Neurogastroenterology & Motility Neurogastroenterol Motil (2014) 26, 489–498

doi: 10.1111/nmo.12291

Dysfunctional endogenous pain modulation in patients with functional dyspepsia C. H. WILDER-SMITH ,*,† X. LI ,† L. SHEN ,‡ Y. CAO ,† K. Y. HO †

& R. K. WONG †

*Brain-Gut Research Group, Bern, Switzerland †Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore ‡Biostatistics Unit, Yong Loo Lin School of Medicine, National University of Singapore, Singapore

Key Messages

• Endogenous modulation of visceral and somatic pain was dysfunctional in patients with functional dyspepsia.

The cognitive modulation of visceral pain by distraction was especially impaired. Diminished visceral pain modulation by distraction correlated with a greater intensity of clinical pain in functional dyspepsia. Endogenous pain modulation is central to the processing and integration of all afferent sensory information and may represent an underlying pathogenic mechanism in functional dyspepsia.

13.6) in controls (p = 0.07) and by 7.1 ( 2.29 to 16.47) in FD (p = 0.1), with no significant difference in EPM between controls and FD ( 2.0 [ 14.5 to 10.5]; p = 0.75). In patients with prominent FD pain, greater pain correlated with decreased visceral EPM by distraction (r = 0.51, p = 0.04). Somatic EPM by heterotopic stimulation significantly decreased foot pain in controls (p = 0.004), but not in FD (p = 0.80). Conclusions & Inferences In FD, visceral pain modulation by distraction was dysfunctional compared to controls. Somatic pain modulation was also decreased in FD. These data and the correlation of abnormal pain modulation by distraction with clinical pain in pain-predominant FD suggest a potential pathophysiological significance of abnormal pain modulation in FD.

Abstract Background Endogenous pain modulation (EPM) is central to the processing of sensory information. Visceral and somatic EPM are abnormal in irritable bowel syndrome, but have not been studied in functional dyspepsia (FD). Methods Visceral EPM was assessed in 34 FD patients and 42 healthy controls. Gastric pain was induced with oral capsaicin and EPM was studied by adding heterotopic thermal foot stimulation or distraction by STROOP test. Somatic EPM was assessed using foot heat stimulation with heterotopic hand electrical stimulation. Key Results Endogenous pain modulation by distraction reduced mean gastric pain by 11.9 on the 0–100 visual analog scale (95% CI: 3.8–20.1) in controls (p = 0.006) and by 2.0 ( 6.18 to 10.44) in FD (p = 0.6), with greater EPM in controls than in FD (difference 13.3 [ 26.1 to 0.5]; p = 0.04). Endogenous pain modulation by heterotopic foot stimulation reduced gastric pain by 6.5 ( 0.7 to

Keywords cognitive modulation, conditioned pain modulation, diffuse noxious inhibitory controls, distraction, endogenous pain modulation, functional dyspepsia, functional gastrointestinal disorders, pain facilitation, pain inhibition, visceral pain. Abbreviations: DNIC, diffuse noxious inhibitory controls; EPM, endogenous pain modulation; FD, functional dyspepsia; IBS, irritable bowel syndrome; TRPV1, transient receptor potential cation channel subfamily V member 1 (capsaicin receptor); VAS, visual analog scale.

Address for Correspondence Clive H. Wilder-Smith, MD, FRCP, AGAF, Brain-Gut Research Group, Gastroenterology Group Practice, Bubenbergplatz 11, Bern CH-3011, Switzerland. Tel: +41 31 312 3737; fax +41 31 312 3770; e-mail: [email protected] Received: 17 May 2013 Accepted for publication: 23 November 2013

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INTRODUCTION

would be associated with increased clinical pain intensity.

A majority of patients with functional dyspepsia (FD) or irritable bowel syndrome (IBS) have visceral sensory abnormalities, including lower discomfort or pain thresholds to gastric distension and increased viscerosomatic sensory convergence compared to healthy controls.1–3 In FD, chemical hypersensitivity to oral capsaicin titration and, in a significant subset, also superficial somatic hypersensitivity have recently been demonstrated.4,5 The mechanisms behind these sensory changes are unclear, but could be driven by abnormal pain modulation at all levels of the nervous system, with a shift in the balance between pain inhibition and facilitation.6 Endogenous pain modulation (EPM) is central in fine-tuning and integrating pain perception and is closely integrated with affective, autonomic, cognitive, homeostatic, immune, and motor responses.6 Consequently, dysfunctional EPM could be implicated in both peripheral (e.g. inflammatory) and central (e.g. psychological) pathophysiological mechanisms in functional gastrointestinal (GI) disorders. The main EPM pathways include the spino-bulbo-spinal feedback loop termed diffuse noxious inhibitory controls (DNIC), the periaqueductal gray-rostroventral medulla network, and the fronto-limbic-brainstem pathways.7–9 The quantification of EPM, specifically DNIC, has been extensively validated and relies on the perceptual modulation of a painful stimulus by a second heterotopically applied nociceptive stimulus (also described as conditioned pain modulation).10–13 Using these techniques, either a decreased pain inhibition or a facilitation compared to controls has been demonstrated in a majority of IBS patients (for review see Ref. 6). This is consistent with brain imaging studies showing divergent activation patterns in areas controlling EPM in IBS.12,14 It is currently unclear if dysfunctional EPM is also implicated in FD, as no corresponding studies have been reported to date. As there is considerable overlap of FD with IBS, and EPM is abnormal in somatic pain syndromes overlapping with functional gastrointestinal disorders, such as fibromyalgia, EPM may well be dysfunctional in FD itself.15,16 Consequently, our aim was to explore EPM in FD patients using previously validated oral capsaicin and somatic stimulation paradigms, together with heterotopic stimulation for activation of EPM. Our main hypothesis was that EPM induced either by heterotopic stimulation or the comparator distraction procedure would be diminished in FD compared to controls. It was postulated that a diminished inhibitory EPM

MATERIALS AND METHODS This was a prospective, randomized, double-blind, and cross-over study performed in FD patients and healthy controls at the National University Hospital of Singapore from September 2008 to September 2011.

Subjects Forty-two male and female FD patients diagnosed according to the Rome III criteria17 and aged between 21 and 70 years were recruited from the National University Hospital gastroenterology and colorectal clinics or by public advertising (Fig. 1). For inclusion, abdominal discomfort or pain had to be the most prominent symptom and patients must have been off all FD and analgesic medication and any drugs potentially influencing sensory function for at least 2 weeks before the beginning of the study. Forty-five male and female healthy age-matched volunteers were recruited by word of mouth. Main exclusion criteria were a history of documented upper GI diseases, current or past GI symptoms, or significant abdominal pain in the last 3 months. In both groups, a clinical history assessed by questioning and medical records of other significant systemic illness, including cardiovascular, psychiatric, neurological and endocrine diseases, any other chronic or acute pain syndromes, bowel resections or abdominal operations except appendectomy, ongoing treatment with any drugs or complementary medication within the last 14 days before the start of the study, pregnancy or lactation, and absence of written informed consent led to exclusion from the study.

Ethics approval and consideration The study protocol was approved by the Institutional Review Board/Domain Specific Review Board of the National Healthcare Group, Singapore. All participants gave their written informed consent. The study was registered at Clinical Trials.gov with the identifier ID NCT00693407.

Experimental procedure Subjects were seen on four occasions. At the first visit written informed consent was obtained, the Leeds Dyspepsia Questionnaire,18 Hospital Anxiety and Depression (HAD),19 Perceived Stress20 scales, and a standard dietary questionnaire21 were completed and subjects were familiarized with the study procedures. Patients then completed a 2-week observation run-in period for prospective assessment of symptoms and pain. During this period, average daily abdominal pain and discomfort intensities were recorded on anchored, horizontal 100 mm visual analog scales (VAS: 0 = none, 100 = maximum bearable). Patients with average pain or discomfort VAS intensities >30 in the run-in period were included in the study. If all study inclusion criteria were fulfilled after these 2 weeks, the actual experimental procedures were performed after an overnight fast on the remaining three study visits, which were separated by at least 2 days (see below for test details). At the second visit, visceral pain stimulation with capsaicin and with nocebo (an inert substance given blindly for induction of pain) was performed in a randomized,

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Enrollment

Assessed for eligibility (FD patients: n = 42; control: n = 45)

Excluded (FD patients: n = 8) Not meeting inclusion criteria (n = 3) Declined to participate (n = 4) Other reasons: not contactable (n = 1)

Excluded (control: n = 3) Not meeting inclusion criteria (n = 3) Declined to participate (n = 0) Other reasons (n = 0)

Randomized: FD patients n = 34; controls n = 42)

Allocation FD patients: Allocated to intervention n = 34 Received allocated intervention n = 34

Controls: Allocated to intervention n = 42 Received allocated intervention n = 42

Did not receive allocated intervention n = 0

Did not receive allocated intervention n = 0

Follow-Up Lost to follow-up n = 1

Lost to follow-up n = 0

Discontinued intervention n = 2: 1 FD patient: failed to reach moderate pain after the maximum dose of capsaicin ingestion. 1 FD patient declined to continue test after visit 2.

Discontinued intervention n = 5: 4 controls: failed to reach moderate pain after the maximum dose of capsaicin ingestion. 1 control declined to continue test after visit 2.

Analysed n = 31 Excluded from analysis n = 0

Analysis

Analysed n = 37 Excluded from analysis n = 0

Figure 1 Study flow chart.

cross-over sequence. After a rest of 1 h somatic pain stimulation, with foot and hand pain stimuli applied alone and then together (somatic EPM) was completed. On the third and fourth study visits, either gastric capsaicin stimulation with foot heat stimulation (visceral EPM) or gastric capsaicin stimulation with mental distraction (cognitive pain modulation) was performed in randomized sequence. Tests were performed during the morning to minimize diurnal rhythm influences and within 7–14 days after the end of the menstrual period in females.

National University Hospital, Dept of Pharmacy) with 100 mL of water in a double-blind, cross-over fashion. Following ingestion, abdominal pain was rated every minute on the 100 mm VAS. If pain scores did not reach a minimum level of moderate pain (VAS 30-54)23 for at least five successive minutes within 15 min after capsule ingestion, a further capsule of the same content was swallowed. This was repeated until moderate pain of at least 5 min duration was reported or a maximum number of eight capsules were ingested. Any adverse events were recorded during this titration process. After conclusion of the titration and rating test, subjects drank 500 mL of plain water to wash out any remaining capsaicin or nocebo. Two hours later, the same dosetitration procedure was completed with the alternative capsule, this wash-out interval having previously been shown to be adequate for exclusion of any residual effect.22,24 The quality and intensity of gastric sensations other than pain were also recorded after each session. If at any time during the study, the pain intensity was >80 on the VAS, pain was immediately eliminated by drinking 500 mL of water. Sensory data from these patients were included for analysis up to this point.

Visceral pain stimulation: double-blind dose-titration regimen using ingested capsaicin or nocebo This visceral stimulation paradigm has been validated and previously described in detail.22 Briefly, subjects were randomized by computer-generated list in one block to oral dosing with identical capsules containing either capsaicin 0.5 mg (SigmaAldrich, Singapore) or nocebo (lactose monohydrate 0.5 mg,

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first. Ten minutes after its completion, capsaicin capsules were administered as for the visceral stimulation above, albeit openly. Once moderate gastric pain was reached, the STROOP test was performed concurrently for 30 s. Gastric pain intensity was rated on the 100 mm VAS intensity scale every minute for 5 min after cessation of STROOP testing and the 5-minute ratings were reported.

Somatic pain stimulation: foot heat stimulation and hand electrical stimulation Foot heat and hand electrical sensation, first pain and pain thresholds were determined using an ascending method of limits paradigm. Foot heat stimulation was applied by a Peltier thermode with a contact area of 9 cm2 and with incremental steps of 1 °C (beginning at 36 °C and with a maximum temperature of 50 °C), and 30-second stimulation and rest periods. Hand electrical stimulation was performed using a nerve stimulator (Pajunk MultiStim Varioâ, Singapore) with incremental steps of 0.5 mA (constant current 1 ms stimulation at 100 Hz) of 30-second duration until sensation, and then steps of 5 mA until pain tolerance was reached. The maximum cut-off current was 60 mA. Continuous pain ratings were recorded by VAS (graded 0–100) immediately after each stimulation. The stimulation temperature and electrical current inducing a moderate pain intensity of VAS 30-54 were determined from the ascending method of limits of foot heat and hand electrical stimulation, respectively.

Data and statistical analysis Statistical analyses were performed using the SAS (Version 9.2; SAS Institute Ins, Cary, NC, USA) and SPSS software (Version 21.0 for Windows, Chicago, IL, USA). Comparisons of demographics, pain scores, and stimulation intensities during titration were performed by t-test. The magnitude of the endogenous visceral pain modulation was defined as the difference in the change in pain intensity from before stimulation (t = 0) to 5 min after cessation of stimulation (t = 5 min), when capsaicin stimulation was performed with and without heterotopic stimulation or distraction. The difference in foot heat pain intensity with and without heterotopic hand electrical stimulation was defined as somatic pain modulation. A mixed-model analysis for repeated data was used to assess the main effects and the two-way interactions of subject groups (controls and FD patients), types of gastric stimulation (capsaicin stimulation alone, capsaicin stimulation plus foot heat stimulation, capsaicin stimulation plus STROOP distraction) and baseline VAS pain score (t = 0) on subjects’ visceral pain scores at the 5th minute (t = 5 min), and EPM. If there was no interaction, only the main effects of group and condition (within subject) were included in the model. In case of an interaction, subgroup analysis was performed to compare the effects of the EPM arms in FD patients and healthy controls. A two-sample independent t-test was used for the separate comparison of heterotopic foot and mental stimulation in FD patients vs healthy controls. Paired t-tests were used for comparing the effect of somatic EPM within groups, and a mixed model was used for comparison between groups.

Endogenous pain modulation by heterotopic stimulation Visceral: gastric capsaicin stimulation with heterotopic foot heat stimulation Capsaicin capsules were administered in identical fashion to the visceral pain stimulation described above, albeit openly. A double-blind nocebo-controlled design was not implemented, as the previous double-blind nocebo-controlled validation study demonstrated no relevant nocebo or order effects in controls or FD patients, allowing us to reduce the number of study arms in this study.22 Once moderate gastric pain was reached, foot heat stimulation at moderate pain intensity was applied simultaneously (heterotopic stimulation) for 30 s. Based on our own preliminary results with pain intensity rating every minute after heterotopic stimulation and STROOP testing, a maximum pain modulation in controls and FD patients was evoked after 5 min, which corresponds to the time-response results of previous authors using other pain models.25,26 We consequently report the pain ratings on the 100 mm VAS intensity scale at 5 min after cessation of heterotopic stimulation in this study.

Correlations of EPM by heterotopic and mental distraction with clinical abdominal pain, and with anxiety, stress, and depression rating were assessed by two-tailed Pearson’s correlation testing. Mean values are shown with their 95% confidence intervals. Median values with interquartile ranges are given for data with a non-normal distribution and categorical variables are expressed as frequencies and percentages. A p < 0.05 was considered statistically significant.

Somatic: foot heat stimulation plus heterotopic hand electrical stimulation The above-described foot heat and hand electrical stimulations at moderate pain intensity were applied concurrently, and foot pain intensity was rated on the 100 mm VAS intensity scale at the end of the heterotopic stimulation.

RESULTS Cognitive pain modulation by computerized mental distraction STROOP test

Characterization of subjects

The standardized computerized STROOP test was used as a distraction paradigm.27 It consisted of three parts. In part one, 10 colored boxes appeared on the screen one by one. Simultaneously, the names of two colors appeared below the box. The color descriptor matching the color of the box had to be chosen. In part two, 10 color words appeared on the screen successively. Below them, two names of colors appeared. Subjects were asked to choose the color descriptor that matched the word above. In part three, the word was written in a color different from the color it named. Subjects were asked to choose the color in which the word on top appeared, rather than the color that the word named. For each part, the time for task completion and the number of mistakes were recorded. The STROOP test was performed alone

Subjects’ demographic data and characteristics are shown in Table 1. The numbers of subjects recruited and reasons for exclusion are shown in Fig. 1. FD patients had similar age, gender, race, and lifestyle factors as controls. Only a small minority in both groups avoided chili meals, due to a dislike of chili. As expected, patients with FD demonstrated a higher frequency of various upper GI symptoms. Baseline HAD anxiety subset scores were higher in patients. Hospital Anxiety and Depression anxiety scores were above eight and below 11 in nine patients and above 11

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Table 1 Characteristics of participants Healthy subjects Number of subjects (n) 42 Age (95% CI): years 39.1 (35.8–42.3) Female subjects: number (%) 25/42 (60%) Chinese subjects: number (%) 31/42 (74%) * Frequency of the symptom over last 2 months, Leeds Dyspepsia Questionnaire (median, IQR) Indigestion 1 (1–2) Heartburn 1 (1–2) Regurgitation 1 (1–2) Nausea 1 (1–3) FD pain scores over last 2 weeks: mean (95% CI) 0.0 (0.0–0.0) FD discomfort scores over last 2 weeks: mean (95% CI) 3.2 (0.0–6.4) 1 Stress scores, PSS Questionnaire: mean (95% CI) 18.3 (16.6–20.0) 2 Anxiety scores, HAD Questionnaire: mean (95% CI) 3.7 (2.9–4.4) 2 Depression scores, HAD Questionnaire: mean (95% CI) 2.1 (1.5–2.7) Regular Chili ingestors: 39/42 (93%) number (%) Chili units eaten per month: 33.3 (32.87–42.8) mean (95% CI) Smokers: number (%) 1/42 (2%) Regular alcohol consumers: number (%) 3/42 (7%) Regular caffeine consumers: number (% 24/42 (57%)

FD patients

p-value

34 39.7 (34.9–44.5) 19/34 (56%) 27/34 (79%)

– 0.62 0.93 0.76

4 (2–5) 2 (1–4) 2 (1–5) 2 (1–5) 35.4 (24.8–46.0) 52.8 (43.8–60.9) 18.7 (16.7–20.7) 7.0 (5.7–8.3) 4.8 (3.6–6.0) 29/34 (85%)

Dysfunctional endogenous pain modulation in patients with functional dyspepsia.

Endogenous pain modulation (EPM) is central to the processing of sensory information. Visceral and somatic EPM are abnormal in irritable bowel syndrom...
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