Impact of visceral pain on migraine symptoms in comorbid patients: a retrospective observational study

Charts relative to migraine patients examined for a first visit at the Headache Center of the « G D’Annunzio » University of Chieti in the period January 2021-January 2024 (plus a follow-up period of 1 year, up to January 1 st, 2025) were considered. Inclusion criteria for the migraine-only patients were: female sex; age range 18–58 years; a diagnosis of migraine without aura according to the ICHD-3 classification [ 15 ]; a baseline level of monthly attacks ≥ 6 in the preceding 6 months; absence of prophylactic treatment for the headache in the preceding 6 months; absence of concurrent: -forms of headache except migraine without aura, -neurologic and psychiatric diseases; recurrent/chronic painful conditions except migraine; - conditions able to influence pain sensitivity (e.g., hypertension, diabetes); prescription, at the first visit, of a stable prophylaxis for migraine with amitriptyline 10 mg/day for 1 year; presence of at least 4 control visits after the first visit (one every 3 months); written informed consent for all data collection and evaluations to be carried out at the visits at the Center [ 3 , 16 , 17 ]. Inclusion criteria for the migraine plus visceral pain patients were: female sex; age range 18–58 years; a diagnosis of migraine without aura according to the ICHD-3 classification [ 15 ]; a baseline level of monthly attacks ≥ 6 in the preceding 6 months; absence of prophylactic treatment for the headache in the preceding 6 months; absence of concurrent: - forms of headache except migraine without aura, -neurologic and psychiatric diseases; - conditions able to influence pain sensitivity (i.e., hypertension, diabetes); presence of one concurrent recurrent/chronic visceral pain diagnosis: from the female reproductive organs (dysmenorrhea, primary or secondary to endometriosis)(M + Dys) OR from the gastrointestinal tract (irritable bowel syndrome)(M + IBS), OR from the urinary tract (painful bladder syndrome or recurrent infectious cystitis)(M + PBS/C) performed by a specialist (gynaecologist or gastroenterologist or urologist) in the preceding year, not currently under specific treatment; prescription at the first visit of a stable prophylaxis for migraine with amitriptyline 10 mg/day for 1-year; presence of at least 4 control visits after the first visit (one every 3 months); written informed consent for all data collection and evaluations to be carried out at the visits at the Center [ 3 , 16 , 17 ]. The choice of migraine prophylaxis with amitriptyline, at a relatively low dose, was motivated by the larger casuistry of the Center with this compound, due to a general preference and better compliance of women patients examined at the Center towards this type of treatment for long periods of time (1 year). As part of the routine evaluations carried out at the first visit at the Headache Center, the following are recorded: mean number of headache attacks/month relative to the 6 months preceding the first visit and subsequently every month throughout the follow-up period (at least 1 year follow-up); type and number of monthly symptomatic drugs taken for the attacks in the preceding 6 months and subsequently every month throughout the follow-up period; monthly average pain intensity of the migraine attacks in the preceding 6 months and subsequently every month throughout the follow-up period (through Visual Analogue Scale -VAS); evaluation of pain thresholds to electrical stimulation in skin, subcutis and muscle in extracranial regions (trapezius, deltoid and quadriceps, unilaterally), as a measure of general pain sensitivity to electrical stimulation; evaluation of pain thresholds to pressure stimulation at muscle level in extracranial regions (trapezius, deltoid and quadriceps, unilaterally) as a measure of general pain sensitivity to pressure stimulation. mean number of headache attacks/month relative to the 6 months preceding the first visit and subsequently every month throughout the follow-up period (at least 1 year follow-up); type and number of monthly symptomatic drugs taken for the attacks in the preceding 6 months and subsequently every month throughout the follow-up period; monthly average pain intensity of the migraine attacks in the preceding 6 months and subsequently every month throughout the follow-up period (through Visual Analogue Scale -VAS); evaluation of pain thresholds to electrical stimulation in skin, subcutis and muscle in extracranial regions (trapezius, deltoid and quadriceps, unilaterally), as a measure of general pain sensitivity to electrical stimulation; evaluation of pain thresholds to pressure stimulation at muscle level in extracranial regions (trapezius, deltoid and quadriceps, unilaterally) as a measure of general pain sensitivity to pressure stimulation. All thresholds are always measured in the pain-free interval in the patients, i.e. never during a headache attack or during any other pain phase, to avoid inteference with the results. -in migraine patients comorbid with visceral pain: (a) visceral pain episodes in the preceding 6 months, i.e., number of painful menstrual cycles for dysmenorrhea patients (number of cycles with pain intensity > 7 cm of VAS, number of IBS or BPS/recurrent cystitis pain days) [ 18 ], (b) request to record : -visceral pain episodes throughout the follow-up period, -any specific therapy carried out for the visceral pain condition, and its duration, throughout the follow-up period. According to the routine protocol established at the Center, in collaboration with the Hospital gynecologists, gastroenterologists and urologists, migraine + visceral pain comorbid patients are normally proposed at the first visit to undergo a specific treatment protocol for the visceral pain comorbidity to be initiated within 15 days (see section on « Treatment of the visceral pain conditions», below). As per the Center protocol, patients are re-evaluated every 3 months (± 1 week) for at least 1 year (control visits with recording of the same parameters). After selection of charts of patients meeting the inclusion criteria step 1, a further selection was carried out, excluding charts of patients lacking complete information about one or more parameters in study, e.g., thresholds incompletely recorded, mainly due to intolerance of the patient to the procedure, migraine and/or visceral pain parameters not fully recorded by the patients; any interruption/lack of adherence to the prophylactic therapy for migraine prescribed at the first visit during the follow-up period; occurrence of new health problems during the follow-up period. A computerized constant current electrical stimulator was employed (R.S.D. Stimulator, prototype, Florence 1997) to deliver the impulses to the stimulated tissues through needle electrodes for muscle and subcutis and surface electrodes for skin. The impulses were trains of 18-ms duration, consisting of 0.5-ms monophasic square wave pulses, frequency 310 Hz, repeated automatically every 2 s. For the muscle, two monopolar needle electrodes (diameter 0.3 mm, length 25 mm, with Teflon isolation except for 2 mm at the tip), were inserted 1.5 cm apart into the tissue; their tips were made to penetrate deep under the fascia and their intramuscular position was verified by observing electrode movement under voluntary contraction. For the subcutis these same needles were pulled up, to have their tips placed just below the cutaneous surface. For the skin, surface electrodes were used, these were a 10-mm diameter circular plate in Ag/AgCl (reference electrode) and a cylinder in Ag/AgCl with a 0.3 mm-diameter base (stimulating electrode), placed 1 cm apart on the skin with interposition of conductor paste. The evaluated sites were the: lateral aspect of the upper border of the trapezius, with electrodes placed in the horizontal direction, lower half of the deltoid and lowest third of the quadriceps (anterior aspect of the thigh) with electrodes placed in the vertical direction. The method of the limits was applied for measurement of thresholds in each tissue at every site, to record typical pain sensations in each tissue, i.e., pricking pain for skin, linearly radiating prickling pain for subcutis, and cramp-like pain for muscle, according to a procedure already described in detail in previous publications [ 2 , 3 , 19 , 20 ]. The patients signalled the sensation by pressing a button connected to the stimulator. For each patient and each tissue of the body wall (muscle, subcutis and skin) the mean threshold was calculated of the 3 values recorded at trapezius, deltoid and quadriceps level as the reference electrical threshold value. Fischer’s algometer (Pain Diagnostic and Treatment, Inc., Great Neck, NY) was used to measure PPTs. This is a pressure dynamometer with a 1-cm diameter rounded probe. Evaluation sites were the trapezius, deltoid, and quadriceps muscles of one side. Two different points were evaluated in each of these 3 muscles, i.e., lateral and medial for trapezius, and upper and lower for deltoid and quadriceps. The algometer was placed perpendicularly on each point of each site and the pressure was gradually increased by 0.1 Kg-f/s until the first report of discomfort by the patient. The corresponding Kg-f value was recorded as the threshold for each point. For each patient, the mean threshold was calculated of the 6 values recorded in trapezius, deltoid and quadriceps as the reference PPT value [ 3 ]. During threshold evaluation the patients were lying comfortably on an adjustable couch in a quiet room. Any visceral pain treatment was initiated subsequently to the first visit (within 15 days from the visit) so that in baseline conditions the visceral disease was not currently under treatment. Patients’ records of the M + Dys category were reviewed for the occurrence of either hormonal treatment of primary dysmenorrhea for 6 months or laser treatment of endometriosis lesions for secondary dysmenorrhea (gynecologists’ prescription). In patients undergoing hormonal treatment, starting within 1 month after suspension of treatment, all parameters relative to the subsequent 6 months were derived from the charts and compared with those relative to the 6 months preceding start of the hormonal therapy. For patients undergoing laser treatment of endometriosis, starting within 1 month after the procedure, all the parameters were considered relative to the subsequent 6 months and compared with those relative to the 6 months preceding laser treatment. Charts were reviewed of patients with M + Dys not undergoing any specific visceral pain treatment, but under the same prophylactic treatment for migraine as those of the patients undergoing visceral treatment, for comparison of the same parameters as for the visceral pain treated group. Records of the M + IBS patients were reviewed for the occurrence of a 6-month dietary regimen for IBS (gastroenterologists’ prescription). Starting within 1 month after discontinuation of the diet, all parameters relative to the subsequent 6 months were derived from the charts and compared with those relative to the 6 months preceding start of the dietary regimen. Charts were reviewed of patients with M + IBS not undergoing any specific IBS treatment, but under the same prophylactic treatment for migraine as those of the patients undergoing visceral treatment, for comparison of the same parameters as for the visceral pain treated group. Records of the M + PBS/C patients were reviewed for the occurrence of : - the commonly applied local treatment program for PBS (urologists’ prescription) [twice weekly vesical instillations for 4 weeks and then weekly instillations (« cocktail » of Dimethyl sulfoxide (DMSO), methylprednisolone or hydrocortisone, alkalised lidocaine and heparin sulfate) for further 4 weeks, for a total of 12 instillations, over a period of 2 months; - repeated cycles of antibiotics for infectious cystitis over 2 months]. Starting within 1 month after cessation of these therapies, all parameters relative to the subsequent 6 months were derived from the charts and compared with those relative to the 6 months preceding start of the visceral therapies. Charts were reviewed of patients with M + PBS/C not undergoing any specific visceral treatment, but under the same prophylactic treatment for migraine as those of the patients undergoing visceral treatment, for comparison of the same parameters as for the visceral pain treated group at comparable times (Fig. 1 ). Fig. 1 schematically summarizes the evaluation steps of patients included in the study schematically summarizes the evaluation steps of patients included in the study For the M and M + VP patients, Means ± Standard Deviation (SD) were calculated of the following parameters recorded in baseline conditions (first visit): age, migraine pain (monthly number of headache attacks and of drugs taken for their control, intensity of migraine pain attacks, retrospectively reported by the patients relative to the 6 months preceding the visit), visceral pain (number of painful episodes/days relative to the preceding 6 months, only for M + VP); pain thresholds to electrical stimulation in muscle, subcutis and skin and pressure pain thresholds in muscles. The Shapiro–Wilk test was applied to test normal distribution of variables. Since in baseline conditions all variables were nonnormally distributed, the comparison between migraine parameters and sensory parameters of the M and M + VP patients was carried out via the Mann-Whitney test (nonparametric). For each of the M + VP comorbid categories (M + Dys, M + IBS, M + PBS/C), the number of patients undergoing visceral pain therapy within 15 days from the first visit was noted (M + Dys treated, M + IBS treated, M + PBS/C treated) vs. the remaining patients not subject to any specific visceral pain therapy (M + Dys untreated, M + IBS untreated, M + PBS/C untreated). For all 3 categories of visceral pain treated patients, Means ± SD were calculated of: visceral pain parameters and migraine parameters relative to the 6 months preceding visceral therapy and the 6 months subsequent to suspension of the visceral therapy, pain thresholds recorded at the visit before start of the visceral pain therapy (6-PRE) and those recorded at 6 months after suspension of the visceral pain therapy (6-POST). For all 3 categories of visceral pain untreated patients, Means ± SD were calculated of the same parameters as for the visceral pain treated patients at comparable times. In dysmenorrhea-treated patients, the Shapiro–Wilk test ascertained normal distribution for all variables, except number of painful menstrual cycles; in dysmenorrhea-untreated patients it ascertained normal distribution for all variables except painful menstrual cycles, migraine parameters, and skin electrical pain thresholds. In IBS-treated patients, normal distribution was ascertained for all variables except migraine pain intensity, in IBS-untreated patients it was ascertained for all variables except skin electrical pain thresholds. In both PBS/C-treated and untreated patients, the Shapiro–Wilk test verified normal distribution for all variables, except migraine pain intensity, PPTs and subcutis electrical pain thresholds. For all 3 categories of visceral pain comorbid patients (dysmenorrhea, IBS, PBS/C, treated and untreated), the comparison between visceral pain and migraine parameters as well as sensory parameters before and after visceral pain treatment or no treatment was performed via Student’s t-test for paired samples for normally distributed variables and Wilcoxon matched-pairs signed ranks test for nonnormally distributed variables. For each category of visceral pain comorbidity (M + Dys, M + IBS, M + PBS/C) and each parameter, the change in percentage after visceral therapy (or no visceral therapy) was calculated vs. parameters before visceral therapy (or no visceral therapy). The comparison of percentage changes between treated and untreated patients was performed via Student’s t-test for unpaired samples. One-way ANOVA was applied to assess the trend for difference in mean age of the different patient categories. The level of significance was established at p  < 0.05.

Charts relative to 2,903 migraine patients evaluated at the Center for a first visit were reviewed, of whom 454 met the inclusion criteria - step 1 established in the protocol (218 for migraine-only patients and 236 for migraine + visceral pain patients). The further selection carried out on these charts according to inclusion criteria - step 2 excluded n. 198 patients lacking complete information about one or more parameters in study. At the end of the process, n. 256 charts were thus finally included in the analysis: migraine-only: 117 patients, mean age: 33.12 ± 7.88 years (Mean ± SD). migraine + visceral pain: 139 patients (mean age: 34.83 ± 8.34 yrs) (50 with primary or secondary dysmenorrhea, mean age: 34.06 ± 8.22 yrs; 48 with IBS, mean age 35.90 ± 9.27 yrs; 41 with painful bladder syndrome or recurrent cystitis, mean age: 34.51 ± 7.37 yrs). migraine-only: 117 patients, mean age: 33.12 ± 7.88 years (Mean ± SD). migraine + visceral pain: 139 patients (mean age: 34.83 ± 8.34 yrs) (50 with primary or secondary dysmenorrhea, mean age: 34.06 ± 8.22 yrs; 48 with IBS, mean age 35.90 ± 9.27 yrs; 41 with painful bladder syndrome or recurrent cystitis, mean age: 34.51 ± 7.37 yrs). M and M + VP patients did not differ significantly for mean age. There was also no significant trend for the difference in mean age among migraine-only patients and M + Dys, M + IBS and M + PBS/C patients. All migraine parameters in M patients were significanly different from those in M + VP comorbid patients. In particular, the mean number of monthly migraine attacks, the number of symptomatics taken for their control (triptans or NSAIDs or simple or combination analgesics), and the intensity of the attack pain in the comorbid patients were significantly higher than those in the migraine only patients ( p  < 0.0001)(Fig. 2 ). Fig. 2 Migraine parameters in migraine- only patients (M, n. 117) and migraine + visceral pain comorbid patients (M + VP, .n. 139) recorded at the first visit. Means ± Standard Deviation (SD). *** : p <0.001, comparison between M and M + VP Migraine parameters in migraine- only patients (M, n. 117) and migraine + visceral pain comorbid patients (M + VP, .n. 139) recorded at the first visit. Means ± Standard Deviation (SD). *** : p <0.001, comparison between M and M + VP Sensory parameters were also significantly different in M vs. M + VP patients, i.e., electrical muscle, subcutis and skin pain thresholds and pressure pain thresholds in M + VP were significantly lower than those in M patients ( p  < 0.0001) (Fig. 3 ). Fig. 3 Pain thresholds to electrical stimulation in muscle (Ms EPTs), subcutis (Sb EPTs) and skin (Sk EPTs) and to pressure stimulation (PPTs). Legend as for Fig. 2 Pain thresholds to electrical stimulation in muscle (Ms EPTs), subcutis (Sb EPTs) and skin (Sk EPTs) and to pressure stimulation (PPTs). Legend as for Fig. 2 N 21 patients of the M + Dys category underwent treatment for the visceral pain condition (n. 17 hormonal treatment, n. 4 laser therapy), while 29 patients did not undergo any visceral pain treatment, but were subject to the same prophylactic treatment of migraine as the visceral-pain treated patients (amitriptyline, 10 mg/die). In the Migraine + Dys category, the 21 patients undergoing treatment for the visceral pain condition showed a significant reduction of their menstrual pain over 6 months post-treatment vs. the 6 months preceding treatment (Table 1 A). The dysmenorrhea-treated patients presented a significant improvement of their migraine parameters over 6 months post-treatment vs. the 6 months preceding treatment (Table 1  A; Fig. 4 ). Table 1 Migraine parameters (monthly number of attacks and of symptomatic consumption, attack pain intensity in cm of VAS) and visceral pain parameters (number of painful menstrual cycles or number of IBS pain days or number of bladder pain days over 6 months) in the three categories of migraine + visceral pain comorbid patients. i.e., Migraine + dysmenorrhea (A), Migraine + IBS (B) and Migraine + PBS/C (C), both visceral pain-treated and visceral pain-untreated, in baseline conditions (6 months before start of treatment or no treatment) and for 6 months after cessation of treatment or no treatment. Means ± SD. P values refer to statistical comparison with baseline. NS: not significant A. Migraine + dysmenorrhea Migraine and Visceral Pain Parameters Baseline Visceral pain-Treated ( N .21) + 6 Months Visceral pain- Treated ( N . 21) Baseline Visceral pain-Untreated ( N .29) + 6 Months Visceral pain- Untreated ( N .29) Migraine attacks 12.57 ± 2.38 6.71 ± 1.31 p  < 0.0001 10.76 ± 2.69 8.31 ± 1.71 p  < 0.0001 Migraine symptomatics 13.48 ± 2.50 6.33 ± 1.28 p  < 0.0001 11.62 ± 2.83 9.07 ± 1.67  p  < 0.0001 Migraine pain intensity 7.09 ± 1.18 5.76 ± 0.70 p  < 0.0001 7.07 ± 1.00 6.41 ± 1.18  p  < 0.0001 Painful menstrual cycles 5.76 ± 0.70 3.29 ± 0.78 p  < 0.0001 5.76 ± 0.74 5.52 ± 0.74 (NS) B. Migraine + IBS Migraine and Visceral Pain Parameters Baseline Visceral pain-Treated ( N .25) + 6 Months Visceral pain- Treated ( N . 25) Baseline Visceral pain-Untreated ( N .23) + 6 Months Visceral pain Untreated ( N .23) Migraine attacks 10.88 ± 2.19 7.44 ± 1.58 p  < 0.0001 10.39 ± 1.53 8.74 ± 1.84  p  < 0.0001 Migraine symptomatics 11.80 ± 1.85 7.56 ± 1.19 p  < 0.0001 11.09 ± 1.70 8.83 ± 2.23  p  < 0.0001 Migraine pain intensity 7.12 ± 1.05 5.80 ± 0.81 p  < 0.0001 7.04 ± 1.19 6.35 ± 1.03  p  < 0.002 IBS pain days 36.92 ± 5.61 30.92 ± 4.67 p  < 0.0003 35.74 ± 5.89 34.65 ± 6.44 NS C. Migraine + PBS/C Migraine and Visceral Pain Parameters Baseline Visceral pain-Treated ( N .23) + 6 Months Visceral pain- Treated ( N . 23) Baseline Visceral pain-Untreated ( N .18) + 6 Months Visceral pain Untreated ( N .18) Migraine attacks 11.39 ± 1.92 8.39 ± 1.75 p  < 0.0001 10.83 ± 2.33 9.22 ± 1.96 p  < 0.0008 Migraine symptomatics 11.78 ± 1.68 8.87 ± 1.46 p  < 0.0001 11.44 ± 2.25 9.89 ± 1.78 p  < 0.0009 Migraine pain intensity 7.17 ± 0.94 5.87 ± 1.01 p  < 0.0001 7.11 ± 1.41 6.61 ± 1.19 NS Bladder pain days 36.78 ± 8.03 25.22 ± 7.72 p  < 0.0001 34.61 ± 5.90 35.28 ± 6.73 NS Migraine parameters (monthly number of attacks and of symptomatic consumption, attack pain intensity in cm of VAS) and visceral pain parameters (number of painful menstrual cycles or number of IBS pain days or number of bladder pain days over 6 months) in the three categories of migraine + visceral pain comorbid patients. i.e., Migraine + dysmenorrhea (A), Migraine + IBS (B) and Migraine + PBS/C (C), both visceral pain-treated and visceral pain-untreated, in baseline conditions (6 months before start of treatment or no treatment) and for 6 months after cessation of treatment or no treatment. Means ± SD. P values refer to statistical comparison with baseline. NS: not significant 6.71 ± 1.31 p  < 0.0001 8.31 ± 1.71 p  < 0.0001 6.33 ± 1.28 p  < 0.0001 9.07 ± 1.67 p  < 0.0001 5.76 ± 0.70 p  < 0.0001 6.41 ± 1.18 p  < 0.0001 3.29 ± 0.78 p  < 0.0001 5.52 ± 0.74 (NS) 7.44 ± 1.58 p  < 0.0001 8.74 ± 1.84 p  < 0.0001 7.56 ± 1.19 p  < 0.0001 8.83 ± 2.23 p  < 0.0001 5.80 ± 0.81 p  < 0.0001 6.35 ± 1.03 p  < 0.002 30.92 ± 4.67 p  < 0.0003 34.65 ± 6.44 NS 8.39 ± 1.75 p  < 0.0001 9.22 ± 1.96 p  < 0.0008 8.87 ± 1.46 p  < 0.0001 9.89 ± 1.78 p  < 0.0009 5.87 ± 1.01 p  < 0.0001 6.61 ± 1.19 NS 25.22 ± 7.72 p  < 0.0001 35.28 ± 6.73 NS The dysmenorrhea-treated patients showed a significant increase in all pain thresholds at the 6 month control visit (Fig. 4 ). Fig. 4 Migraine and sensory parameters in migraine + dysmenorrhea comorbid patients (M + Dys) before and after dysmenorrhea treatment (Means ± SD, n. 21). ***= p <0.001, comparison of values before and after treatment Migraine and sensory parameters in migraine + dysmenorrhea comorbid patients (M + Dys) before and after dysmenorrhea treatment (Means ± SD, n. 21). ***= p <0.001, comparison of values before and after treatment In the 29 M + Dys comorbid patients not undergoing visceral pain treatment but only the same prophylactic treatment for migraine, visceral pain parameters remained unchanged over 6 months post-treatment vs. the 6 months preceding treatment (Table 1  A). All migraine parameters showed a significant improvement (Table 1 A, Fig. 5 ). Fig. 5 Migraine and sensory parameters in migraine + dysmenorrhea comorbid patients (M + Dys) before and after no dysmenorrhea treatment (Means ± SD, n. 29). * = p <0.05; **= p <0.01, *** p <0.001, comparison between values before and after no treatment Migraine and sensory parameters in migraine + dysmenorrhea comorbid patients (M + Dys) before and after no dysmenorrhea treatment (Means ± SD, n. 29). * = p <0.05; **= p <0.01, *** p <0.001, comparison between values before and after no treatment All pain thresholds to electrical stimulation significantly improved, while pain thresholds to pressure stimulation increased only slightly and not significantly (Fig. 5 ). In dysmenorrhea-treated patients all migraine parameters improved significantly more than in dysmenorrhea-untreated patients, i.e., there was a higher decrease in number of attacks and of symptomatic consumption as well as of attack pain intensity (Table 2  A). Table 2 Percentage of improvement of pain and sensory parameters in visceral pain-treated and visceral pain-untreated patients at follow-up (6 months after cessation of visceral treatment or no treatment) vs. baseline (6 months before start of treatment for pain parameters, values at first visit for pain thresholds) A. Migraine + Dysmenorrhea Migraine and Sensory Parameters % improvement Dysmenorrhea- Treated ( N .21) Dysmenorrhea- Untreated ( N .29) Treated vs. Untreated Migraine attacks 45.25 ± 12.65% 22.15 ± 9.03% p  < 0.0001 Migraine symptomatics 48.52 ± 16.44% 19.66 ± 14.72%. p  < 0.0001 Migraine pain intensity 16.79 ± 11.23% 9.31 ± 9.93% p  < 0.02 Muscle EPTs 17.36 ± 13.66% 8.02 ± 15.33% p  < 0.04 Subcutis EPTs 21.21 ± 21.65% 10.75 ± 13.01% p  < 0.04 Skin EPTs 21.74 ± 16.34% 11.61 ± 12.34% p  < 0.02 PPTs 35.14 ± 37.30% 4.22% ± 15.14% p  < 0.0003 B. Migraine + IBS Migraine and Sensory Parameters % improvement IBS- Treated ( N .25) IBS- Untreated ( N .23) Treated vs. Untreated Migraine attacks 29.93 ± 16.86% 16.22 ± 10.50% p  < 0.002 Migraine symptomatics 35.06 ± 10.94% 21.52 ± 12.26%. p  < 0.0003 Migraine pain intensity 17.80 ± 10.39% 9.05 ± 12.49%. p  < 0.02 Muscle EPTs 24.29 ± 20.63% 6.55 ± 19.96% p  < 0.005 Subcutis EPTs 42.25 ± 42.65% 16.46 ± 14.38% p  < 0.009 Skin EPTs 28.40 ± 24.13% 14.83 ± 19.85% p  < 0.04 PPTs 18.28 ± 10.90% 11.25 ± 11.96% p  < 0.04 C. Migraine + PBS/C Migraine and Sensory Parameters % improvement PBS/C- Treated ( N .23) PBS/C- Untreated ( N .18) Treated vs. Untreated Migraine attacks 25.17 ± 15.74% 13.89 ± 13.15% p  < 0.02 Migraine symptomatics 24.28 ± 10.41% 12.29 ± 12.46% p  < 0.002 Migraine pain intensity 17.67 ± 12.76% 10.81 ± 5.62% p  < 0.006 Muscle EPTs 18.07 ± 11.97% 8.21 ± 5.97%. p  < 0.003 Subcutis EPTs 29.29 ± 18.22% 6.79 ± 12.07% p  < 0.0001 Skin EPTs 27.49 ± 31.07% 3.93 ± 6.66% p  < 0.004 PPTs 17.15 ± 12.15% 7.17 ± 12% p  < 0.02 Percentage of improvement of pain and sensory parameters in visceral pain-treated and visceral pain-untreated patients at follow-up (6 months after cessation of visceral treatment or no treatment) vs. baseline (6 months before start of treatment for pain parameters, values at first visit for pain thresholds) Electrical pain thresholds in muscle, subcutis and skin and pressure pain thresholds all improved more in dysmenorrhea-treated than in dysmenorrhea-untreated patients. The difference in improvement was always significant (Table 2  A). N. 25 patients underwent a 6-month dietary regimen fot their IBS, while 23 patients did not undergo any IBS treatment, but were under the same prophylaxis for migraine as the IBS-treated patients (amitriptyline, 10 mg/die). In the migraine + IBS category, the 25 patients undergoing treatment of the visceral pain condition showed a significant improvement of their IBS pain over a period of 6 months post-therapy with respect to 6 months preceding therapy (Table 1 B). The IBS-treated patients presented a significant improvement of their migraine parameters over 6 months post-therapy vs. the 6 months preceding therapy (Table 1 B, Fig. 6 ). Fig. 6 Migraine and sensory parameters in migraine + IBS comorbid patients (M + IBS) before and after IBS treatment (Means ± SD, n. 25). *** = p <0.001, comparison of values before and after treatment Migraine and sensory parameters in migraine + IBS comorbid patients (M + IBS) before and after IBS treatment (Means ± SD, n. 25). *** = p <0.001, comparison of values before and after treatment In the IBS-treated patients all pain thresholds to electrical stimulation and to pressure stimulation significantly improved (Fig. 6 ). The 23 patients not undergoing IBS dietary treatment but only the same prophylactic treatment for migraine, visceral pain parameters remained unchanged over 6 months post IBS no treatment vs. 6 months preceding IBS no treatment (no significant difference)(Table 1 B). Migraine parameters significantly improved over 6 months post IBS no treatment vs. 6 months preceding IBS no treatment (Table 1 B; Fig. 7 ). Fig. 7 Migraine and sensory parameters in migraine + IBS comorbid patients (M + IBS) before and after no IBS treatment (Means ± SD, n. 23). ** = p <0.01; *** = p <0.001 Migraine and sensory parameters in migraine + IBS comorbid patients (M + IBS) before and after no IBS treatment (Means ± SD, n. 23). ** = p <0.01; *** = p <0.001 Electrical pain thresholds and pressure pain thresholds significantly increased after 6 months of IBS no treatment vs. values recorded before IBS no treatment (Fig. 7 ). In IBS-treated patients all migraine parameters improved significantly more than in IBS-untreated patients, i.e., there was a higher decrease in number of attacks and of symptomatics as well as of attack pain intensity (Table 2 B). Electrical pain thresholds in muscle, subcutis and skin and pressure pain thresholds all improved more in IBS-treated patients than in IBS-untreated patients. The difference in improvement was always significant (Table 2 B). N 23 patients with PBS/recurrent cystitis underwent visceral treatment: a standard local treatment regimen for PBS (n. 9) or repeated cycles of antibiotics for their cystitis (n. 14). N. 18 patients did not undergo any specific therapy for their visceral pain condition, but were under the same prophylactic treatment for their migraine. For the migraine + PBS/recurrent cystitis category, the 23 patients undergoing treatment of the visceral pain condition showed a significant improvement of bladder pain over 6 months post-treatment vs. 6 months preceding treatment (Table 1  C). Treated patients also presented a significant improvement of all their migraine parameters (Table 1  C; Fig.  7 ). Electrical pain thresholds in muscle, subcutis and skin and pressure pain thresholds all significantly improved post-treatment (Fig. 8 ). Fig. 8 Migraine and sensory parameters in migraine + PBS/C comorbid patients before and after PBS/C treatment (Means ± SD, n. 23). *** = p <0.001, comparison between values before and after treatment Migraine and sensory parameters in migraine + PBS/C comorbid patients before and after PBS/C treatment (Means ± SD, n. 23). *** = p <0.001, comparison between values before and after treatment In the 18 patients not undergoing bladder pain treatment but only the same prophylactic treatment for migraine, visceral pain parameters remained unchanged (no significant difference)(Table 1  C). Migraine parameters all improved after PBS/C no treatment but the difference with baseline values was significant only for the decrease in the number of monthly attacks and of symptomatics (Table 1 C; Fig.  8 ). Electrical pain thresholds and pressure pain thresholds all significantly increased (Fig. 9 ). Fig. 9 Migraine and sensory parameters in Migraine + PBS/C comorbid patients before and after PBS/C no treatment (Means ± SD, n.18). * = p <0.05; ** = p <0.01; ***= p <0.001 Migraine and sensory parameters in Migraine + PBS/C comorbid patients before and after PBS/C no treatment (Means ± SD, n.18). * = p <0.05; ** = p <0.01; ***= p <0.001 In PBS/C-treated patients all migraine parameters improved significantly more than in PBS/C-untreated patients, i.e., there was a higher decrease in number of attacks and of symptomatics as well as of attack pain intensity (Table 2  C). Electrical pain thresholds in muscle, subcutis and skin and pressure pain thresholds all improved to a greater extent in PBS/C-treated patients than in PBS/C-untreated patients. The difference in improvement was always significant (Table 2  C).

Migraine is a highly frequent and disabling neurological condition [ 1 ]. Especially migraine at a high number of attacks/chronic is characterized by hyperalgesia of somatic tissues which is not only localized in cranial areas but is also present in distant, nonpainful areas, similarly, though to a lesser extent, to what is observed in fibromyalgia (FM) patients, indicating a central sensitization state [ 2 – 8 ]. Migraine also presents a high degree of comorbidity with other recurrent/chronic painful conditions, which complicates the clinical picture of the patients [ 9 ]. Barad et al. [ 10 ] recently demonstrated that patients with chronic migraine and other chronic overlapping pain conditions as noted on body maps, report significantly worse pain-related physical function, psychosocial functioning, increased health-care utilization, and greater association with adverse life experiences, compared with those with chronic migraine only. Pain from internal organs is a condition of great diffusion in the general population, with epidemiologic studies suggesting a high degree of comorbidity with migraine, especially in women; typical examples are represented by dysmenorrhea – primary or secondary to endometriosis-, irritable bowel syndrome, and bladder pain from painful bladder syndrome or recurrent infectious cystitis [ 11 – 14 ]. Preliminary clinical observations suggest that in the visceral-migraine comorbidity the expression of migraine pain and the somatic tissue pain sensitivity can be modulated by occurrence and extent of the visceral pain episodes, with enhancement of the headache and generalized hyperalgesia [ 12 ]. If confirmed, these observations would suggest a role for specific treatment of the visceral painful condition in the global management of migraine pain. Based on these considerations, the aim of the present study was firstly to verify the hypothesis that the level of spontaneous migraine pain and general somatic pain sensitivity in migraine patients with concurrent visceral pain syndromes is higher with respect to patients with migraine only, and secondly if effective treatment of the visceral pain condition in comorbid patients also results in an improvement of the migraine pain and diffuse hyperalgesia.

Visceral pain-migraine comorbid patients versus patients with migraine only present with higher levels of migraine pain, in terms of frequency and intensity of attacks, and consequent higher consumption of symptomatics. They also present with higher levels of generalized somatic hyperalgesia as shown by lower pain thresholds in muscle, subcutis and skin to different modalities of stimulation, i.e., electrical and pressure, in extracranial regions. In all comorbid patients, migraine prophylaxis with amitriptyline effectively reduces migraine pain and somatic hyperalgesia, However, comorbid patients undergoing an effective treatment of the concurrent visceral pain condition – of gynecological, gastroenterological or urinary origin – present with a significantly higher improvement of migraine pain and somatic hyperalgesia than comorbid patients not subject to any visceral pain therapy. These data suggest that visceral pain represents a triggering factor for migraine expression in comorbid patients. This probably occurs through an enhancement of the state of central sensitization, in turn responsible for a higher probability of manifesting headache attacks [ 12 , 21 ]. In this perspective, the importance would emerge of systematically performing a thorough evaluation of the headache patients for the presence of painful comorbidities in internal organs and of treating these concurrent syndromes as an integral part of the therapeutic plan for management of the headache. The present study also adds to the increasing recognition [ 22 ] that some prevalent chronic pain conditions seem to coexist in the same individual and that these coexisting conditions tend to be more common in women as compared to men. The concept of these coexisting pain conditions has been recognized by the US National Institutes of Health and the United States Congress and the term Chronic Overlapping Pain Conditions (COPCs) has been coined to refer to these disorders that often occur together [ 11 , 23 ]. This study has limitations: firstly the retrospective nature of the analysis, secondly the relatively limited number of analyzed patients. Also, patients were not randomized to the treatment of visceral pain conditions as they were selected according to the severity and characteristics of their disorders; hence, selection bias cannot be excluded from our study and the comparison between patients treated and untreated for visceral pain conditions should be taken with caution. Future prospective studies on a larger number of patients are needed for further confirmation of the results; these should also include a separate investigation of pre-menopausal women and women in peri-menopause and menopause, considering the importance of the female sex hormones in the modulation of migraine pain and the documented enhancement of migraine pain in the critical peri-menopausal period [ 24 ] However, in spite of these limitations, to the best of our knowledge this is the first study to address the impact of visceral pain and its treatment on migraine expression. If confirmed in future prospective studies, these results shed light into the complex interplay between visceral pain and migraine in patients and have important potential implications for the management of complex comorbid patients. In addition, the results of the present study have significant implications for the design of future clinical pain trials and emphasize the importance to incorporate rather than exclude COPCs to promote identification of safe and effective therapies for patients with these conditions, rather than focussing on a single pain condition [ 3 , 23 , 25 ].

Visceral pain comorbidity in migraine involves higher levels of migraine pain and generalized somatic hyperalgesia with respect to migraine only. Effective treatment of the visceral pain condition results in improvement of the migraine pain and general hyperalgesia suggesting a systematic approach towards visceral pain management in migraine comorbid patients in addition to the specific migraine treatment.