summation

(serving as proxies for central sensitization), and conditioned pain modulation as shown in figure 1.

From this protocol, the ultimate goal is to develop a treatment algorithm such as proposed in figure 3,

which will enable us to tailor the best-suited treatment plan for each patient. Before this is possible,

additional drugs should be examined to establish their effect on pain mechanisms. This could include

more studies on e.g. ketamine, cannabinoids, opioids, and antidepressant agents.

Treatment of psychological factors and the accompanying effect on pain ratings and quality-of-life

should be documented. This could include both pharmacological management as well as cognitive

behavioral therapy and help to evoke beneficial coping mechanisms. Quality of life is equally as

important as pain ratings when assessing effect of treatment, as complete pain relief often is a too

ambitious goal, and quality of life can be enhanced despite minor changes in pain intensity.

6. Article highlights

• Although pain is the most frequent symptom in chronic pancreatitis, pain management is an

ongoing challenge

• In chronic pain conditions, several pain mechanisms can be affected, and pain can therefore

affect each individual differently

• Although still in a developmental phase, somatic quantitative sensory testing can be used to

diagnose visceral pain mechanisms

• Many analgesics are targeting specific pain mechanisms

• By individualizing pain treatment, pain control is achieved faster, and the patient need not

test several analgesics, each accompanied by different side effects

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• There are several psychological factors that influence pain perception, and these should be

treated alongside the pain to achieve sufficient pain control

Funding

This paper has been solely funded by the salary of the involved author from North Denmark Regional

Hospital and Aalborg University.

Declaration of Interest

The authors have no relevant affiliations or financial involvement with any organization or entity with

a financial interest in or financial conflict with the subject matter or materials discussed in the

manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert

testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

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Figure legends

Figure 1. Illustration of the bedside method used for objective assessment of the pain system in a

patient with chronic pancreatitis without the use of visceral stimulations. Due to convergence

between afferents from the pancreas and those of the skin in the Th10 dermatome (abdomen and

back), any increased afferent barrage from the pancreas may result in local neuronal sensitization at

this level. This will result in a lowering of the pain threshold (hyperalgesia) to experimental pain

stimuli of the skin and deep tissue (QST 1). In the left insert showing the dermatomes, this is

illustrated as white circles, whereas the remaining test sites are illustrated as black circles. If the

sensitization spreads along the neuraxis there will also be a lowering of pain thresholds in other areas

(QST 2; black circles in the dermatome-figure).

The efficacy of inhibitory bulbo-spinal descending pathways (black arrow) is tested as a change in the

pain threshold to pressure stimulation before and after the descending pathways are activated with a

tonic heterotopic stimulus. Finally, neuronal sensitization is also assessed as an increased response to

repeated pinprick stimuli (temporal summation). This is illustrated in the right insert.

Figure 2. A fictive example of pressure pain detection thresholds in a patient with generalized

sensitization compared with preliminary data from a healthy reference population.

Figure 3. If smoking cessation and alcohol abstinence do not provide pain relief, the flowchart

exemplifies a mechanism-based treatment algorithm that can be used to guide management of pain

in patients with chronic pancreatitis. Simple analgesics include non-steroidal anti-inflammatory drugs

(NSAID) and acetaminophen, complementary treatments include acupuncture, vagal nerve

stimulations etc. Abbreviations: Gaba = gabapentinoids, QST = Quantitative Sensory Testing, SNRI =

Serotonin and Norepinephrine Reuptake Inhibitor, TCA = Tricyclic Antidepressants

Table 1. An overview of QST modalities studied in this review including which pain mechanism the test

is designed to examine.

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Table 1:

QST Method Stimulation Pain mechanism

Conditioned pain modulation

Conditioning stimulus in between to test pain stimuli

Conditioning stimulus Test pain stimulus

Descending pain inhibition

Cold pressor test, ischemic pain, heat, chemically induced pain, electrical induced pain.

Mechanical pressure, electrical stimulation, heat, cold

Windup phenomenon

A series of identical noxious stimuli of a frequency of 0,33 Hz or higher

Pin prick, electrical stimulation, heat, cold

Temporal summation

Pain detection/tolerance threshold

Pain detection threshold and pain tolerance threshold at various sites including control sites

Mechanical pressure, electrical stimulation, heat, cold

Sensitization (both peripheral and central)

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Figure 1

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Figure 2

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Figure 3