Abstract
Introduction:
Although pain is recognized as an important symptom in gastroparesis, it has not been well studied and characterized. Quantitative sensory testing (QST) is a psychophysical method that has the potential to provide a measure of pain processing, as well as insight into pain pathophysiology and the prediction of response to specific therapies. We aimed to characterize somatic QST in a well-characterized cohort of patients with gastroparesis.
Methods:
Adults with scintigraphically-defined gastroparesis underwent abdominal QST with assessment of mechanical pain: pain sensitivity (thresholds and tolerance) and pain facilitation (temporal summation). The Patient Assessment of Upper GI Symptoms (PAGI-SYM©) upper and lower abdominal pain scales were used.
Results:
QST was performed on 264 participants (87% female; age=18–78y). In both the upper and lower abdomen, smaller pain thresholds and lower pain tolerance were significantly associated with greater PAGI-SYM upper abdominal pain severity (b’s=0.07–0.15; p’s=.007–.02), but not lower abdominal pain severity. Scores on the PAGI-SYM upper and lower abdominal pain scales were moderately correlated (r=0.48, p<.0001). No significant associations were found for temporal summation.
Conclusions:
Our findings suggest self-reported upper abdominal pain severity correlated with both lower and upper abdominal mechanical pain sensitivity—possibly reflecting secondary sensitization of the abdominal wall, due to viscerosomatic convergence in upper abdominal somatic segments. Lower abdominal pain severity association with only upper (but not lower) abdominal QST may be due to cross-organ sensitization. Further investigation are needed to test the clinical utility of abdominal QST in gastric sensorimotor disorders.
Keywords: gastroparesis, gastric emptying, dyspepsia, abdominal pain, pain threshold
Plain Language Summary:
Adults with gastroparesis commonly report abdominal pain. While abdominal pain is recognized as an important symptom, it has not been well studied and characterized. We administered a battery of standardized pain processing tests called quantitative sensory testing (QST) in the abdomen among a large cohort of adults with gastroparesis. Smaller thresholds to and tolerance of pain stimulation via QST in the upper abdomen was associated with participants’ self-reported lower and upper abdominal pain severity in the prior two weeks via survey. These findings may reflect referred visceral pain from the stomach to the abdomen and abdominal QST could be a complementary, and perhaps more clinically scalable, method to quantify sensory responsiveness in gastroparesis. Further research including associations with treatment response is needed.
Introduction
Patients with gastroparesis present with various upper gastrointestinal symptoms, including nausea, vomiting, early satiation, post-prandial fullness, bloating/distension, and abdominal pain.1–3 Abdominal pain is common in individuals with gastroparesis and is associated with negative impacts on quality of life.4,5 Subjective report of abdominal pain has been reported in up to 90%4, and daily to constant abdominal pain in up to 43%.6 Moderate to severe upper abdominal pain has also been associated with a lack of improvement in overall gastroparesis symptom severity.7 In fact, a recent best practice advisory deemed refractory abdominal pain as one of two phenotypes of medically refractory gastroparesis.3 However, the mechanisms contributing to abdominal pain in gastroparesis are not well understood which makes assessment and treatment of abdominal pain in patients with gastroparesis difficult.
Quantitative sensory testing (QST) is a psychophysical method used to characterize peripheral and central pain processing. QST involves calibrated and standardized methods to evaluate inter-individual variation in pain processing by measuring responses to noxious stimuli under highly controlled conditions.8,9 In gastrointestinal pain disorders, invasive visceral pain sensitivity testing has been used to understand visceral pain thresholds with disorder-relevant stimulation. In one study of adults with idiopathic gastroparesis, hypersensitivity to gastric balloon distension (a form of visceral QST) was associated with a greater frequency of upper abdominal (epigastric) pain.10 In a small study of 18 adults with diabetic gastroparesis, while hypersensitivity to gastric distension compared to controls in both fasted and post-prandial states, sensitivity was not significantly associated with any self-reported symptoms, including abdominal pain.11
Sensory testing based on gastric distention is invasive (due to catheter discomfort/anxiety) and while other methods are being investigated (e.g., capsaicin),12 they may not be practical to implement in routine clinical care. On the other hand, non-invasive somatic QST affords various parameters to understand different aspects of pain processing, including somatic pain sensitivity, pain tolerance, and pain facilitation.8 The rationale for using somatic QST in conditions such as gastroparesis is that chronic visceral pain is often accompanied by sensitization of topologically convergent afferent pathways from somatic tissues (abdominal wall and the skin).13,14 Such an approach has been most widely used to understand the neurobiology of pain from chronic pancreatitis15—there is promise for bedside QST methods in chronic pancreatitis16 and already validated bedside QST measures in neuropathic pain.17
In other chronic pain conditions, prior studies show that QST results are reflective of clinical pain —subjects who rate QST stimuli as most painful, or show large increases in pain with repeated stimulation (i.e., high pain facilitation), report more frequent, disabling clinical pain.18 However, how well abdominal QST is associated with self-reported abdominal pain severity in gastroparesis is unknown. There is limited evidence on somatic QST in gastric sensorimotor disorders - a study in adults with functional dyspepsia showed no difference as compared with controls in QST parameters obtained from non-abdominal regions (hand electrical stimulation and foot thermal stimulation).12 QST applied to abdominal regions that converge on viscerotropic spinal segments may therefore provide more insight into condition-specific pain mechanisms.
As an initial step to characterize QST as a technique to capture physical response to pain in gastroparesis, we aimed to evaluate the relationship between both upper and lower abdominal QST parameters with self-reported abdominal pain scores among adults with scintigraphically defined gastroparesis. We hypothesized that measures of upper and lower abdominal pain sensitivity (thresholds and tolerance) and pain facilitation (by temporal summation, i.e., an increase in pain perception with repeated, identical painful stimuli) would be significantly related to corresponding (upper and lower) abdominal pain severity. We also explored the potential relationship of QST parameters with the severity of other upper gastrointestinal symptoms and 4-hour gastric retention.
Methods
Participants
Participants included adults (age ≥18 years) with symptoms of gastroparesis enrolled in the Gastroparesis Clinical Research Consortium Gastroparesis Registry 3 (GpR3) (ClinicalTrials.gov NCT03680859). The GpR3 was an observational study across six tertiary clinical centers in the United States with patients who had symptoms of gastroparesis (nausea, vomiting, abdominal pain, bloating, and/or early satiety) for at least 12 weeks with no structural abnormality seen on upper endoscopy within one year of enrollment. We included participants who had delayed gastric emptying by gastric emptying scintigraphy within 6 months of enrollment defined by retention >60% at 2 hours and/or >10% at 4 hours.19
The Institutional Review Board at each center approved the study and informed consent was obtained from each participant. All authors had access to the study data and reviewed and approved the final manuscript.
Measures
Participants completed an in-person visit after an overnight fast of at least 8 hours and after a 3-day discontinuation of prokinetics, narcotics, anticholinergics, and cannabinoids. Participants provided a medical history and underwent physical examination, including measured height and weight to calculate body mass index (BMI).
.Following an overnight fast, participants underwent standardized 4-hour gastric emptying scintigraphy. In participants with diabetes, low blood sugar (hypoglycemia <70 mg/dl) or high blood sugar (hyperglycemia >275 mg/dl) was corrected or the test was rescheduled for another day. Following ingestion of a technetium-99m labelled low-fat egg white sandwich meal (Egg Beaters®), gastric emptying scintigraphy was performed capturing retention at 0, 1, 2, and 4 hours.20
We used the Patient Assessment of Upper GI Symptom Severity (PAGI-SYM©) to evaluate self-reported abdominal pain severity and other gastroparesis symptoms. Participants rated the severity of symptoms over the prior two weeks on a scale of 0=None to 5=Very Severe. Scores for each subscale ranged from 0 to 5, with higher scores indicating worse severity.21 Our primary subscales of interest were the Upper Abdominal Pain (average of pain and discomfort items) and Lower Abdominal Pain subscales (average of pain and discomfort items). We also explored potential relationships between the QST parameters and the other PAGI-SYM subscales of satiety/fullness, nausea/vomiting, heartburn/regurgitation, and bloating.
Participants underwent a series of abdominal QST at the study baseline visit to assess: (1) mechanical pain thresholds, (2) mechanical pain tolerance, and (3) temporal summation, a putative marker of the degree of pain facilitation. Participants were supine on an exam table with their abdomen exposed. The center of each abdominal quadrant was lightly marked with a marker. For each of the three QST assessments, the probe was applied to the center of each abdominal quadrant in succession, moving clockwise (left upper, right upper, left lower, right lower), then repeated in a second trial.
Mechanical pain thresholds and tolerance were assessed using a handheld digital pressure algometer (Wagner FPX 50; Greenwich, CT), which was applied using a 0.5cm2 rubber probe with pressure increasing at a rate of approximately 1 kilogram-force per second (1 kgf/s). Pressure did not exceed 15 kgf, aligned with other protocols;22 maximum force levels are set to minimize the potential of bruising. Pressure pain threshold (PPTh) levels were determined when the participant first reported the pressure level as painful. Pressure pain tolerance levels were determined when the participant reported the pain was intolerable (pressure did not exceed 15 kgf). For both pain threshold and pain tolerance, the second trial was conducted after a 30 second break. There was no significant difference between trials within participants, thus an average value across the two trials at for each quadrant was used.
Temporal summation was determined by delivering a train of 10 mechanical stimuli and assessing the change in pain intensity across the first, fifth, and tenth stimulation using von Frey filaments ranging in force from 0.6g to 300 g (VFF, Ugo Basile Semmes-Weinstein). First, to identify the filament strength to be used for temporal summation testing, filaments were tapped three times within each quadrant with ascending strengths until the participant reported they could feel the filament. Then, the detected filament strength was applied for 1–2 seconds in further ascending order of strength until the participant reported feeling a sharp prick or needle like sensation (strengths of 0.6–300 g); filament application with ascending strengths were completed in each quadrant. The first painful filament strength was then used for testing temporal summation. The filament was applied for approximately 1 second and repeated every second for a total of 10 times, with the participant reporting pain severity (0-no pain; 10-worst pain you can imagine) at the 1st, 5th and 10th stimulation; temporal summation was completed in each quadrant. The second trial was conducted after a 10-second break. There was no significant difference between trials within subjects.
Statistical Analysis
Participant demographic/clinical and QST characteristics were compared across two groups of PAGI-SYM abdominal pain subscores for both the upper and lower abdomen: None/very mild/mild (≤ 3) vs. Moderate/severe/very severe (≥3).4 No. (%) are presented for categorical and binary variables and Mean ± SD or Median (IQR) for continuous data are reported. Fisher’s exact or Kruskal-Wallis tests were used to compare categorical and continuous baseline characteristics by the dichotomized PAGI-SYM subscore, respectively. We calculated Pearson correlation coefficients for the association between PAGI-SYM upper and lower abdominal pain scales.
Both unadjusted and adjusted multiple linear regression models were used to assess the association between the PAGI-SYM upper and lower abdominal pain subscores and each QST test. The adjusted models include all baseline characteristics as covariates: age, sex (male vs. female), BMI, etiology of gastroparesis (idiopathic vs. diabetic), race (White vs. Other), ethnicity (Hispanic/Latino/a), and clinical center. We also controlled for the effects of history of abdominal surgery (yes vs. no) and extra-intestinal chronic primary pain conditions—history of migraines/chronic headaches (yes vs. no), history of fibromyalgia (yes vs. no), history ofand rheumatoid arthritis (yes vs. no). Using unadjusted multiple linear regression models, we also explored the association of each QST test with: (a) other PAGI-SYM subscales of satiety/fullness, nausea/vomiting, heartburn/regurgitation, and bloating, and (b) 4-hour gastric retention.
For all analyses, we averaged QST results to create two scores, upper (RUQ and LUQ) and lower (RLQ and LLQ) quadrants, to match the locations of the PAGI-SYM assessment subscores. For temporal summation, we calculated difference scores (10th stimulus pain rating minus 1st stimulus pain rating) for each trial; we then averaged the difference scores and created a dichotomized variable, with a mean difference score >0 indicating temporal summation. We dichotomized Race due to low numbers in categories other than White. We used two-sided p-values and conducted analyses using SAS 9.423 and Stata 15.1.24
Results
QST data were available for 264 participants with delayed gastric emptying, 55.7% idiopathic, and the rest diabetic by etiology (Table 1). Participants were on average 44.6 (SD=15.2) years old. Sex reported was 86.7% female and 13.3% male. Hispanic/Latino(a) ethnicity was reported by 29.6%. Race was reported as follows: 1.1% Asian, 0.8% Native Hawaiian/Pacific Islander, 9.0% Black/African American, 87.5% White, 1.1% more than one race (n=1 American Indian and White; n=1 Black/African American and White; n=1 Native Hawaiian/Pacific Islander and White).
Table 1.
Clinical characteristics by PAGI-SYM upper and lower abdominal pain severity subscore (N=264).
| Upper Abdominal Pain Severity (PAGI-SYM) |
||||
|---|---|---|---|---|
| None/Very Mild/ Mild (n=102) | Moderate/Severe/Very Severe (n=162) | Total | P-valuea | |
|
| ||||
| QST characteristics – Upper (RUQ and LUQ) | ||||
| Pressure pain threshold (kgf) | 1.46 (0.83, 2.78) | 1.12 (0.60, 2.20) | 1.26 (0.70, 2.56) | 0.03 |
| Pressure pain tolerance (kgf) | 2.44 (1.65, 4.45) | 1.85 (1.10, 3.82) | 2.12 (1.40, 4.22) | 0.004 |
| Temporal summationb | 0.15 | |||
| Increase in pain score | 31 (32.6%) | 64 (67.4%) | 95 (36.0%) | |
| No increase or decrease in pain score | 71 (42.0%) | 98 (58.0%) | 169 (64.0%) | |
| QST characteristics – Lower (RLQ and LLQ) | ||||
| Pressure pain threshold (kgf) | 1.59 (0.90, 2.62) | 1.18 (0.60, 2.28) | 1.28 (0.70, 2.38) | 0.03 |
| Pressure pain tolerance (kgf) | 2.70 (1.68, 4.50) | 1.82 (1.15, 3.98) | 2.12 (1.30, 4.01) | 0.004 |
| Temporal summation | 0.30 | |||
| Increase in pain score | 35 (34.3%) | 66 (40.7%) | 101 (38.3%) | |
| No increase or decrease in pain score | 67 (65.7%) | 96 (59.3%) | 163 (61.7%) | |
| Demographics | ||||
| Age (years) | 46.6 ± 16.0 | 43.4 ± 14.6 | 44.6 ± 15.2 | 0.10 |
| Sex | 0.002 | |||
| Male | 22 (62.9%) | 13 (37.1%) | 35 (13.3%) | |
| Female | 80 (34.9%) | 149 (65.1%) | 229 (86.7%) | |
| Race | 0.85 | |||
| White | 90 (39.0%) | 141 (61.0%) | 231 (87.5%) | |
| Otherc | 12 (36.4%) | 21 (63.6%) | 33 (12.5%) | |
| Ethnicity | 0.27 | |||
| Hispanic/Latino(a) | 26 (33.3%) | 52 (66.7%) | 78 (29.6%) | |
| Not Hispanic/Latino(a) | 76 (40.9%) | 110 (59.1%) | 186 (70.4%) | |
| Body Mass Index (kg/m2) | 29.9 ± 8.5 | 28.9 ± 7.4 | 29.3 ± 7.9 | 0.29 |
| Etiology | 0.25 | |||
| Idiopathic | 52 (35.4%) | 95 (64.6%) | 147 (55.7%) | |
| Diabetic | 50 (42.7%) | 67 (57.3%) | 117 (44.3%) | |
| Clinical characteristics | ||||
| Migraine/chronic headache | 33 (32.4%) | 73 (45.1%) | 162 (61.4%) | 0.05 |
| Fibromyalgia | 8 (7.8%) | 25 (15.4%) | 33 (12.5%) | 0.09 |
| Rheumatoid arthritis | 10 (9.8%) | 14 (8.6%) | 24 (9.1%) | 0.83 |
| History of abdominal surgery | 59 (57.8%) | 111 (68.5%) | 170 (64.4%) | 0.09 |
| Lower Abdominal Pain Severity (PAGI-SYM) |
||||
| None/Very Mild/ Mild (n=143) | Moderate/Severe/Very Severe (n=121) | Total | P-valuea | |
|
| ||||
| QST characteristics – RLQ and LLQ | ||||
| Pressure pain threshold (kgf) | 1.28 (0.78, 2.28) | 1.25 (0.52, 2.55) | 1.28 (0.70, 2.38) | 0.64 |
| Pressure pain tolerance (kgf) | 2.30 (1.45, 4.12) | 1.98 (1.23, 4.00) | 2.13 (1.30, 4.01) | 0.25 |
| Temporal summation | 0.80 | |||
| Increase in pain score | 56 (39.2%) | 45 (37.2%) | 101 (38.3%) | |
| No increase or decrease in pain score | 87 (60.8%) | 76 (62.8%) | 163 (61.7%) | |
| QST characteristics – Upper (RUQ and LUQ) | ||||
| Pressure pain threshold (kgf) | 1.25 (0.72, 2.20) | 1.28 (0.65, 2.68) | 1.26 (0.70, 2.56) | 0.99 |
| Pressure pain tolerance (kgf) | 2.25 (1.45, 4.20) | 2.00 (1.28, 4.28) | 2.12 (1.40, 4.22) | 0.34 |
| Temporal summationb | 0.30 | |||
| Increase in pain score | 47 (32.9%) | 48 (39.7%) | 95 (36.0%) | |
| No increase or decrease in pain score | 96 (67.1%) | 73 (60.3%) | 169 (64.0%) | |
| Demographics | ||||
| Age (years) | 44.6 ± 16.1 | 44.6 ± 14.2 | 44.6 ± 15.2 | 0.99 |
| Sex | 0.03 | |||
| Male | 25 (71.4%) | 10 (28.6%) | 35 (13.3%) | |
| Female | 118 (51.5%) | 111 (48.5%) | 229 (86.7%) | |
| Race | 0.27 | |||
| White | 122 (52.8%) | 109 (47.2%) | 231 (87.5%) | |
| Otherb | 21 (63.6%) | 12 (36.4%) | 33 (12.5%) | |
| Ethnicity | 0.06 | |||
| Hispanic/Latino(a) | 35 (44.9%) | 43 (55.1%) | 78 (29.6%) | |
| Not Hispanic/Latino(a) | 108 (58.1%) | 78 (41.9%) | 186 (70.4%) | |
| Body Mass Index (kg/m2) | 29.5 ± 8.0 | 29.0 ± 7.8 | 29.3 ± 7.9 | 0.59 |
| Etiology | 0.99 | |||
| Idiopathic | 80 (54.4%) | 67 (45.6%) | 147 (55.7%) | |
| Diabetic | 63 (53.8%) | 54 (46.2%) | 117 (44.3%) | |
| Clinical characteristics | ||||
| Migraine/chronic headache | 53 (37.1%) | 53 (43.8%) | 106 (40.2%) | 0.31 |
| Fibromyalgia | 10 (7.0%) | 23 (19.0%) | 33 (12.5%) | 0.005 |
| Rheumatoid arthritis | 12 (8.4%) | 12 (9.9%) | 24 (9.1%) | 0.67 |
| History of abdominal surgery | 85 (59.4%) | 85 (70.2%) | 170 (64.4%) | 0.07 |
Note. PAGI-SYM=Patient Assessment of Upper GI Symptoms©; LUQ=left upper quadrant; RUQ=right upper quadrant; LLQ=left lower quadrant; RLQ=right lower quadrant; kgf=kilogram-force. No. (%) presented for categorical or binary variables and Mean ± SD or Median (IQR) for continuous data are reported.
P-values (2-sided) determined using Fisher’s exact test for categorical variables and Kruskal-Wallis tests for continuous variables. Bolded p’s denote P<0.05.
Change in pain score (range=0–10) from the 1st to the 10th stimuli.
Race was dichotomized due to low numbers in racial groups other than White. Across the full sample, participant racial identification was as follows: n=0 American Indian/Alaska Native; n=3 Asian; n=2 Native Hawaiian/Pacific Islander; n=24 Black/African American; n=231 White; n=3 More than one race; n=1 Refused. Numbers add up to more than 264, as some participants identified with multiple race categories.
Among the whole cohort, average scores on the PAGI-SYM upper abdominal pain scale were 2.90±1.54 (range=0–5) and lower abdominal pain scores were 2.20±1.54 (range=0–5). Scores across subscales were moderately correlated (r=0.48, p<.0001). Table 1 summarizes participant characteristics by PAGI-SYM upper and lower abdominal pain scales, including the total score on each subscale as well as two groups for high scores (Moderate/Severe/Very Severe) versus low scores (None/Very Mild/Mild). High score groups included 61% of participants on the upper abdominal pain scale and 46% of participants on the lower abdominal pain scale, significantly associated with female sex (p=.002, 0.03) in both upper and lower abdominal pain scales, and significantly associated with the presence of fibromyalgia (p=0.005) in the lower abdominal pain scale only.
Compared to the low score group, the high PAGI-SYM upper abdominal score group (Moderate/Severe/Very Severe) had significantly lower QST-assessed pain thresholds as well as lower pain tolerance for stimulation applied in both the upper and lower abdominal quadrants (p=.03-.004; Table 1). A similar correlation was seen with continuous PAGI-SYM upper abdominal pain scale scores, even after adjusting for all demographic and clinical characteristics and clinical center locations (Table 2). Specifically, a one-point increase in PAGI-SYM upper abdominal pain was associated with an overall 0.13 kgf decrease in upper quadrant QST pain threshold levels (95%CI= −0.25, −0.02, p=.02) and an overall 0.09 kgf decrease in upper quadrant QST pain tolerance (95%CI= −0.16, −0.01, p=.02). Similar relationships were seen between PAGI-SYM upper abdominal pain and lower quadrant QST pain threshold and tolerance levels (Table 2). No significant associations were found for QST temporal summation. There were also no significant relationships between either upper or lower QST measures with PAGI-SYM lower abdominal pain scale scores.
Table 2:
Association of PAGI-SYM upper and lower abdominal pain subscores to quantitative sensory testing measures of the upper and lower abdominal quadrants (N=264).
|
|
||||||||
|---|---|---|---|---|---|---|---|---|
| Upper abdominal pain (PAGI-SYM subscore) | Lower abdominal pain (PAGI-SYM subscore) | |||||||
|
| ||||||||
| Unadjusted | Adjusteda | Unadjusted | Adjusteda | |||||
|
| ||||||||
| Slope [95% CI] | P-value | Slope [95% CI] | P-value | Slope [95% CI] | P-value | Slope [95% CI] | P-value | |
| Upper Abdomen QST b | ||||||||
| Pressure pain threshold (kgf) | −0.18 [−0.29, −0.08] | 0.001 | −0.13 [−0.25, −0.02] | 0.02 | −0.04 [−0.15, 0.07] | 0.45 | 0.04 [−0.07, 0.16] | 0.47 |
| Pressure pain tolerance (kgf) | −0.13 [−0.20, −0.06] | 0.001 | −0.09 [−0.16, −0.01] | 0.02 | −0.02 [−0.10, 0.05] | 0.53 | 0.02 [−0.05, 0.10] | 0.58 |
| Temporal summation | 0.37 [−0.02, 0.76] | 0.06 | 0.20 [−0.20, 0.60] | 0.33 | 0.38 [−0.01, 0.77] | 0.06 | 0.30 [−0.10, 0.70] | 0.14 |
| Lower Abdomen QST c | ||||||||
| Pressure pain threshold (kgf) | −0.18 [−0.29, −0.08] | 0.001 | −0.15 [−0.26, −0.04] | 0.007 | −0.02 [−0.13, 0.08] | 0.65 | 0.05 [−0.06, 0.17] | 0.35 |
| Pressure pain tolerance (kgf) | −0.11 [−0.18, −0.04] | 0.002 | −0.07 [−0.14, −0.002] | 0.04 | −0.02 [−0.09, 0.05] | 0.59 | 0.02 [−0.05, 0.09] |
0.54 |
| Temporal summation | 0.18 [−0.20, 0.57] | 0.36 | 0.04 [−0.34, 0.43] | 0.82 | −0.05 [−0.44, 0.33] | 0.79 | −0.16 [−0.54, 0.23] | 0.43 |
Note. PAGI-SYM=Patient Assessment of Upper GI Symptoms©; LUQ=left upper quadrant; RUQ=right upper quadrant. Pressure pain threshold and pressure pain tolerance: kilogram-force (kgf) per 1 unit change. Temporal summation: change in pain score (0–10) from the 1st to the 10th stimuli.
Adjusted for age, sex (male vs female), body mass index, etiology (idiopathic vs diabetic), race (White vs Other), ethnicity [Hispanic/Latino(a) vs Non-Hispanic/Latino(a)], history of migraines/chronic headaches (yes vs. no), history of fibromyalgia (yes vs. no), history of rheumatoid arthritis (yes vs. no), history of abdominal surgery (yes vs. no), and clinical center.
Linear regression predicting PAGI-SYM upper and lower abdominal pain subscores with upper abdominal QST measures (LUQ and RUQ values averaged).
Linear regression predicting PAGI-SYM upper and lower abdominal pain subscores with lower abdominal QST measures (LLQ and RLQ values averaged).
When evaluating the potential relationships between each QST measure with demographic and clinical characteristics (Table 3), lower pressure pain thresholds were significantly associated with younger age, female sex, idiopathic etiology, non-Hispanic/Latino(a) ethnicity, and history of fibromyalgia. Lower pressure pain thresholds were also significantly associated with normal BMI, relative to other BMI categories. There was a trend towards an association between lower pain thresholds and history of migraines/chronic headaches. Temporal summation was not significantly associated with any demographic or clinical characteristic.
Table 3:
Quantitative Sensory Test measures by Clinical Characteristics (N=264).a
|
|
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|---|---|---|---|---|---|---|
| Pressure Pain Threshold (kgf) | Pressure Pain Tolerance (kgf) | Temporal summation (Increase) | ||||
|
| ||||||
| Characteristic | Median (IQR) | P-valueb | Median (IQR) | P-valueb | n (%) | P-valueb |
| Age | 0.001 | 0.15 | 0.62 | |||
| ≥ 45 years | 1.65 (0.88, 2.94) | 2.57 (1.36, 4.46) | 59 (46.5%) | |||
| < 45 years | 1.15 (0.65, 1.75) | 1.83 (1.34, 3.51) | 59 (43.1%) | |||
| Sex | 0.03 | 0.001 | 0.10 | |||
| Female | 1.24 (0.69, 2.38) | 2.04 (1.29, 3.91) | 107 (46.7%) | |||
| Male | 1.83 (1.01, 2.96) | 3.08 (1.83, 6.54) | 11 (31.4%) | |||
| Etiology | 0.01 | 0.49 | 0.46 | |||
| Diabetic | 1.49 (0.76, 2.93) | 2.35 (1.35, 4.38) | 49 (41.9%) | |||
| Idiopathic | 1.18 (0.64, 2.08) | 2.04 (1.35, 3.81) | 69 (46.9%) | |||
| Body Mass Indexc | 0.001 | 0.18 | 0.35 | |||
| Underweight (< 18.5 kg/m2) | 1.20 (0.47, 1.98) | 2.03 (1.38, 4.44) | 9 (56.2%) | |||
| Normal weight (18.5 to 25 kg/m2) | 0.94 (0.51, 1.69) | 1.74 (1.16, 2.96) | 34 (51.5%) | |||
| Overweight (25 to 30 kg/m2) | 1.38 (0.91, 2.51) | 2.62 (1.76, 5.09) | 24 (38.7%) | |||
| Obese (≥30 kg/m2) | 1.50 (0.82, 3.07) | 2.31 (1.37, 4.19) | 51 (42.5%) | |||
| Raced | 0.84 | 0.67 | 0.58 | |||
| White | 1.31 (0.72, 2.51) | 2.11 (1.35, 4.24) | 105 (45.5%) | |||
| Other | 1.18 (0.81, 1.85) | 1.98 (1.38, 3.20) | 13 (39.4%) | |||
| Ethnicity | 0.003 | 0.20 | 0.28 | |||
| Hispanic/Latino(a) | 1.67 (0.96, 3.02) | 2.57 (1.38, 4.56) | 39 (50%) | |||
| Not Hispanic/Latino | 1.18 (0.61, 2.11) | 2.06 (1.32, 3.91) | 79 (42.5%) | |||
| Migraines/ chronic headaches | 0.05 | 0.04 | 0.17 | |||
| Yes | 1.14 (0.64, 2.18) | 1.82 (1.25, 3.74) | 53 (50.0%) | |||
| No | 1.46 (0.76, 2.68) | 2.52 (1.38, 4.46) | 65 (41.1%) | |||
| Fibromyalgia | 0.006 | 0.003 | 0.13 | |||
| Yes | 0.91 (0.46, 1.39) | 1.53 (0.81, 2.51) | 19 (57.6%) | |||
| No | 1.41 (0.81, 2.56) | 2.28 (1.38, 4.38) | 99 (42.9%) | |||
| Rheumatoid arthritis | 0.21 | 0.14 | 0.83 | |||
| Yes | 1.71 (0.84, 3.09) | 3.13 (1.39, 5.17) | 10 (41.7%) | |||
| No | 1.26 (0.73, 2.41) | 2.06 (1.33, 4.04) | 108 (45.0%) | |||
| History of abdominal surgery | 0.77 | 0.58 | 0.90 | |||
| Yes | 1.29 (0.68, 2.51) | 2.26 (1.25, 4.14) | 75 (44.1%) | |||
| No | 1.29 (0.78, 2.40) | 2.04 (1.59, 4.08) | 43 (45.7%) | |||
Note. Pressure pain threshold and pressure pain tolerance: kilogram-force (kgf) per 1 unit change. Temporal summation: change in pain score (0–10) from the 1st to the 10th stimuli.
All abdominal quadrant (RUQ, LUQ, RLQ, LLQ) averaged.
P-values (2-sided) determined using Fisher’s exact test for temporal summation. Other QST measures used Kruskal-Wallis tests for all variables other than BMI categories, which was determined using ordinal regression. Bolded p’s denote p<0.05.
Participants in each BMI category were n=16 underweight, n=66 normal weight, n=62 overweight, n=120 obese.
Race was dichotomized due to low numbers in racial groups other than White. Across the full sample, participant racial identification was as follows: n=0 American Indian/Alaska Native; n=3 Asian; n=2 Native Hawaiian/Pacific Islander; n=24 Black/African American; n=231 White; n=3 More than one race; n=1 Refused. Numbers add up to more than 264, as some participants identified with multiple race categories.
Exploratory relationships between each QST measure with other PAGI-SYM subscales are reported in Supplemental Table 1. We found that lower pain thresholds and lower pain tolerance (both in the upper and lower abdominal quadrants) were significantly associated with worse PAGI-SYM satiety/fullness and nausea/vomiting subscales, but not heartburn/regurgitation and bloating subscales. No significant associations were found for QST temporal summation. There were no significant relationships between any QST measure and gastric retention at 2 hours and 4 hours on scintigraphy (Supplemental Table 2).
Discussion
Alterations in peripheral and central nociceptive processing are both important in the maintenance of chronic pain states including visceral disorders such as gastroparesis. In this first report of abdominal QST in adults with gastroparesis, we found that upper, but not lower, self-reported abdominal pain severity may adequately map on to both upper and lower abdominal QST pain sensitivity by mechanical stimulation. Our findings for the QST association with upper abdominal scores possibly reflect secondary sensitization and hyperalgesia of the abdominal wall due to viscerosomatic convergence in upper abdominal somatic segments. This interpretation is further supported by our finding that greater upper and lower abdominal QST pain sensitivity was associated with worse satiety/fullness and nausea/vomiting scores but not bloating scores. Gastric visceral pain may be “referred” through visceral afferent neurons that converge with somatic afferent neurons from the upper abdominal segments with the spinal cord, resulting in viscerosomatic convergence.25 In addition, visceral pain may be driven by macrophage-driven inflammatory response in the myenteric plexus, already known to be associated with gastroparesis.26
The finding that lower abdominal pain scores were associated with upper (but not lower) abdominal QST sensitivity is arguably even more intriguing mechanistically. Lower and upper abdominal pain scores on the PAGI-SYM were positively correlated. Cross-organ sensitization at the spinal cord may explain these findings. Visceral afferents from the stomach may converge with afferents from the colon due to the close proximity between the gastric and thoracolumbar spinal segments.27 It is plausible that aberrant gastric afferent signals blend together with the colonic (non-aberrant) afferent signals. The brain then processes the information from colonic afferents similarly to those from the stomach, resulting in the perception of pain in the lower abdomen as well. This explanation predicts that both self-reported upper and lower abdominal pain severity reflect visceral pain from the stomach, which we captured by the association with QST sensitivity in the upper abdominal segments. While some patients with gastroparesis also have comorbid constipation or other lower-GI symptoms, we would have expected a correlation between lower abdominal QST and lower abdominal pain scores. These findings also suggest that abdominal QST may be applied to any part of the abdomen in this patient population to capture pain sensitivity.
Interestingly, several factors were associated with lower pain thresholds including younger age, female sex, idiopathic etiology, non-Hispanic/Latino(a) ethnicity, and history of fibromyalgia, most of which are not unexpected. Sex differences in pain sensitivity are well established28 and pain thresholds, particularly to heat, increase with age.29 Higher pain thresholds in diabetic patients may reflect underlying neuropathy, which is common.30 Aligned with studies in fibromyalgia,31 comorbid fibromyalgia was also significantly associated with lower pain thresholds and tolerance. We also found that normal BMI, relative to other BMI categories, was associated with lower pain thresholds; underweight BMI did not show this relation, possibly due to the relatively lower number of cases (n=16) in this BMI category. Greater adiposity may be associated with higher pain thresholds as demonstrated with non-abdominal QST in other clinical conditions,32 but abdominal QST testing in healthy adults has not yet investigated whether there is a relationship with weight status or adiposity.33
Abdominal temporal summation was not associated with either self-reported upper or lower abdominal pain severity. Temporal summation is used to assess degree of pain facilitation; that is, how much pain ratings increase with repeated stimulation of the same stimulus. Even in conditions with established high pain facilitation such as fibromyalgia (compared to healthy controls)34, temporal summation studies have not always been reported as abnormal.35 It is likely that a smaller number of individuals in our sample had abdominal temporal summation, and future research identifying profiles of pain processing may be useful for precision medicine efforts.36 Beyond temporal summation, there are also other aspects pain processing that should be evaluated including the degree of pain inhibition (e.g., conditioned pain modulation). Using non-abdominal pain stimulation may also contribute to pain processing profiles. For example, females with irritable bowel syndrome with comorbid fibromyalgia had greater pain sensitivity to thermal stimulation in the foot.37
Our sample of adults with gastroparesis overall had worse pain sensitivity for pressure thresholds compared to published reference values in healthy adults. Normative median pressure pain threshold levels33 for both the upper and lower abdomen are 1.7 kgf for females (compared to 1.2 in our sample) and 3.3–3.4 kgf for males (compared to 1.8 in our sample). Intriguingly, males in our sample had median pressure pain tolerance levels (3.1 kgf) that were below the normative threshold levels. Taken together, our findings suggest that adults with gastroparesis overall may have a lower threshold for somatic pain in both the lower and upper abdomen than healthy individuals. However, in the absence of a control cohort, comparisons to existing normative values have significant limitations (e.g., the effect of demographic factors, QST administration reliability). Also, normative values are lacking for abdominal pressure tolerance and temporal summation. Thus, future research contrasting adults with gastroparesis to demographically-matched controls on abdominal QST will be important.
Our study has several other limitations. We did not examine differences in patients those who did or did not meet criteria for functional dyspepsia or other gastric sensorimotor diagnoses. Asynchronous reporting of pain (which may vary with time) in QST testing is another potential confounding factor, and future studies should include pain scores immediately prior to assessment of objective measures of sensitivity. In addition, our assessment of temporal summation resulted in many 0/10 pain ratings and was limited to a dichotomous variable rather than a full range of numeric scores. Future studies in this area may consider alternative assessment methodologies for investigating temporal summation, such as using a broader range of filament strengths. Our base force was 0.6g, but six lower strength filaments as low as 0.008 g are available (VFF, Ugo Basile Semmes-Weinstein). Further, our study was limited to the use of mechanical pain stimulation, and an important next step will be to use multimodal comprehensive somatic QST testing. Our sample demographics also may not be generalizable to the general population of adults with gastroparesis, particularly those outside of tertiary care settings. While we had equitable representation of individuals identifying as Hispanic/Latino(a), individuals identifying as Asian, Black or African American, or more than one race were underrepresented compared to the general US population.38
In conclusion, abdominal QST represents a complementary, and perhaps more clinically scalable method to quantify sensory responsiveness in gastroparesis since abdominal visceral pain is usually concordant with somatic pain in the abdominal wall.13,14 Our data show that self-reported upper, but not lower, abdominal pain severity may adequately map on to overall abdominal QST pain sensitivity. These data provide an initial step in the process of developing non-invasive, standardized measures of disease-specific somatic (i.e., abdominal) pain processing in adults with gastroparesis and offer insight into factors that may be contributing to these pain processing abnormalities. Additional research is needed to further validate abdominal QST, including its prospective clinical utility and potential relationships to gastric visceral pain testing. In particular, comparisons to healthy controls are needed to identify the value of such testing in potentially identifying gastroparesis endophenotypes based on QST parameters and their potential correlation with other symptoms, outcomes or response to different treatments.
Supplementary Material
Acknowledgements:
We acknowledge the efforts of Richard McCallum, MD, Kenneth Koch, MD, and Robert Bulat, MD for patient recruitment for this study and James Tonascia, PhD for his oversight of the Scientific Data Research Center. We also acknowledge the encouragement of Frank Hamilton, MD for his substantive intellectual contributions in design and performance of this study. The authors thank the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) for its support of the GpCRC and this research. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Source of Funding:
The Gastroparesis Consortium (GpCRC) is supported by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (grants U01DK112193, U01DK112194, U01DK073983, U01DK073975, U01DK074035, U01DK074007, U01DK073974, U24DK074008). HBM is also supported by K23 DK131334.
Conflict of interest:
HBM receives royalties from Oxford University Press for her book Cognitive-Behavioral Therapy for Rumination Syndrome and from Cambridge University Press for the forthcoming sale of their book Untangling the Unhappy Gut: A Step-by-Step Guide to IBS Symptom Relief through the Gut-Brain Connection. HPP has served as a consultant for Dr. Falk and Cin Dom. TLA has served as a consultant for UpToDate, ADEPT GI, and Enterra Medical, and has a financial interest in ADEPT GI. MG has received research support from Alfasigma, and has served as a consultant for Takeda and Alfasigma. WLH has received research support from Enterra Medical, Atmo Biosciences, Alimetry, and Aclipse Therapeutics and has served on the advisory boards of Cumberland Pharmaceuticals and Enterra Medical. BPC is a consultant for Ironwood Pharmaceuticals and may receive royalties from the Rome Foundation. RJS may receive royalties from the Rome Foundation. BM has received research support from CINDOME. GF has a financial interest for intellectual property with Aclipse Two, Inc. JP has served as a consultant for Vanda and has a financial interest in Neurogastrx. BK has received research support from Vanda, Takeda, and Atmo, and has served as a consultant to Vanda, Atmo, Evoke, Novo Nordisk, Restalsis, Cindome, and Neurogastrix. EPM, LAM, IS, RJS, GAP, JT, and REE have no personal or financial conflicts to declare.
Footnotes
ClinicalTrials.gov Identifier: NCT01696747
Data availability statement:
The data that support the findings of this study will be openly available in NIDDK data repository at https://repository.niddk.nih.gov/home/.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
The data that support the findings of this study will be openly available in NIDDK data repository at https://repository.niddk.nih.gov/home/.