Publications by authors named "Oliver H Wilder-Smith"

72 Publications

Is Preoperative Quantitative Sensory Testing Related to Persistent Postsurgical Pain? A Systematic Literature Review.

Anesth Analg 2020 10;131(4):1146-1155

From the Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, the Netherlands.

Persistent postsurgical pain (PPSP) is a common complication of surgery that significantly affects quality of life. A better understanding of which patients are likely to develop PPSP would help to identify when perioperative and postoperative pain management may require specific attention. Quantitative sensory testing (QST) of a patient's preoperative pain perception is associated with acute postoperative pain, and acute postoperative pain is a risk factor for PPSP. The direct association between preoperative QST and PPSP has not been reviewed to date. In this systematic review, we assessed the relationship of preoperative QST to PPSP. We searched databases with components related to (1) preoperative QST; (2) association testing; and (3) PPSP. Two authors reviewed all titles and abstracts for inclusion. Inclusion criteria were as follows: (1) QST performed before surgery; (2) PPSP assessed ≥3 months postoperatively; and (3) the association between QST measures and PPSP is investigated. The search retrieved 905 articles; 24 studies with 2732 subjects met inclusion criteria. Most studies (22/24) had moderate to high risk of bias in multiple quality domains. Fourteen (58%) studies reported a significant association between preoperative QST and PPSP. Preoperative temporal summation of pain (4 studies), conditioned pain modulation (3 studies), and pressure pain threshold (3 studies) showed the most frequent association with PPSP. The strength of the association between preoperative QST and PPSP varied from weak to strong. Preoperative QST is variably associated with PPSP. Measurements related to central processing of pain may be most consistently associated with PPSP.
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http://dx.doi.org/10.1213/ANE.0000000000004871DOI Listing
October 2020

Avoiding Catch-22: validating the PainDETECT in a in a population of patients with chronic pain.

BMC Neurol 2018 Jun 29;18(1):91. Epub 2018 Jun 29.

Department of Anesthesiology, Pain and Palliative Medicine, Radboud university medical center, Huispost 549, PO Box 9101, 6500, HB, Nijmegen, the Netherlands.

Background: Neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory nervous system and is a major therapeutic challenge. Several screening tools have been developed to help physicians detect patients with neuropathic pain. These have typically been validated in populations pre-stratified for neuropathic pain, leading to a so called "Catch-22 situation:" "a problematic situation for which the only solution is denied by a circumstance inherent in the problem or by a rule". The validity of screening tools needs to be proven in patients with pain who were not pre-stratified on basis of the target outcome: neuropathic pain or non-neuropathic pain. This study aims to assess the validity of the Dutch PainDETECT (PainDETECT) in a large population of patients with chronic pain.

Methods: A cross-sectional multicentre design was used to assess PainDETECT validity. Included where patients with low back pain radiating into the leg(s), patients with neck-shoulder-arm pain and patients with pain due to a suspected peripheral nerve damage. Patients' pain was classified as having a neuropathic pain component (yes/no) by two experienced physicians ("gold standard"). Physician opinion based on the Grading System was a secondary comparison.

Results: In total, 291 patients were included. Primary analysis was done on patients where both physicians agreed upon the pain classification (n = 228). Compared to the physician's classification, PainDETECT had a sensitivity of 80% and specificity of 55%, versus the Grading System it achieved 74 and 46%.

Conclusion: Despite its internal consistency and test-retest reliability the PainDETECT is not an effective screening tool for a neuropathic pain component in a population of patients with chronic pain because of its moderate sensitivity and low specificity. Moreover, the indiscriminate use of the PainDETECT as a surrogate for clinical assessment should be avoided in daily clinical practice as well as in (clinical-) research. Catch-22 situations in the validation of screening tools can be prevented by not pre-stratifying the patients on basis of the target outcome before inclusion in a validation study for screening instruments.

Trial Registration: The protocol was registered prospectively in the Dutch National Trial Register: NTR 3030 .
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http://dx.doi.org/10.1186/s12883-018-1094-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6026336PMC
June 2018

Qualitative and Quantitative Aspects of Pain in Patients With Myotonic Dystrophy Type 2.

J Pain 2018 08 27;19(8):920-930. Epub 2018 Mar 27.

Department of Anesthesiology, Pain and Palliative Medicine, Radboud University Medical Center, Nijmegen, The Netherlands; Center for Sensory-Motor Interaction, Department of Health Sciences and Technology, Aalborg University, Aalborg, Denmark.

Pain is a common but often ignored symptom in patients with myotonic dystrophy type 2 (DM2). In this explorative study, we assessed qualitative and quantitative aspects of pain in DM2 using 4 questionnaires and quantitative sensory testing. A disease control group (fibromyalgia [FMS]) as well as healthy controls were used to compare the results, because pain in DM2 shows many clinical similarities to pain in FMS. Thirty-four patients with genetically confirmed DM2 (71% female, mean age 54 years), 28 patients with FMS, and 33 healthy controls were included, age- as well as sex-matched. Pain prevalence was 65% in DM2, 100% in FMS (P < .001), and 15% in healthy controls (P < .001). The mean of the pressure pain thresholds was lower in DM2 than in healthy controls (P = .016), with the largest differences in the rectus femoris, trapezius, and thenar muscles. Mechanical and electric pain thresholds were significantly higher in DM2 than in FMS, and no differences were found in electric pain thresholds between DM2 and healthy controls. These results confirm that pain is a frequent and important symptom in patients with DM2, affecting quality of life. Peripheral mechanisms of pain seem to play a role in DM2. The widespreadness of the hyperalgesia suggests central sensitization, but this finding was not supported by the other results. This study opens new avenues for further research and eventually novel treatment strategies, in DM2 as well as in other muscular disorders.

Perspective: This article presents qualitative as well as quantitative aspects of pain in patients with DM2. Pain is a frequent and important symptom in patients with DM2, affecting quality of life. We found mechanical hyperalgesia, indicative of a peripheral mechanism of pain. The widespreadness of hyperalgesia may suggest central sensitization, but this finding was not supported by other results and needs further exploration.
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http://dx.doi.org/10.1016/j.jpain.2018.03.006DOI Listing
August 2018

Predicting Persistent Pain After Surgery: Can Predicting the Weather Serve as an Example?

Anesth Analg 2018 11;127(5):1264-1267

From the Department of Anaesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.

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http://dx.doi.org/10.1213/ANE.0000000000003318DOI Listing
November 2018

A Quantitative Sensory Testing Paradigm to Obtain Measures of Pain Processing in Patients Undergoing Breast Cancer Surgery.

J Vis Exp 2018 01 18(131). Epub 2018 Jan 18.

Department of Anesthesiology, Pain, and Palliative Medicine, Radboud University Medical Center.

Chronic pain following surgery, persistent postsurgical pain, is an important highly prevalent condition contributing to significant symptom burden and lower quality of life. Persistent postsurgical pain is relatively refractory to treatment hence generating a high need for preventive strategies and treatments. Therefore, the identification of patients at risk of developing persistent pain is an area of active ongoing research. Recently it was demonstrated that peri-operative disruptions in central pain processing may be able to predict persistent postsurgical pain at long term follow-up in breast cancer patients. The aim of the current report is to present a short protocol to obtain pain thresholds to different stimuli at multiple sites and a measure of endogenous analgesia in breast cancer patients. We have used this method successfully in a clinical context and detail some representative results from a clinical study.
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http://dx.doi.org/10.3791/56918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908658PMC
January 2018

Towards a neurobiological understanding of pain in chronic pancreatitis: mechanisms and implications for treatment.

Pain Rep 2017 Nov 25;2(6):e625. Epub 2017 Oct 25.

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

Introduction: Chronic pancreatitis (CP) is a disease characterized by inflammation of the pancreas resulting in replacement of the normal functioning parenchyma by fibrotic connective tissue. This process leads to progressively impairment of exocrine and endocrine function and many patients develop a chronic pain syndrome.

Objectives: We aimed to characterize the neurobiological signature of pain associated with CP and to discuss its implications for treatment strategies.

Methods: Relevant basic and clinical articles were selected for review following an extensive search of the literature.

Results: Pathophysiological changes in the peripheral (pancreatic gland) and central nervous system characterize the pain syndrome associated with CP; involved mechanisms can be broken down to 3 main branches: (1) peripheral sensitization, (2) pancreatic neuropathy, and (3) neuroplastic changes in the central pain pathways. Disease flares (recurrent pancreatitis) may accelerate the pathophysiological process and further sensitize the pain system, which ultimately results in an autonomous and self-perpetuating pain state that may become independent of the peripheral nociceptive drive. These findings share many similarities with those observed in neuropathic pain disorders and have important implications for treatment; adjuvant analgesics are effective in a subset of patients, and neuromodulation and neuropsychological interventions may prove useful in the future.

Conclusion: Chronic pancreatitis is associated with abnormal processing of pain at the peripheral and central level of the pain system. This neurobiological understanding of pain has important clinical implications for treatment and prevention of pain chronification.
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http://dx.doi.org/10.1097/PR9.0000000000000625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5741325PMC
November 2017

Investigating the validity of the DN4 in a consecutive population of patients with chronic pain.

PLoS One 2017 30;12(11):e0187961. Epub 2017 Nov 30.

Radboud university medical center, Department of Anesthesiology, Pain and Palliative Medicine, Nijmegen, the Netherlands.

Neuropathic pain is clinically described as pain caused by a lesion or disease of the somatosensory nervous system. The aim of this study was to assess the validity of the Dutch version of the DN4, in a cross-sectional multicentre design, as a screening tool for detecting a neuropathic pain component in a large consecutive, not pre-stratified on basis of the target outcome, population of patients with chronic pain. Patients' pain was classified by two independent (pain-)physicians as the gold standard. The analysis was initially performed on the outcomes of those patients (n = 228 out of 291) in whom both physicians agreed in their pain classification. Compared to the gold standard the DN4 had a sensitivity of 75% and specificity of 76%. The DN4-symptoms (seven interview items) solely resulted in a sensitivity of 70% and a specificity of 67%. For the DN4-signs (three examination items) it was respectively 75% and 75%. In conclusion, because it seems that the DN4 helps to identify a neuropathic pain component in a consecutive population of patients with chronic pain in a moderate way, a comprehensive (physical-) examination by the physician is still obligate.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0187961PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5708633PMC
December 2017

Treatment response and central pain processing in Anterior Cutaneous Nerve Entrapment Syndrome: An explorative study.

Scand J Pain 2017 01 4;14:53-59. Epub 2016 Nov 4.

Pain and Nociception Neuroscience Research Group, Department of Surgery, Radboud university medical center, Nijmegen, The Netherlands.

Background: 10-30% of chronic abdominal pain originates in the abdominal wall. A common cause for chronic abdominal wall pain is the Anterior Cutaneous Nerve Entrapment Syndrome (ACNES), in which an intercostal nerve branch is entrapped in the abdominal rectus sheath. Treatment consists of local anaesthetics and neurectomy, and is ineffective in 25% of cases for yet unknown reasons. In some conditions, chronic pain is the result of altered pain processing. This so-called sensitization can manifest as segmental or even generalized hyperalgesia, and is generally difficult to treat.

Objective: The aim of this study was to assess pain processing in ACNES patients responsive and refractory to treatment by using Quantitative Sensory Testing, in order to explore whether signs of altered central pain processing are present in ACNES and are a possible explanation for poor treatment outcomes.

Methods: 50 patients treated for ACNES with locally orientated treatment were included. They were allocated to a responsive or refractory group based on their response to treatment. Patients showing an improvement of the Visual Analogue Scale (VAS) pain score combined with a current absolute VAS of <40mm were scored as responsive. Sensation and pain thresholds to pressure and electric skin stimulation were determined in the paravertebral bilateral ACNES dermatomes and at four control areas on the non-dominant side of the body, i.e. the musculus trapezius pars medialis, musculus rectus femoris, musculus abductor hallucis and the thenar. The ACNES dermatomes were chosen to signal segmental hyperalgesia and the sum of the control areas together as a reflection of generalized hyperalgesia. Lower thresholds were interpreted as signs of sensitized pain processing. To test for alterations in endogenous pain inhibition, a conditioned pain modulation (CPM) response to a cold pressor task was determined. Also, patients filled in three pain-related questionnaires, to evaluate possible influence of psychological characteristics on the experienced pain.

Results: Patients refractory to treatment showed significantly lower pressure pain thresholds in the ACNES dermatomes and for the sum of as well as in two individual control areas. No differences were found between groups for electric thresholds or CPM response. Duration of complaints before diagnosis and treatment was significantly longer in the refractory compared to the responsive group, and refractory patients scored higher on the pain-related psychological surveys.

Conclusion And Implications: In this hypothesis-generating exploratory study, ACNES patients refractory to treatment showed more signs of sensitized segmental and central pain processing. A longer duration of complaints before diagnosis and treatment may be related to these alterations in pain processing, and both findings could be associated with less effective locally orientated treatment. In order to validate these hypotheses further research is needed.

Registration Number: NCT01920880 (Clinical Trials Register; http://www.clinicaltrials.gov).
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http://dx.doi.org/10.1016/j.sjpain.2016.09.014DOI Listing
January 2017

High Body Mass Index Is a Potential Risk Factor for Persistent Postoperative Pain after Breast Cancer Treatment.

Pain Physician 2017 07;20(5):E661-E671

Department of Anesthesiology, Pain, and Palliative medicine, Radboud University Nijmegen Medical Center, The Netherlands.

Background: Risk factors associated with persistent pain after breast cancer treatment are needed to develop prevention and treatment strategies to improve the quality of life for patients with breast cancer.

Objectives: To identify factors associated with persistent pain in women undergoing breast cancer treatments.

Study Design: Retrospective study.

Setting: Regional hospital in the Netherlands.

Methods: The primary outcome was pain associated with surgery at more than 6 months postoperatively and patients were stratified based on the associated visual analog" scale score they reported: reporting no pain as "no pain," pain 1 - 29 mm as "mild pain," and pain 30 - 100 mm as "moderate/severe pain." Secondary outcomes were function, symptom, and total quality of life scores. Predefined risk factors analyzed for association with outcomes included: age, smoking status, diabetes, body mass index (BMI), disease stage, surgery type, axillary lymph node dissection, reoperation, chemotherapy, radiotherapy, and hormone therapy.

Results: Of the 718 patients who were approached, 492 were included (follow-up 2.5 ± 1.8 years). Thirty-five percent of patients developed persistent pain (n = 122 "mild pain," n = 53 "moderate/severe pain'"). Age, BMI, surgery type, axillary lymph node dissection, disease stage, reoperation, chemotherapy, and radiotherapy were identified as potential risk factors in univariate ordinal regression analyses (P < 0.10). Age (P < 0.01) and BMI (P = 0.04) remained independently predictive in the multivariate model. BMI and age were associated with odds ratios (ORs) of 1.04 (95% confidence intervals (CI): 1.00 - 1.08) and 0.97 (95% CI: 0.95 - 0.99), respectively per point and year increase. BMI was associated with a higher symptom score (r = 0.14, P < 0.01), a lower level of function (r = -0.11, P = 0.01), and lower total quality of life scores (r = -0.13, P < 0.01).

Limitations: The retrospective nature of this study makes it prone to response and misclassification bias.

Conclusions: BMI and age may be risk factors for persistent postoperative pain after breast cancer treatment.

Key Words: Persistent postsurgical pain, breast cancer treatment, BMI, age, chronic postoperative pain, breast cancer surgery.
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July 2017

Hyperalgesia and Persistent Pain after Breast Cancer Surgery: A Prospective Randomized Controlled Trial with Perioperative COX-2 Inhibition.

PLoS One 2016 9;11(12):e0166601. Epub 2016 Dec 9.

Department of Anaesthesiology, Pain and Palliative Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Background: Persistent pain is a challenging clinical problem after breast cancer treatment. After surgery, inflammatory pain and nociceptive input from nerve injury induce central sensitization which may play a role in the genesis of persistent pain. Using quantitative sensory testing, we tested the hypothesis that adding COX-2 inhibition to standard treatment reduces hyperalgesia after breast cancer surgery. A secondary hypothesis was that patients developing persistent pain would exhibit more postoperative hyperalgesia.

Methods: 138 women scheduled for lumpectomy/mastectomy under general anesthesia with paravertebral block were randomized to COX-2 inhibition (2x40mg parecoxib on day of surgery, thereafter 2x200mg celecoxib/day until day five) or placebo. Preoperatively and 1, 5, 15 days and 1, 3, 6, 12 months postoperatively, we determined electric and pressure pain tolerance thresholds in dermatomes C6/T4/L1 and a 100mm VAS score for pain. We calculated the sum of pain tolerance thresholds and analyzed change in these versus preoperatively using mixed models analysis with factor medication. To assess hyperalgesia in persistent pain patients we performed an additional analysis on patients reporting VAS>30 at 12 months.

Results: 48 COX-2 inhibition and 46 placebo patients were analyzed in a modified intention to treat analysis. Contrary to our primary hypothesis, change in the sum of tolerance thresholds in the COX-2 inhibition group was not different versus placebo. COX-2 inhibition had an effect on pain on movement at postoperative day 5 (p<0.01). Consistent with our secondary hypothesis, change in sum of pressure pain tolerance thresholds in 11 patients that developed persistent pain was negative versus patients without pain (p<0.01) from day 5 to 1 year postoperatively.

Conclusions: Perioperative COX-2 inhibition has limited value in preventing sensitization and persistent pain after breast cancer surgery. Central sensitization may play a role in the genesis of persistent postsurgical pain.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0166601PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5147830PMC
July 2017

Tetrahydrocannabinol Does Not Reduce Pain in Patients With Chronic Abdominal Pain in a Phase 2 Placebo-controlled Study.

Clin Gastroenterol Hepatol 2017 Jul 5;15(7):1079-1086.e4. Epub 2016 Oct 5.

Department of Surgery, Radboud University Medical Center, Nijmegen, The Netherlands.

Background & Aims: Delta-9-tetrahydrocannabinol (THC) is the most abundant cannabinoid from the plant Cannabis sativa. There is only equivocal evidence that THC has analgesic effects. We performed a phase 2 controlled trial to evaluate the analgesic efficacy, pharmacokinetics, safety, and tolerability of an oral tablet containing purified THC in patients with chronic abdominal pain.

Methods: Sixty-five patients with chronic abdominal pain for 3 months or more (numeric rating scale scores of 3 or more) after surgery or because of chronic pancreatitis were randomly assigned to groups given the THC tablet or identical matching placebos for 50-52 days. Subjects in the THC group were given the tablet first in a step-up phase (3 mg 3 times daily for 5 days and then 5 mg 3 times daily for 5 days), followed by a stable dose phase (8 mg 3 times daily until days 50-52). Preceding and during the entire study period, patients were asked to continue taking their medications (including analgesics) according to prescription. Patients reported any additional pain medications in a diary. Efficacy and safety assessments were conducted preceding medication intake (day 1), after 15 days, and at 50-52 days. Plasma samples were collected on study days 1, 15, and 50-52; mean plasma concentration curves of THC and 11-OH-THC were plotted. The primary end point was pain relief, which was measured by a visual analogue scale (VAS) of the mean pain (VAS mean scores) on the basis of information from patient diaries. Secondary end points included pain and quality of life (determined from patient questionnaires), pharmacokinetics, and safety.

Results: At days 50-52, VAS mean scores did not differ significantly between the THC and placebo groups (F = 0.016; P = .901). Between the start and end of the study, VAS mean scores decreased by 1.6 points (40%) in the THC group compared with 1.9 points (37%) in the placebo group. No differences were observed in secondary outcomes. Oral THC was generally well-absorbed. Seven patients in the THC group stopped taking the tablets because of adverse events, compared with 2 patients in the placebo group. All (possibly) related adverse events were mild or moderate.

Conclusions: In a phase 2 study, we found no difference between a THC tablet and a placebo tablet in reducing pain measures in patients with chronic abdominal pain. THC, administered 3 times daily, was safe and well-tolerated during a 50-day to 52-day treatment period. ClinicalTrials.gov number: NCT01562483 and NCT01551511.
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http://dx.doi.org/10.1016/j.cgh.2016.09.147DOI Listing
July 2017

Psychophysiological Processing of Itch in Patients with Chronic Post-burn Itch: An Exploratory Study.

Acta Derm Venereol 2016 Jun;96(5):613-8

Unit Health, Medical and Neuropsychology, Faculty of Social and Behavioural Sciences, Leiden University, PO Box 9555, NL-2300 RB Leiden, The Netherlands.

A substantial proportion of patients with burn injury develop chronic itch, which can severely affect their quality of life. As found in research on chronic pain, different psychophysiological processes may also play a role in chronic itch, of which central sensitization, conditioned modulation, and attentional processes have been studied most frequently. This study aimed to explore psychophysiological processes of chronic post-burn itch by comparing 15 patients with long-term itch due to burn injury with 15 matched healthy controls. Exploratory results indicated tendencies for higher itch sensitivity in patients than in controls, for mechanical stimuli and histamine, but not for electrical stimulation. Results further suggest that the efficacy of itch modulation by an itch- or pain-conditioning stimulus or directing attention towards itch stimuli do not differ between these patients and controls. Further elucidation of the processes underlying post-burn itch may improve the early identification and treatment of burn patients developing chronic itch.
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http://dx.doi.org/10.2340/00015555-2323DOI Listing
June 2016

Single dose delta-9-tetrahydrocannabinol in chronic pancreatitis patients: analgesic efficacy, pharmacokinetics and tolerability.

Br J Clin Pharmacol 2016 Mar 17;81(3):525-37. Epub 2016 Jan 17.

Department of Surgery, Radboud University Medical Center, Nijmegen.

Aim: We aimed to assess the analgesic efficacy, pharmacokinetics, tolerability and safety of a single dose of Δ9-THC in patients with chronic abdominal pain resulting from chronic pancreatitis (CP).

Methods: This was a randomized, single dose, double-blinded, placebo-controlled, two way crossover study in patients suffering from abdominal pain as result of CP (n = 24), post hoc subdivided into opioid and non-opioid users. Δ9-THC (8 mg) or active placebo (5 mg/10 mg diazepam) was administered orally in a double dummy design.

Results: No treatment effect was shown for delta VAS pain scores after Δ9-THC compared with diazepam. Δ9-THC was well absorbed with a mean tmax of 123 min. No significant differences were found between Δ9-THC vs. diazepam for alertness, mood, calmness or balance. Feeling anxious and heart rate were significantly increased after Δ9-THC compared with diazepam. The most frequently reported adverse events (AEs) after Δ9-THC administration were somnolence, dry mouth, dizziness and euphoric mood.

Conclusions: A single dose of Δ9-THC was not efficacious in reducing chronic pain resulting from CP, but was well tolerated with only mild or moderate AEs. The PK results in CP patients showed delayed absorption and an increased variability compared with healthy volunteers.
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http://dx.doi.org/10.1111/bcp.12811DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4767190PMC
March 2016

Is Timing of Medical Therapy Related to Outcome in Painful Chronic Pancreatitis?

Pancreas 2016 Mar;45(3):381-7

From the *Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Aalborg, Denmark; †Pain and Nociception Neuroscience Research Group, Department of Surgery, and ‡Department of Anesthesiology, Pain and Palliative Care, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands; §Department of Clinical Medicine and Center for Sensory-Motor Interaction (SMI), Aalborg University, Aalborg, Denmark.

Objectives: The authors investigated if timing of medical treatment is associated with the analgesic effect of pregabalin or placebo in patients with chronic pancreatitis (CP).

Methods: Sixty-four patients received pregabalin (150-300 mg twice a day) or matching placebo for 3 consecutive weeks. Responders to treatment were defined as patients with a reduction in clinical pain scores of 30% or greater. Factors associated with timing of pain treatment (ie, duration of CP and opioid usage) were collected at baseline. In addition, other factors that potentially could influence outcome (eg, clinical pain scores prior to study medication, diabetes, and exocrine pancreatic insufficiency) were also included. Conventional groupwise logistic regression and analysis on the individual patient level with a machine learning technique were used to predict treatment response.

Results: In the conventional statistical analysis duration of CP (odds ratio, 0.9; 95% confidence interval, 0.8-1.1; P = 0.3) and opioid treatment (odds ratio, 1.0; 95% confidence interval, 0.9-1.1; P = 0.6) were not associated with pain relief. In addition, none of the supplementary factors were associated with treatment response (all P > 0.1). Likewise, in the individual patient-level analysis, none of the included variables reached classification accuracies greater than chance level (all P > 0.1).

Conclusions: Pregabalin can be added as adjuvant analgesic at any time point during the disease course of CP.
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http://dx.doi.org/10.1097/MPA.0000000000000475DOI Listing
March 2016

Risk factors for chronic postsurgical abdominal and pelvic pain.

Pain Manag 2015 ;5(2):107-16

Pain & Nociception Neuroscience Research Group, Department of Surgery, Radboud university medical center, Nijmegen, The Netherlands.

Chronic postsurgical pain (CPSP) may develop after any surgical procedure, and is a common feature after abdominal and pelvic surgery with a prevalence varying between 10 and 40%. The pathological mechanisms leading to chronic CPSP are probably inflammation, tissue and nerve damage and alterations in central pain processing. The mechanisms in chronic postsurgical abdominal and pelvic pain are poorly studied and research has largely focused on reporting of prevalence and describing risk factors, including patient characteristics, psychological factors, surgical procedure and pre- and acute postoperative pain. In this review, the most important risk factors are discussed, and aiming for preventive, personalized health care, possible methods for prediction of susceptibility and potential strategies for diminishing chronic postsurgical abdominal and pelvic pain are provided.
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http://dx.doi.org/10.2217/pmt.14.47DOI Listing
January 2016

Systematic mechanism-orientated approach to chronic pancreatitis pain.

World J Gastroenterol 2015 Jan;21(1):47-59

Stefan AW Bouwense, Marjan de Vries, Luuk TW Schreuder, Harry van Goor, Pain and Nociception Neuroscience Research Group, Department of Surgery, Radboud University Medical Center, 6500HB Gelderland, The Netherlands.

Pain in chronic pancreatitis (CP) shows similarities with other visceral pain syndromes (i.e., inflammatory bowel disease and esophagitis), which should thus be managed in a similar fashion. Typical causes of CP pain include increased intrapancreatic pressure, pancreatic inflammation and pancreatic/extrapancreatic complications. Unfortunately, CP pain continues to be a major clinical challenge. It is recognized that ongoing pain may induce altered central pain processing, e.g., central sensitization or pro-nociceptive pain modulation. When this is present conventional pain treatment targeting the nociceptive focus, e.g., opioid analgesia or surgical/endoscopic intervention, often fails even if technically successful. If central nervous system pain processing is altered, specific treatment targeting these changes should be instituted (e.g., gabapentinoids, ketamine or tricyclic antidepressants). Suitable tools are now available to make altered central processing visible, including quantitative sensory testing, electroencephalograpy and (functional) magnetic resonance imaging. These techniques are potentially clinically useful diagnostic tools to analyze central pain processing and thus define optimum management approaches for pain in CP and other visceral pain syndromes. The present review proposes a systematic mechanism-orientated approach to pain management in CP based on a holistic view of the mechanisms involved. Future research should address the circumstances under which central nervous system pain processing changes in CP, and how this is influenced by ongoing nociceptive input and therapies. Thus we hope to predict which patients are at risk for developing chronic pain or not responding to therapy, leading to improved treatment of chronic pain in CP and other visceral pain disorders.
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http://dx.doi.org/10.3748/wjg.v21.i1.47DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4284360PMC
January 2015

Pain severity reduces life quality in chronic pancreatitis: Implications for design of future outcome trials.

Pancreatology 2014 Nov-Dec;14(6):497-502. Epub 2014 Oct 7.

Mech-Sense, Department of Gastroenterology & Hepatology, Aalborg University Hospital, Denmark; Center for Sensory-Motor Interaction (SMI), Department of Health Science and Technology, Aalborg University, Denmark.

Background/objectives: Chronic pancreatitis (CP) is a disabling disease characterised by abdominal pain, and various pancreatic and extra-pancreatic complications. We investigated the interactions between pain characteristics (i.e. pain severity and its pattern in time), complications, and quality of life (QOL) in patients with CP.

Methods: This was a cross-sectional study of 106 patients with CP conducted at two North European tertiary medical centres. Detailed information on clinical patient characteristics was obtained from interviews and through review of the individual patient records. Pain severity scores and pain pattern time profiles were extracted from the modified brief pain inventory short form and correlated to QOL as assessed by the EORTC QLQ-C30 questionnaire. Interactions with exocrine and endocrine pancreatic insufficiency, as well as pancreatic and extra-pancreatic complications were analysed using regression models.

Results: Pain was the most prominent symptom in our cohort and its severity was significantly correlated with EORTC global health status (r = -0.46; P < 0.001) and most functional and symptom subscales. In contrast the patterns of pain in time were not associated with any of the life quality subscales. When controlling for interactions from exocrine and endocrine pancreatic insufficiency no effect modifications were evident (P = 0.72 and P = 0.85 respectively), while the presence of pancreatic and extra-pancreatic complications was associated with an almost 15% decrease in life quality (P = 0.004).

Conclusions: Pain severity and disease related complications significantly reduce life quality in patients with CP. This information is important in order to design more accurate and clinical meaningful endpoints in future outcome trials.
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http://dx.doi.org/10.1016/j.pan.2014.09.009DOI Listing
August 2015

Dronabinol and chronic pain: importance of mechanistic considerations.

Expert Opin Pharmacother 2014 Aug 12;15(11):1525-34. Epub 2014 May 12.

Radboud University Medical Center, Department of Surgery, Pain and Nociception Neuroscience Research Group , Route 690, PO Box 9101, 6500 HB Nijmegen , The Netherlands +31 024 361 0903 ; +31 024 354 0501 ;

Introduction: Although medicinal cannabis has been used for many centuries, the therapeutic potential of delta-9-tetrahydrocannabinol (Δ9-THC; international non-proprietary name = dronabinol) in current pain management remains unclear. Several pharmaceutical products with defined natural or synthesized Δ9-THC content have been developed, resulting in increasing numbers of clinical trials investigating the analgesic efficacy of dronabinol in various pain conditions. Different underlying pain mechanisms, including sensitization of nociceptive sensory pathways and alterations in cognitive and autonomic processing, might explain the varying analgesic effects of dronabinol in chronic pain states.

Areas Covered: The pharmacokinetics, pharmacodynamics and mechanisms of action of products with a defined dronabinol content are summarized. Additionally, randomized clinical trials investigating the analgesic efficacy of pharmaceutical cannabis based products are reviewed for the treatment of chronic nonmalignant pain.

Expert Opinion: We suggest a mechanism-based approach beyond measurement of subjective pain relief to evaluate the therapeutic potential of dronabinol in chronic pain management. Development of objective mechanistic diagnostic biomarkers reflecting altered sensory and cognitive processing in the brain is essential to evaluate dronabinol induced analgesia, and to permit identification of responders and/or non-responders to dronabinol treatment.
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http://dx.doi.org/10.1517/14656566.2014.918102DOI Listing
August 2014

Role of conditioning and verbal suggestion in placebo and nocebo effects on itch.

PLoS One 2014 19;9(3):e91727. Epub 2014 Mar 19.

Unit of Health, Medical and Neuropsychology, Institute of Psychology, Leiden University, Leiden, The Netherlands; Department of Medical Psychology, Radboud University Medical Center, Nijmegen, The Netherlands.

Placebo and nocebo effects are known to play a key role in treatment effects in a wide variety of conditions. These effects have frequently been investigated with regard to pain and also in other physical sensations, but have hardly been investigated with regard to itch. In addition, neither in pain nor in any other physical sensation, the single and combined contribution of the expectancy mechanisms of conditioning and verbal suggestion have ever been investigated in both placebo and nocebo effects within one design. For the first time, the role of verbal suggestion and conditioning in placebo and nocebo effects on itch was experimentally investigated. Expectations about itch stimuli were induced in healthy subjects by verbal suggestion, conditioning, or a combination of both procedures, and compared with a control group without expectation induction. Itch was induced electrically by means of quantitative sensory testing. Significant placebo and nocebo effects were induced in the group in which combined procedures of conditioning and verbal suggestion were applied in comparison with the control group. The conditioning and verbal suggestion procedures applied individually did not induce significant placebo and nocebo effects when compared with the control group. The results of this study extend existing evidence on different physical sensations, like pain, by showing that also for itch, the combination of conditioning and verbal suggestion is most promising in inducing both placebo and nocebo effects. More research on placebo and nocebo effects at a perceptive and neurobiological level is warranted to further elucidate the common and specific mechanisms underlying placebo and nocebo effects on itch and other physical sensations.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0091727PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3960153PMC
December 2014

Altered cortical responsiveness to pain stimuli after high frequency electrical stimulation of the skin in patients with persistent pain after inguinal hernia repair.

PLoS One 2013 23;8(12):e82701. Epub 2013 Dec 23.

Department of Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Background: High Frequency electrical Stimulation (HFS) of the skin induces enhanced brain responsiveness expressed as enhanced Event-Related Potential (ERP) N1 amplitude to stimuli applied to the surrounding unconditioned skin in healthy volunteers. The aim of the present study was to investigate whether this enhanced ERP N1 amplitude could be a potential marker for altered cortical sensory processing in patients with persistent pain after surgery.

Materials And Methods: Nineteen male patients; 9 with and 10 without persistent pain after inguinal hernia repair received HFS. Before, directly after and thirty minutes after HFS evoked potentials and the subjective pain intensity were measured in response to electric pain stimuli applied to the surrounding unconditioned skin.

Results: The results show that, thirty minutes after HFS, the ERP N1 amplitude observed at the conditioned arm was statistically significantly larger than the amplitude at the control arm across all patients. No statistically significant differences were observed regarding ERP N1 amplitude between patients with and without persistent pain. However, thirty minutes after HFS we did observe statistically significant differences of P2 amplitude at the conditioned arm between the two groups. The P2 amplitude decreased in comparison to baseline in the group of patients with pain.

Conclusion: The ERP N1 effect, induced after HFS, was not different between patients with vs. without persistent pain. The decreasing P2 amplitude was not observed in the patients without pain and also not in the previous healthy volunteer study and thus might be a marker for altered cortical sensory processing in patients with persistent pain after surgery.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0082701PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3871559PMC
March 2015

Systemic inflammation decreases pain threshold in humans in vivo.

PLoS One 2013 17;8(12):e84159. Epub 2013 Dec 17.

Department of Intensive Care Medicine, RUNMC, Nijmegen, The Netherlands ; The Nijmegen Institute for Infection, inflammation and Immunity. RUNMC, Nijmegen, The Netherlands.

Background: Hyperalgesia is a well recognized hallmark of disease. Pro-inflammatory cytokines have been suggested to be mainly responsible, but human data are scarce. Changes in pain threshold during systemic inflammation evoked by human endotoxemia, were evaluated with three quantitative sensory testing methods.

Methods And Results: Pressure pain thresholds, electrical pain thresholds and tolerance to the cold pressor test were measured before and 2 hours after the intravenous administration of 2 ng/kg purified E. coli endotoxin in 27 healthy volunteers. Another 20 subjects not exposed to endotoxemia served as controls. Endotoxemia led to a rise in body temperature and inflammatory symptom scores and a rise in plasma TNF-α, IL-6, IL-10 and IL-1RA. During endotoxemia, pressure pain thresholds and electrical pain thresholds were reduced with 20 ± 4 % and 13 ± 3 %, respectively. In controls only a minor decrease in pressure pain thresholds (7 ± 3 %) and no change in electrical pain thresholds occurred. Endotoxin-treated subjects experienced more pain during the cold pressor test, and fewer subjects were able to complete the cold pressor test measurement, while in controls the cold pressor test results were not altered. Peak levels and area under curves of each individual cytokine did not correlate to a change in pain threshold measured by one of the applied quantitative sensory testing techniques.

Conclusions And Significance: In conclusion, this study shows that systemic inflammation elicited by the administration of endotoxin to humans, results in lowering of the pain threshold measured by 3 quantitative sensory testing techniques. The current work provides additional evidence that systemic inflammation is accompanied by changes in pain perception.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0084159PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3866228PMC
September 2014

Pharmacological pain management in chronic pancreatitis.

World J Gastroenterol 2013 Nov;19(42):7292-301

Søren S Olesen, Jacob Juel, Asbjørn M Drewes, Mech-Sense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, 9000 Aalborg, Denmark.

Intense abdominal pain is a prominent feature of chronic pancreatitis and its treatment remains a major clinical challenge. Basic studies of pancreatic nerves and experimental human pain research have provided evidence that pain processing is abnormal in these patients and in many cases resembles that seen in neuropathic and chronic pain disorders. An important ultimate outcome of such aberrant pain processing is that once the disease has advanced and the pathophysiological processes are firmly established, the generation of pain can become self-perpetuating and independent of the initial peripheral nociceptive drive. Consequently, the management of pain by traditional methods based on nociceptive deafferentation (e.g., surgery and visceral nerve blockade) becomes difficult and often ineffective. This novel and improved understanding of pain aetiology requires a paradigm shift in pain management of chronic pancreatitis. Modern mechanism based pain treatments taking into account altered pain processing are likely to increasingly replace invasive therapies targeting the nociceptive source, which should be reserved for special and carefully selected cases. In this review, we offer an overview of the current available pharmacological options for pain management in chronic pancreatitis. In addition, future options for pain management are discussed with special emphasis on personalized pain medicine and multidisciplinarity.
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http://dx.doi.org/10.3748/wjg.v19.i42.7292DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3831211PMC
November 2013

Patients with persistent pain after breast cancer treatment show enhanced alpha activity in spontaneous EEG.

Pain Med 2013 Dec 19;14(12):1893-9. Epub 2013 Aug 19.

Donders Institute for Brain, Cognition and Behavior, Radboud University Nijmegen, Nijmegen, The Netherlands.

Objective: The aim of the present study was to investigate whether patients with persistent pain after breast cancer treatment show an enhanced and slowed dominant alpha activity in their electroencephalogram (EEG) recorded during rest in comparison with patients that also had undergone breast cancer treatment but do not have pain.

Methods: The spontaneous EEG was recorded during rest and before painful stimulation of the calf and analyzed with spectral analysis (Fast Fourier Transformation). Outcome measures, i.e., alpha indices (center of gravity and overall amplitude), were statistically tested between patients with and without persistent pain.

Results: In comparison with patients without pain, patients with persistent pain after breast cancer treatment show more alpha activity in their spontaneous EEG observed from parietal-occipital brain regions.

Conclusion: Persistent pain after breast cancer treatment affects spontaneous brain activity, which might influence cognitive functioning.
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http://dx.doi.org/10.1111/pme.12216DOI Listing
December 2013

Sensitivity to itch and pain in patients with psoriasis and rheumatoid arthritis.

Exp Dermatol 2013 Aug 27;22(8):530-4. Epub 2013 Jun 27.

Department of Medical Psychology, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

Symptoms of itch and pain in chronic inflammatory conditions of psoriasis (PS) and rheumatoid arthritis (RA) can highly affect patients' quality of life. Studies in other patient groups indicate that sensitivity to itch and pain is altered in line with the patient's main symptom of either chronic itch or pain, as a result of sensitization processes. This study directly compared whether patients with chronic inflammatory conditions associated with chronic itch or pain display a heightened sensitivity to itch and pain, respectively. Sensitivity to itch and pain was measured by applying stimuli of quantitative sensory testing (QST) in female patients with chronic itch due to PS or chronic pain due to RA. Levels of itch and pain evoked by the QST stimuli as well as the tolerance to the stimuli were determined. Patients with PS reacted to the stimuli with a higher itch response (histamine), while the patients with RA displayed a lowered tolerance to the stimuli (cold pressor test and mechanical stimulation) in comparison with the other patient group. In line with previous studies in other patient groups with chronic itch or pain, further support was found that somatosensory stimuli are processed in line with the patients' main symptom through generic sensitization processes, also in chronic inflammatory conditions such as PS and RA.
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http://dx.doi.org/10.1111/exd.12189DOI Listing
August 2013

Early surgery versus optimal current step-up practice for chronic pancreatitis (ESCAPE): design and rationale of a randomized trial.

BMC Gastroenterol 2013 Mar 18;13:49. Epub 2013 Mar 18.

Department of Surgery, Academic Medical Center Amsterdam, PO 22660, 1100 DD, Amsterdam, the Netherlands.

Background: In current practice, patients with chronic pancreatitis undergo surgical intervention in a late stage of the disease, when conservative treatment and endoscopic interventions have failed. Recent evidence suggests that surgical intervention early on in the disease benefits patients in terms of better pain control and preservation of pancreatic function. Therefore, we designed a randomized controlled trial to evaluate the benefits, risks and costs of early surgical intervention compared to the current stepwise practice for chronic pancreatitis.

Methods/design: The ESCAPE trial is a randomized controlled, parallel, superiority multicenter trial. Patients with chronic pancreatitis, a dilated pancreatic duct (≥5 mm) and moderate pain and/or frequent flare-ups will be registered and followed monthly as potential candidates for the trial. When a registered patient meets the randomization criteria (i.e. need for opioid analgesics) the patient will be randomized to either early surgical intervention (group A) or optimal current step-up practice (group B). An expert panel of chronic pancreatitis specialists will oversee the assessment of eligibility and ensure that allocation to either treatment arm is possible. Patients in group A will undergo pancreaticojejunostomy or a Frey-procedure in case of an enlarged pancreatic head (≥4 cm). Patients in group B will undergo a step-up practice of optimal medical treatment, if needed followed by endoscopic interventions, and if needed followed by surgery, according to predefined criteria. Primary outcome is pain assessed with the Izbicki pain score during a follow-up of 18 months. Secondary outcomes include complications, mortality, total direct and indirect costs, quality of life, pancreatic insufficiency, alternative pain scales, length of hospital admission, number of interventions and pancreatitis flare-ups. For the sample size calculation we defined a minimal clinically relevant difference in the primary endpoint as a difference of at least 15 points on the Izbicki pain score during follow-up. To detect this difference a total of 88 patients will be randomized (alpha 0.05, power 90%, drop-out 10%).

Discussion: The ESCAPE trial will investigate whether early surgery in chronic pancreatitis is beneficial in terms of pain relief, pancreatic function and quality of life, compared with current step-up practice.

Trial Registration: ISRCTN: ISRCTN45877994.
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http://dx.doi.org/10.1186/1471-230X-13-49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3610165PMC
March 2013

Quantitative sensory testing predicts pregabalin efficacy in painful chronic pancreatitis.

PLoS One 2013 1;8(3):e57963. Epub 2013 Mar 1.

Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital, Aalborg, Denmark.

Background: A major problem in pain medicine is the lack of knowledge about which treatment suits a specific patient. We tested the ability of quantitative sensory testing to predict the analgesic effect of pregabalin and placebo in patients with chronic pancreatitis.

Methods: Sixty-four patients with painful chronic pancreatitis received pregabalin (150-300 mg BID) or matching placebo for three consecutive weeks. Analgesic effect was documented in a pain diary based on a visual analogue scale. Responders were defined as patients with a reduction in clinical pain score of 30% or more after three weeks of study treatment compared to baseline recordings. Prior to study medication, pain thresholds to electric skin and pressure stimulation were measured in dermatomes T10 (pancreatic area) and C5 (control area). To eliminate inter-subject differences in absolute pain thresholds an index of sensitivity between stimulation areas was determined (ratio of pain detection thresholds in pancreatic versus control area, ePDT ratio). Pain modulation was recorded by a conditioned pain modulation paradigm. A support vector machine was used to screen sensory parameters for their predictive power of pregabalin efficacy.

Results: The pregabalin responders group was hypersensitive to electric tetanic stimulation of the pancreatic area (ePDT ratio 1.2 (0.9-1.3)) compared to non-responders group (ePDT ratio: 1.6 (1.5-2.0)) (P = 0.001). The electrical pain detection ratio was predictive for pregabalin effect with a classification accuracy of 83.9% (P = 0.007). The corresponding sensitivity was 87.5% and specificity was 80.0%. No other parameters were predictive of pregabalin or placebo efficacy.

Conclusions: The present study provides first evidence that quantitative sensory testing predicts the analgesic effect of pregabalin in patients with painful chronic pancreatitis. The method can be used to tailor pain medication based on patient's individual sensory profile and thus comprises a significant step towards personalized pain medicine.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0057963PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3585877PMC
August 2013

Is altered central pain processing related to disease stage in chronic pancreatitis patients with pain? An exploratory study.

PLoS One 2013 6;8(2):e55460. Epub 2013 Feb 6.

Pain and Nociception Neuroscience Research Group, Department of Surgery Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

Background: The most dominant feature in chronic pancreatitis is intense abdominal pain. Changes in spinal and/or supraspinal central nervous system pain processing due to visceral nociceptive input play an important role in this pain. How altered pain processing is related to disease stage still needs study.

Methodology/principal Findings: Sixty chronic pancreatitis patients were compared to 15 healthy controls. Two subgroups of pancreatitis patients were defined based on the M-ANNHEIM severity index of chronic pancreatitis; i.e. moderate and severe. Pain detection and tolerance thresholds for pressure and electric stimuli were measured in six selected dermatomes (C5, T4, T10, L1, L4 and T10BACK). In addition, the conditioned pain modulation response to cold pressor task was determined. These measures were compared between the healthy controls and chronic pancreatitis patients. Severe pancreatitis patients showed lower pain thresholds than moderate pancreatitis patients or healthy volunteers. Healthy controls showed a significantly larger conditioned pain modulation response compared to all chronic pancreatitis patients taken together.

Conclusions/significance: The present study confirms that chronic pancreatitis patients show signs of altered central processing of nociception compared to healthy controls. The study further suggests that these changes, i.e. central sensitization, may be influenced by disease stage. These findings underline the need to take altered central pain processing into account when managing the pain of chronic pancreatitis.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0055460PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3566206PMC
December 2013

Effects of pregabalin on central sensitization in patients with chronic pancreatitis in a randomized, controlled trial.

PLoS One 2012 6;7(8):e42096. Epub 2012 Aug 6.

Pain and Nociception Neuroscience Research Group, Department of Surgery, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.

Background: Intense abdominal pain is the dominant feature of chronic pancreatitis. During the disease changes in central pain processing, e.g. central sensitization manifest as spreading hyperalgesia, can result from ongoing nociceptive input. The aim of the present study is to evaluate the effect of pregabalin on pain processing in chronic pancreatitis as assessed by quantitative sensory testing (QST).

Methods: This randomized, double-blind, placebo-controlled trial evaluated effects of pregabalin on pain processing. QST was used to quantify pain processing by measuring thresholds to painful electrical and pressure stimulation in six body dermatomes. Descending endogenous pain modulation was quantified using the conditioned pain modulation (CPM) paradigm to elicit a DNIC (diffuse noxious inhibitory controls) response. The main effect parameter was the change in the sum of all body pain threshold values after three weeks of study treatment versus baseline values between both treatment groups.

Results: 64 patients were analyzed. No differences in change in sum of pain thresholds were present for pregabalin vs. placebo after three weeks of treatment. For individual dermatomes, change vs. baseline pain thresholds was significantly greater in pregabalin vs. placebo patients for electric pain detection threshold in C5 (P = 0.005), electric pain tolerance threshold in C5 (P = 0.04) and L1 (P = 0.05), and pressure pain tolerance threshold in T4 (P = 0.004). No differences were observed between pregabalin and placebo regarding conditioned pain modulation.

Conclusion: Our study provides first evidence that pregabalin has moderate inhibitory effects on central sensitization manifest as spreading hyperalgesia in chronic pancreatitis patients. These findings suggest that QST can be of clinical use for monitoring pain treatments in the context of chronic pain.

Trial Registration: ClinicalTrials.gov NCT00755573.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0042096PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3412837PMC
January 2013

The effect of high-frequency conditioning stimulation of human skin on reported pain intensity and event-related potentials.

J Neurophysiol 2012 Oct 1;108(8):2276-81. Epub 2012 Aug 1.

Department of Surgery, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.

High-frequency conditioning electrical stimulation (HFS) of human skin induces an increased pain sensitivity to mechanical stimuli in the surrounding nonconditioned skin. The aim of this study was to investigate the effect of HFS on reported pain sensitivity to single electrical stimuli applied within the area of conditioning stimulation. We also investigated the central nervous system responsiveness to these electrical stimuli by measuring event-related potentials (ERPs). Single electrical test stimuli were applied in the conditioned area before and 30 min after HFS. During electrical test stimulation, the reported pain intensity (numerical rating scale) and EEG (ERPs) were measured. Thirty minutes after conditioning stimulation, we observed a decrease of reported pain intensity at both the conditioned and control (opposite arm) skin site in response to the single electrical test stimuli. In contrast, we observed enhanced ERP amplitudes after HFS at the conditioned skin site, compared with control site, in response to the single electrical test stimuli. Recently, it has been proposed that ERPs, at least partly, reflect a saliency detection system. Therefore, the enhanced ERPs might reflect enhanced saliency to potentially threatening stimuli.
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http://dx.doi.org/10.1152/jn.00391.2012DOI Listing
October 2012

Reliability of static and dynamic quantitative sensory testing in patients with painful chronic pancreatitis.

Reg Anesth Pain Med 2012 Sep-Oct;37(5):530-6

Mech-Sense, Department of Gastroenterology, Aalborg Hospital, Aarhus University Hospital, Aarhus N, Denmark.

Background And Objectives: Quantitative sensory testing (QST) has proven to be an important instrument to characterize mechanisms underlying somatic and neuropathic pain disorders. However, its reliability has not previously been established in patients with visceral pain. We investigated the test-retest reliability of static and dynamic QST in patients with visceral pain due to chronic pancreatitis.

Methods: Sixty-two patients (38 men, 53 [11] y) with painful chronic pancreatitis were included. Static QST comprised sensory thresholds for pressure and electrical stimulation performed in the ventral and dorsal T10 dermatomes (sharing spinal innervation with the pancreas, ie, pancreatic viscerotomes) and in 4 heterologous regions (control areas). Dynamic QST comprised conditioned pain modulation. Measurements were obtained from 2 subsequent test sessions separated by 1 week.

Results: The reliability of static QST was generally high, with the best test-retest performance seen for pressure pain thresholds (intraclass correlation coefficients [ICC], 0.74) and electrical sensation thresholds (ICC, 0.66). In contrast, the reliability of dynamic QST was poor (ICC, 0.01). For static QST measures, the reliability was higher for pain thresholds compared with suprapain thresholds (P < 0.01). No differences between assessments in the pancreatic viscerotomes compared with heterologous regions were seen (P = 0.6).

Conclusions: Sensory thresholds in the pancreatic viscerotomes and control areas were reproducible over time. In contrast, dynamic QST measurements reflecting active central modulation of pain processing state (ie, conditioned pain modulation) were not stable over time and showed considerable variability. These factors should be taken into consideration in case QST is used to follow disease mechanisms, drug effects, or effects of pain intervention.
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http://dx.doi.org/10.1097/AAP.0b013e3182632c40DOI Listing
June 2013
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