Skip to main content
Download PDF
Download ePub

Offset analgesia as a marker of dysfunctional pain modulation in episodic and chronic migraine

The Journal of Headache and Pain volume 26, Article number: 50 (2025) Cite this article

Abstract

Background

The offset analgesia phenomenon refers to the disproportionately large decrease in the perceived pain following a slight decrease in intensity of a noxious heat stimulus. It is considered an expression of the activation of the endogenous pain-modulation system. The main aim of this study was to examine pain processing using the offset analgesia paradigm in subjects with interictal episodic migraine compared to those with non-ictal chronic migraine. Additionally, as secondary outcome measures, we aimed to: (1) explore fluctuations in the endogenous pain modulation system throughout the migraine cycle by including small subgroups of episodic migraine patients in different migraine phases, and (2) compare different subgroups of non-ictal chronic migraine patients with or without medication overuse headache (MOH).

Methods

A total of 68 subjects with episodic migraine (different subjects were evaluated during the interictal, preictal, ictal, or postictal phase), 34 with non-ictal chronic migraine with or without MOH, and 30 healthy controls were enrolled. Participants underwent six trials involving constant temperature and stimulus offset applied to the forehead, with pain responses measured using a continuous analogue-to-digital converter of VAS.

Results

The offset analgesia phenomenon was recorded predominantly during the postictal phase among the population of episodic migraine patients, as well as in healthy subjects. Offset analgesia was generally absent in interictal episodic migraine subjects and in subjects with chronic migraine with MOH, though some individual variability was observed. A paradoxical increase in pain facilitation was observed in most preictal and ictal episodic migraine subjects, as well as in chronic migraine subjects without MOH. The severity of offset analgesia impairment correlated with scores on the Allodynia Symptom Checklist and the Numeric Pain Rating Scale, which assessed average headache intensity during untreated migraine attacks.

Conclusions

Episodic and chronic migraine patients exhibit disrupted top-down pain modulation pathways, with more significant alterations in chronic migraine without MOH. Additionally, we provide preliminary evidence that cyclical changes in the endogenous pain modulation system could contribute to migraine recurrence in episodic migraine sufferers. However, given the small subgroups of interictal patients evaluated in different migraine phases and the cross-sectional study design, these findings should be interpreted with caution and confirmed by future longitudinal studies with larger sample sizes.

Peer Review reports

Introduction

Migraine is a chronic disease with recurrent acute attacks characterized by fluctuating changes in the activity of various areas of the brain and brainstem [1,2,3]. There is a general assumption of a pro-nociceptive pain modulation pattern in migraine, which could be at least partly due to impaired endogenous pain inhibitory systems [4, 5]. However, there is a surprising paucity of studies in this regard, and the use of different experimental paradigms has led to conflicting results, showing either normal [6,7,8,9,10] or abnormal [8, 11,12,13,14] responses to pain stimuli in migraine. Moreover, almost all studies have assessed only subjects with episodic migraine in the headache-free interval. Thus, the role of dysfunctional pain modulation in the recurrence of migraine attacks and the tendency of migraine to evolve, in some individuals, from an episodic to a chronic pattern remains unexplained.

Offset analgesia is a psychophysical paradigm increasingly used to assess the functioning of descending pain modulation systems in different chronic pain disorders [15]. Offset analgesia assesses temporal filtering mechanisms engaged when dynamic noxious stimuli are applied [16]. It is defined as a disproportionately large decrease in pain sensation following a tiny decrease in a heat pain stimulus applied to the skin [15, 17]. Offset analgesia has at least partially distinct underlying mechanisms compared to Conditioned Pain Modulation (CPM), probably the most used tests to examine inhibitory pain modulation capabilities based on the spatial filtering of pain by the ‘pain inhibits pain’ phenomenon [18]. While peripheral mechanisms may contribute to offset analgesia [19], behavioural studies [20,21,22], neuroimaging research [18, 23,24,25], and computational modelling [22, 26] suggest that central mechanisms are primarily involved. These include activation of both the descending pain modulatory and the reward systems [17, 27, 28]. Research in chronic pain populations, including those with neuropathic pain and migraine, has revealed reduced or absent offset analgesia responses, suggesting dysfunction in these central mechanisms [4, 17]. In migraine, this dysfunction may be linked to changes in brain areas such as the periaqueductal gray and rostral ventromedial medulla, which are implicated in the modulation of pain during different phases of the migraine cycle [3, 29].

To date, a single study has tested the response to the offset analgesia paradigm in a group of subjects with episodic migraine [4], revealing absent inhibitory pain modulation in the trigeminal area during the headache-free interval. Considering its potential as a marker of dysfunctional pain control in migraine, assessing offset analgesia in various phases of the migraine cycle and in chronic migraine patients could provide valuable insights into the mechanisms of attack recurrence and chronification.

The primary objective of the present study was to use the offset analgesia paradigm to evaluate whether distinct dysfunctional patterns of dynamic pain modulation underlie episodic and chronic migraine. Our a priori hypothesis was that individuals with chronic migraine would exhibit greater dysfunction in the response to the offset analgesia paradigm compared to those with episodic migraine. As secondary outcomes, we explored whether the response to the offset analgesia paradigm would change across the migraine cycle, and whether distinct response patterns are evident in individuals with non-ictal chronic migraine with or without medication-overuse headache (MOH).

Materials and methods

Subjects

Participants with episodic migraine, with or without aura, and with chronic migraine, with or without MOH according to the International Headache Society (IHS) Classification [30, 31] were included. All patients were recruited from the Headache Unit of IRCCS Mondino Foundation (Pavia, Italy) between January 2022 and January 2024. Age- and gender-matched healthy volunteers (HVs) without a personal history of migraine or first-degree relatives with migraine were also included, recruited from the institute’s staff and among partners or friends accompanying migraine patients. All subjects, including both migraine patients and healthy controls, were examined in the morning, within a time window between 9:00 AM and 1:00 PM, to minimize potential circadian influences on pain perception and offset analgesia responses. Different subgroups of participants with episodic migraine were assessed during various phases of the migraine cycle, all confirmed via a prospective headache diary and a telephone call after the experimental session: (1) interictal phase, defined as being migraine-free for at least 24 h before and 48 h after the experimental assessment (according to Peng and May [32]); (2) preictal phase, defined as the 48 h prior to the onset of a migraine attack; (3) ictal phase, during which subjects experienced a migraine attack; and (4) postictal phase, defined as up to 24 h after the ictal phase [32]. Participants with chronic migraine, with or without MOH, were evaluated during periods without headache exacerbations, the latter being defined by a headache intensity > 6 on a 0–10 Numeric Pain Rating Scale (NPRS) and migraine associated symptoms, reflecting the moderate to severe pain levels typically linked to migraine attacks [33]. Additionally, the pain intensity was required to remain ≤ 6 during the 24 h prior to and after the evaluation.

Exclusion criteria included any other headache diagnosis according to the IHS classification and, for both HVs and migraine subjects, acute or chronic pain conditions, clinically significant insomnia, and serious internal, psychiatric, or neurological diseases. Clinically significant insomnia was defined as sleep difficulties occurring at least three times per week, persisting for at least three months, and significantly impairing daytime functioning. Subjects with mild or transient sleep disturbances (e.g., occasional difficulty falling or staying asleep, early awakenings, or non-restorative sleep occurring intermittently but without major daytime impairment) were not excluded, as these are common in both the general population and individuals with migraine, without necessarily fulfilling the criteria for an insomnia disorder (see Table 1). Additionally, pregnancy, breastfeeding, skin pathologies in the tested trigeminal nerve area (V1), poor sleep quality the night before testing (defined as a self-reported poorer sleep than usual or a deviation in total sleep duration of more than 20% from the participant’s typical pattern), and alcohol consumption or intense exercise within 24 h prior to the examination were also considered as exclusion criteria. Women were not tested during their menstrual period. However, testing did not occur in the same phase of the menstrual cycle, and women undergoing hormonal therapy were not excluded (Table 1), in line with evidence suggesting that offset analgesia is independent of sex and menstrual cycle phase [34]. Use of migraine preventive medication was an exclusion criterion for subjects with episodic migraine. For participants with chronic migraine, with or without MOH, concurrent use of a single preventive migraine treatment was permitted only if stable for at least three months. Botulinum toxin and migraine-specific preventive drugs targeting Calcitonin Gene-Related Peptide (CGRP) were excluded due to their direct effects on nociceptive mechanisms.

Subjects with episodic migraine, chronic migraine without MOH, and HVs were excluded if they had taken acute pain medication within the last 48 h. For patients with chronic migraine with MOH we chose a narrower window of 24 h to avoid rebound headache.

The recruitment process, including the number of subjects initially contacted, excluded based on screening criteria, and included in the final analysis, is summarized in Fig. 1.

Written informed consent was obtained from all participants. The study adhered to the principles of the Declaration of Helsinki, and the experimental procedures were approved by the local ethics committee (IRCCS San Matteo Polyclinic in Pavia, p-20210047886). The study was retrospectively registered on ClinicalTrials.gov with the identifier NCT06599905.

Fig. 1
figure 1

Flowchart of the recruitment process. The diagram illustrates the number of subjects contacted, those who declined participation, exclusions based on eligibility criteria, and the final number of participants included in the study for both migraine patients and healthy controls

Full size image

Study procedures

All subjects underwent a single experimental session. Participants were asked to complete the questionnaires listed in the next paragraph. Subsequently, the Warm Detection Threshold (WDT) and then the heat pain threshold corresponding to a Visual Analog Scale (VAS) score of approximately 50–60 out of 100 (Pain50 − 60) were assessed at the forehead (1st branch of the trigeminal nerve, V1), followed by the assessment of three constant trials and three offset trials in the same area. We applied the stimulation to the trigeminal area based on previous evidence suggesting that alterations in pain processing and modulation in migraine may primarily or exclusively manifest in the affected area or adjacent area [4, 12, 35]. Of note, the WDT was assessed to explore potential variations in warm temperature perception during the migraine cycle, independently of whether the stimulus causes pain.

The examination was scheduled according to the subject’s availability. In the case of pain medication intake within 48 h prior to the exam for the participants with episodic migraine or chronic migraine without MOH, and for HVs, the experimental evaluation was rescheduled. Rescheduling was also put in place for participants with chronic migraine with MOH who took an acute drug within 24 h prior to the test session and for the subjects with chronic migraine enduring an exacerbation immediately before or during the test.

Headache features and questionnaires

In addition to demographic data collected in all participants, headache features were assessed by participants interview and review of the clinical history and headache diary. The following information was collected: disease duration, predominant headache side, presence of aura symptoms, mean headache intensity during a migraine attack assessed by NPRS, mean attack duration, mean number of days with mild or moderate-to-severe intensity headache over the last three months, mean number of symptomatic medications taken in the last three months, mean number of days in which symptomatic medications have been taken in the last three months (Table 1). The following questionnaires were also administered: 12-item Allodynia Symptom Checklist (ASC-12), Migraine Disability Assessment (MIDAS), and Hospital Anxiety and Depression Scale (HADS) for assessing self-reported patient levels of anxiety and depression in the previous week (Table 2).

Table 1 Characteristics of participants with episodic or chronic migraine and healthy controls
Full size table

ASC-12, 12-item Allodynia Symptom Checklist; HADS: Hospital Anxiety and Depression Scale; MIDAS, migraine disability assessment; MOH: medication overuse; n = number; NSAIDs: Non-Steroidal Anti-Inflammatory Drugs; NPRS, numeric pain rating scale; SD: standard deviation.

Warm detection threshold, 50 − 60 and offset analgesia assessment

The experimental examinations were conducted in a quiet room with the temperature maintained at 22–24 °C, performed by one of two well-trained neurophysiology technicians. The technician administering the tests was blinded to the patients’ migraine classification (episodic vs. chronic) and phase; however, full blinding was not entirely feasible. Patients in the ictal phase may have exhibited visible signs of discomfort despite being instructed not to disclose their migraine status. Additionally, complete blinding of healthy controls was challenging, as some were recruited from the institute’s staff. Before the investigation, participants were familiarized with the VAS scoring system and the experimental procedures by having the tests demonstrated at the forehead contralaterally to the tested side. Both WDT, Pain50 − 60, constant trials, and offset trials were measured on the forehead at the predominant headache side in participants with migraine and at a randomly selected forehead side in subjects without a predominant headache side and in HVs.

The experimental tests were performed using a 30 × 30 mm air-cooled heat probe capable of delivering a constant temperature in the range of 20 to 50 °C using a ramp (0.1–2 °C/s) and hold strategy. The probe was connected to a Q-sense CPM device (Medoc, Ramat Yishai, Israel). Before starting all the experimental procedures, conditions of abnormally low (< 35 °C) or high (> 37 °C) local skin temperature values were ruled out by using an infrared thermometer.

The WDT and the Pain50 − 60 were measured following standardized procedures [36, 37]. For the assessment of the WDT, we used the ‘method of levels,’ in which patients are asked to respond with ‘yes’ or ‘no’ depending on whether they perceive the warm stimulus [38, 39]. The time interval between stimuli was randomly varied within a range of 4 to 6 s. The initial temperature shift was set to 3 °C. If the participant responded ‘yes,’ the subsequent stimulus was delivered with a step size reduced by half. On the other hand, if the response was ‘no,’ the step size was doubled. Each time the response direction changed, the step size was either halved or doubled accordingly. The procedure continued until the step size was minimized to 0.1 °C, at which point the threshold was established by averaging the temperatures associated with the last ‘yes’ and ‘no’ responses. A standard sequence of level-based stimuli ultimately yielded a single threshold value. Throughout all trials, the thermode’s baseline adaptation temperature was kept at 32°C, with temperature adjustments occurring at a rate of 1°C per second. Conversely, the Pain50 − 60 was assessed using the ‘method of limits,’ where stimuli at increasing temperatures, moving from the adaptation range to the pain sensation range, were applied and the subjects were instructed to press a mouse button as soon as the pain induced by the increasing heat stimuli reached a peak of 50–60 mm on a 0-100 VAS. The test for assessing Pain50 − 60 was repeated three times to verify consistency of temperature determination. Average values were calculated to obtain a single score. The interstimulus interval of 8–10 s was kept, and no clues were given to the subject at stimulus onset. In all trials, thermode adaptation temperature was set to 32°C, with rates of temperature change of 1°C/s.

After Pain50 − 60 determination, three offset trials and three constant trials were applied at the forehead using a well-established procedure [4, 36, 40]. Average values were calculated to obtain a single score for offset trials and for constant trials. Offset trials included a 5-s exposure to a heating stimulus set at the individualized Pain50 − 60 (T1), 5-s exposure to a temperature 1 °C higher than T1 (T2), and 20-s exposure to the same temperature as T1 (T3). Constant trials included 30-s exposure to a heating stimulus set at the individualized Pain50 − 60. For subjects with Pain50 − 60 greater than 48 °C, stimulation intensity was set at 48 °C for both offset and constant trials (T1 and T3). Interstimulus intervals between trials were at least 30 s, and a new trial was not applied until any sensation of pain in the stimulated area had completely disappeared, with a minimum waiting time of 20 s after the pain had subsided. Both for offset and constant trials initial increase and final decrease rates were 2 °C/s and 1 °C/s, respectively. The six trials were performed according to two pseudorandomized sequences (offset–constant– offset– offset– constant– constant, and constant– offset– constant– constant– offset– offset). For all trials, participants were asked to evaluate pain intensity by using a continuous analogue-to-digital converter of VAS (CoVAS, Medoc, Israel) anchoring at 0 = ‘no pain’ and 100 = ‘the most intense pain imaginable’. VAS values were measured at 1-s intervals via offline analysis. Participants were unaware of the details of the offset analgesia paradigm and the study aims. All participants were instructed to carefully assess even the slightest changes in pain sensation.

Throughout the experiment, the thermode was firmly fixed on the forehead by using an elastic band with velcro. Care was taken in placing the probe, such that the best contact between probe and skin surface was achieved without causing a feeling of constriction. Subjects were informed about how to respond correctly, and, during the test, they could not see the change in temperatures on the computer screen.

Statistical analysis

Based on the previous study by Szikszay et al. [4], a sample size of N = 60 (30 participants with interictal episodic migraine and 30 HVs) was calculated. The calculation was based on a power of 0.85 and a type I error probability (α) of 0.05, using delta constant-offset mean values ± SD of 5.7 ± 19.3 recorded in participants with episodic migraine, and 19.4 ± 16 recorded in control subjects. The same number of 30 subjects was established for individuals with chronic migraine. Additional participants with episodic or chronic migraine were enrolled to account for potential dropouts. For episodic migraine, this also accommodated the possibility that some subjects might be in the preictal rather than the interictal phase. Regarding secondary outcome measures, although a specific number of participants with episodic migraine in the preictal, ictal, and postictal phases, as well as participants with chronic migraine with or without MOH, was not calculated a priori, we aimed for a minimum of 10 subjects in each of these subgroups. This decision was based on a previous study where significant neurophysiological differences were observed with similarly small subgroups of subjects with episodic migraine in different phases of the migraine cycle and chronic migraine without MOH [1].

Parametric statistics were employed since data were normally distributed according to the Kolmogorov–Smirnov test. ANOVAs were conducted to examine differences in the WDT and mean Pain50 − 60 values. Three-way repeated-measures ANOVAs were used to analyze variations in VAS scores across time (30 levels: VAS score at every second during the 30-second offset and constant trials) and conditions (two trials: offset and constant). Three separate ANOVAs were performed: 1) using ‘group’ as the between-subjects factor with three levels to compare interictal episodic migraine, chronic migraine with and without MOH, and HVs; 2) using ‘phase of the migraine cycle’ as the between-subjects factor with four levels to compare episodic migraine patients in the interictal, preictal, ictal, and postictal phases; and 3) using ‘group’ as a between-subjects factor to compare the two groups of chronic migraineurs, with or without MOH. Even though only two groups were analyzed in the latter comparison, ANOVA was used as it accounted for additional factors (‘condition’ and ‘time’), allowing assessment of interaction effects.

To disentangle adaptation or sensitization phenomena and offset effects, the magnitude of offset analgesia was quantified by subtracting pain ratings assessed during the offset trial from those during the constant trial. Specifically, average VAS values between the 19th and 28th second, the time window in which a significant offset analgesia phenomenon was observed in HVs in the present study, were computed for both offset and constant trials. This approach was chosen as it minimizes the influence of adaptation and sensitization, allowing for a more precise focus on the offset analgesia phenomenon. The difference between the mean values during constant and offset trials (Δconstant-offset) was then calculated for each subject. A more positive Δconstant-offset value indicates a greater magnitude of offset analgesia. Conversely, negative values indicate the lack of offset analgesia phenomenon or even a paradoxical facilitation.

Three separate analyses were performed for Δconstant-offset values, considering the same groups as previously mentioned. Additionally, comparative analyses including all groups together are provided in the Supplementary Materials.

ANOVAs or t-tests were used for other continuous variables, while chi-squared test corrected for continuity was carried out for categorical variables. The Huynh–Feldt correction was applied when sphericity assumptions were violated in all ANOVAs. Duncan’s post hoc test for multiple comparisons was conducted following the ANOVAs.

Two-tailed Pearson’s correlation coefficients were calculated to study the relationships between Δconstant-offset value and clinical variables.

Additional statistical analyses were conducted to further explore potential factors influencing the observed results, including assessments of order effects, group differences, correlations with pain intensity, and the impact of covariates such as sex, age, and average VAS scores during constant trials. These supplementary analyses, along with detailed results, are available in the Supplementary Materials (available as supplemental digital content).

For all analyses, P < 0.05 was considered as significant. The statistical analyses were performed using Statsoft’s Statistica version 14.2.0.

Results

We enrolled a total of 132 participants, including 68 subjects with episodic migraine (31 assessed interictally, 11 preictally, 12 ictally and 14 postictally), 34 subjects with chronic migraine (23 with and 11 without MOH) and 30 HVs. Demographic and clinical data of the subjects are summarized in Table 1.

All the recruited subjects completed all the planned experimental evaluations. The Quantitative Sensory Testing (QST) assessment was well tolerated and no drop-out occurred. No significant differences for age and gender proportions were found between HVs (mean age 37.8 years ± 17.8 SD; 19 females), participants with episodic migraine (mean age 43.6 years ± 11.9 SD; 51 females) and participants with chronic migraine (mean age 45.3 years ± 13.4 SD; 31 females).

Table 2 Presents the WDT and Pain50 − 60 values across different subgroups, reported as mean ± standard deviation (SD) along with the minimum-maximum range
Full size table

Comparison between interictal episodic migraine, non-ictal chronic migraine and healthy subjects

No significant differences in WDT and Pain50 − 60 were observed between subjects with interictal episodic migraine, chronic migraine, and HVs (Fig. 2A, B).

Fig. 2
figure 2

Warm detection threshold and Pain50 − 60 values. In A and B: subjects with episodic migraine and chronic migraine (with or without medication overuse) in comparison to healthy subjects. In C and D: comparison between subjects with chronic migraine with or without medication overuse. Mean values are reported, with standard error (box) and two standard deviations (whiskers). Dots indicate individual data points. CM: chronic migraine; EM: episodic migraine; HVs: healthy volunteers; Pain50 − 60: heat pain threshold corresponding to a Visual Analog Scale peak of 50–60 mm out of 100; MOH: medication overuse headache; WDT: Warm Detection Threshold

Full size image

An interaction between the three factors (i.e., ‘condition’, ‘time’, and ‘group’) was observed (F7,310 = 3.9, P = 0.0005) when evaluating VAS scores during offset and constant trials within the three experimental groups. Post-hoc tests were carried out to investigate differences in the VAS scores between the average values of the three constant trials and the three offset trials (Fig. 3). In HVs, a difference was observed from the 19th to the 28th s, for lower VAS values recorded during the offset trials compatible with the offset analgesia phenomenon (P < 0.05 at each 1-s time point). Instead, no significant differences were observed in the same time window in episodic migraine subjects, indicating lack of the offset analgesia phenomenon. Finally, a difference was observed from the 19th to the 25th s in the chronic migraine subjects, for higher VAS values during the offset trials compatible with a paradoxical facilitation of pain (P < 0.05 at each 1-s time point).

During constant trials, a reduction in the VAS score compared to the peak VAS recorded during the trial (indicating adaptation to the stimulus) was observed during the last 7 s in HVs, the last 8 s in episodic migraine subjects, and the last 6 s in chronic migraine subjects (P < 0.05 at each 1-second time point within every subgroup). No significant differences were observed among the three groups as regards VAS scores at each 1-s time point during constant or offset trials.

Fig. 3
figure 3

VAS values recorded during the constant trial and the offset analgesia trial. Findings are reported for healthy volunteers (A), subjects with episodic migraine during the interictal phase (B), and subjects with chronic migraine with or without medication overuse (C). Mean values are reported. Dashed lines represent standard error of the mean. The horizontal bar with an asterisk indicates significant differences (P < 0.05 at each 1-s time point) in the time window between 19 s and 28 s (indicated by the box with a dashed line). Note the absence of the offset analgesia phenomenon in episodic migraine subjects during the interictal phase and the paradoxical facilitation of pain in chronic migraine subjects

Full size image

The upper part of the figure represents the paradigm timeline for both the offset trial (blue line, showing temperature variation during the trial) and the constant trial (red line). VAS: visual analogue scale.

A mean positive Δconstant-offset value was only observed in the HVs, while negative values were recorded both in the participants with episodic and chronic migraine compared to HVs (P = 0.001 and 0.0005, respectively) (Fig. 4).

Fig. 4
figure 4

Magnitude of offset analgesia (positive values) or paradoxical facilitation of pain (negative values). Magnitude of offset analgesia is calculated as a difference between the mean VAS value recorded during the constant trial and the mean VAS value recorded during the offset trial (Δconstant-offset) in the time window between 19 s and 28 s. In A: differences between healthy volunteers, subjects with interictal episodic migraine and subjects with chronic migraine with or without medication overuse. In B: differences between different subgroups of patients with episodic migraine assessed during different phases of the migraine cycle. In C: differences between subjects with chronic migraine with or without medication overuse headache. The time window from the 19th to the 28th second (indicated by the box with a dashed line) was considered for the analyses (see text for details). Mean values are reported, with SE (box) and 2SD (whiskers). Dots indicate individual data points. The horizontal bars with an asterisk indicate significant differences (P < 0.05). Note: post-hoc comparisons following ANOVA were performed when more than two groups were compared

Full size image

CM: chronic migraine; EM: episodic migraine; HVs: healthy volunteers; MOH: medication overuse headache; VAS: visual analogue scale.

Comparison of subjects with episodic migraine evaluated in different phases of the migraine cycle

No significant differences in WDT and average Pain50 − 60 were observed between episodic migraine subjects assessed in the four different phases of the migraine cycle (Fig. 5).

Fig. 5
figure 5

Warm detection threshold (A) and Pain50 − 60 (B) during different phases of the migraine cycle. Mean values are reported. Mean values are reported, with standard error (box) and two standard deviations (whiskers). Dots indicate individual data points. Pain50 − 60: heat pain threshold corresponding to a Visual Analog Scale peak of 50–60 mm out of 100; WDT: Warm Detection Threshold

Full size image

The ANOVA performed to compare variations in VAS scores between the four subject groups revealed an interaction among the three factors ‘condition’, ‘time’, and ‘phase of the migraine cycle’ (F13,269 = 2, P = 0.02) (Fig. 6). Post-hoc tests for differences in the VAS scores between constant and offset trials were carried out considering the 19th to 28th s time window, as previously described. Higher VAS values during the offset trials, compatible with paradoxical facilitation of pain, were observed from the 19th to 24th s in subjects assessed in a preictal phase (P < 0.05 at each 1-s time point), and from the 19th to 26th s in subjects assessed during the ictal phase (P < 0.05 at each 1-s time point). Lower VAS values during the offset trials, compatible with offset analgesia phenomenon, were observed only in the subjects assessed in the postictal phase from the 23rd to 29th s (P < 0.05 at each 1-s time point). A reduction in the VAS score compared to the peak VAS during the constant trials, indicating adaptation to the stimulus, was observed during all preictal (peak vs. last 15 s), ictal (peak vs. last 5 s) and postictal (peak vs. last 6 s) phases (P < 0.05 at each 1-s time point).

Fig. 6
figure 6

VAS values recorded during the constant and offset analgesia trials throughout the migraine cycle. Findings are reported for the interictal (A), preictal (B), ictal (C), and postictal (D) phases. Mean values are reported. Dashed lines represent standard error of the mean. The horizontal bar with an asterisk indicates significant differences (P < 0.05 at each 1-s time point) in the time window between 19 s and 28 s (indicated by the box with a dashed line). Note that subjects with episodic migraine during the interictal phase are depicted in Fig. 3B. Observe the presence of the offset analgesia phenomenon only in the subgroup of subjects in the postictal phase, while a paradoxical facilitation of pain is observed in the other two subgroups

Full size image

The upper part of the figure represents the paradigm timeline for both the offset trial (blue line, showing temperature variation during the trial) and the constant trial (red line). VAS: visual analogue scale.

A mean positive Δconstant-offset value was only recorded in the postictal subgroup, while negative values were recorded during both the preictal and ictal phases (Fig. 4). A difference between subgroups was observed (p = 0.001). At post-hoc analysis, lower values were recorded in ictal vs. interictal subgroup, while significant higher values were recorded in the postictal subgroup vs. all other subgroups, also including episodic migraine subjects in the interictal phase (P < 0.05).

Comparison of chronic migraine with and without MOH

No significant between-group differences were observed in the WDT and Pain50 − 60 values (Fig. 2C, D). An interaction (F3,108 = 3.5, P = 0.01) between the three factors (i.e., ‘condition’, ‘time’, and ‘group’) was observed (Fig. 7). The post-hoc analysis for differences in the VAS scores in the 19th to 28th s time window showed higher VAS values in the chronic migraine without MOH subgroup during the offset compared to the constant trials, compatible with paradoxical facilitation of pain (P < 0.05 at each 1-s time point). No significant differences in the VAS values between offset and constant trials were observed in the chronic migraine with MOH subgroup. A reduction in the VAS score compared to the peak VAS during the constant trials was observed during the last 3 s and 7 s in chronic migraine with or without MOH, respectively (P < 0.05 at each 1-s time point). T-test showed a significantly lower mean Δconstant-offset value in chronic migraine with vs. without MOH (P = 0.005) (Fig. 4).

Fig. 7
figure 7

VAS values recorded during the constant and offset analgesia trials in subjects with chronic migraine. Findings are reported for patients with (A) or without (B) medication overuse. Mean values are reported. Dashed lines represent standard error of the mean. The horizontal bar with an asterisk indicates significant differences (P < 0.05 at each 1-s time point) in the time window between 19 s and 28 s (indicated by the box with a dashed line), compatible with paradoxical facilitation of pain

Full size image

The upper part of the figure represents the paradigm timeline for both the offset trial (blue line, showing temperature variation during the trial) and the constant trial (red line). VAS: visual analogue scale.

Correlation between the degree of offset analgesia impairment and clinical variables

Two-tailed Pearson’s correlation coefficients showed a negative correlation of Δconstant-offset values with both ASC-12 (r = -0.25, P = 0.040) and NPRS (r = -0.296, P = 0.020) scores when considering the total number of subjects with interictal episodic migraine and the subjects with chronic migraine (participants with episodic migraine assessed during the preictal, ictal, and postictal phases were excluded to mitigate the influence of migraine attack-related changes on the offset analgesia phenomenon). No other correlations were observed with other clinical variables, including frequency of attacks, disease duration, as well as HADS and MIDAS scores.

Discussion

The present findings support our primary hypothesis of greater offset analgesia dysfunction in chronic compared to episodic migraine patients, specifically in the subgroup of chronic patients without MOH, where paradoxical responses were observed. Cyclical offset analgesia changes were observed throughout the migraine cycle in episodic migraine patients.

Migraine pain is transmitted by peripheral trigeminal neurons to central neurons in the spinal trigeminal nucleus (SpV) [41]. Ascending nociceptive signals are modulated by descending inputs from brainstem areas, particularly the periaqueductal gray (PAG) and rostral ventromedial medulla (RVM) [42, 43]. PAG suppresses SpV activity [44, 45], while RVM neurons can either enhance (ON cells) or inhibit (OFF cells) pain signals (Fig. 8) [42, 46,47,48,49].

In this study, we recorded lower Pain50 − 60 thresholds in both healthy subjects and patients compared to previous reports, which may be influenced by a combination of methodological and pathophysiological factors. From a methodological standpoint, differences in assessment methods (e.g., Pain50 − 60 vs. Pain60), instrumentation (air-cooled vs. water-cooled thermode), and the tested region (trigeminal vs. extracephalic sites) could contribute to these discrepancies. However, beyond these technical aspects, our findings may also reflect phase-dependent fluctuations in pain sensitivity throughout the migraine cycle. Peng and May [50] highlight that heat pain thresholds progressively decrease toward the ictal phase, suggesting that endogenous pain modulation dynamically oscillates across different migraine stages. While we did not observe significant differences in Pain50 − 60 values across phases, the overall lower thresholds in migraine patients may still indicate subclinical sensitization phenomena that fluctuate throughout the cycle. Similarly, the increased variability in WDT observed in migraine patients, particularly the presence of values exceeding the expected normative range, may also reflect phase-dependent fluctuations in sensory processing [50].

Functional changes in pain modulation networks are thought to contribute to migraine onset, maintenance, and associated symptoms [29, 42]. Most studies on endogenous pain control have focused on episodic migraine subjects in the interictal phase, limiting understanding of pain-modulation mechanisms across the migraine cycle. Consistent with Szikszay et al. [4], we confirm that the offset analgesia phenomenon was absent or reduced in the trigeminal area in most, but not all, episodic migraine subjects during the interictal phase. No significant differences in Pain50 − 60 values and responses to tonic pain stimuli were observed between interictal episodic migraineurs and HVs, suggesting a specific disruption in modulatory mechanisms for dynamic painful stimuli. Notably, our findings reveal a shift toward paradoxical pronociceptive facilitation in the preictal and ictal phases, potentially implicating the RVM in migraine onset. This could support the theoretical hypothesis of an imbalance favoring increased activation of ON pro-nociceptive neurons over OFF anti-nociceptive neurons during the preictal phase (Fig. 8).

Marciszewski et al. [51] observed cyclical changes in brainstem function during the migraine cycle using fMRI. Specifically, in episodic migraine subjects assessed preictally, they found that increased SpV activation in response to repeated tonic noxious stimuli correlated with reduced self-reported pain and diminished RVM-SpV connectivity, suggesting a homeostatic shift favoring OFF cell input to the SpV. In our study, lower VAS values during the constant trials in both preictal and ictal migraineurs compared to the interictal phase were observed, although these differences were not statistically significant. This suggests that the paradoxical pronociceptive facilitation observed during the preictal and ictal phases may reflect a cyclical dysfunction specifically involving temporal filtering mechanisms for dynamic noxious stimuli (Fig. 8). In particular, it is possible that during these phases of the migraine cycle, the 1 °C temperature increase during T2 in the offset trial induced paradoxical pronociceptive mechanisms that are not activated during constant trials. Therefore, the results should be interpreted by considering the possible interplay between different anti-nociceptive and pronociceptive mechanisms, which may be differentially engaged by tonic versus dynamic noxious stimuli. The restoration of the offset analgesia phenomenon during the postictal phase suggests that endogenous anti-nociceptive mechanisms may continue to be activated in episodic migraine, potentially aiding in terminating migraine pain.

Fig. 8
figure 8

Schematic representation of the pain modulatory circuitry and ascending nociceptive pathway. The figure illustrates a theoretical model of the pathophysiological mechanisms underlying migraine. In the lower dashed box, the connections between the RVM and the SpV are magnified, distinguished into pronociceptive (red arrow) and antinociceptive (blue dashed line) with respect to the ascent of nociceptive sensory information. In the centre, a physiological balance favouring the antinociceptive connections is depicted, which is hypothesised to contribute to the phenomenon of offset analgesia observed in HVs and episodic migraineurs during the postictal phase. On the left, an imbalance favouring the pronociceptive projections is illustrated, hypothesised as a possible explanation for the paradoxical facilitation of pain observed in chronic migraineurs without MOH and episodic migraineurs during the preictal and ictal phases. Finally, on the right, a functional imbalance still favouring the pronociceptive projections, albeit less pronounced than the previous one, is represented, which may underlie the absence of the offset analgesia phenomenon in episodic migraineurs during the interictal phase and in chronic migraineurs with MOH. Amyg: amygdala; Hyp: hypothalamus; HVs: healthy volunteers; MOH: medication overuse headache; PAG: periaqueductal gray matter; RVM: rostroventromedial medulla; SpV: spinal trigeminal nucleus; Th: thalamus (figure made by Biorender.com)

Full size image

Functional changes in brainstem pain modulatory areas before migraine onset may be influenced by higher brain regions. Mungoven et al. [8] reported reduced connectivity between the dorsolateral prefrontal cortex (dlPFC) and key cortical, subcortical, and brainstem areas (e.g., RVM and dorsolateral pons) involved in pain modulation in episodic migraine subjects preictally. A functional near-infrared spectroscopy study in HVs found that right dlPFC activation during offset heat stimuli was associated with deactivation of medial prefrontal and somatosensory cortices, suggesting the right dlPFC’s role in inhibiting ascending noxious inputs via subcortical pathways [27].

A paradoxical pronociceptive response during the T3 period of the offset trials, similar to that observed in most episodic migraine during the preictal and ictal phases, was observed in chronic migraine without MOH. This may reflect a persistent shift from anti-nociceptive to pro-nociceptive mechanisms, preventing the PAG-RVM system from resetting after migraine onset, leading to a ‘never-ending attack’ (Fig. 8). This perspective is supported by animal studies showing that descending facilitatory input from the RVM can trigger and sustain hyperalgesia in chronic pain [52], and by clinical research linking dysfunctions in descending pain inhibitory systems to chronic pain conditions [53]. Migraine is considered a threshold disease, where recurring attacks progressively lower the threshold for future episodes, contributing to chronification [54, 55]. This may involve a decline in inhibitory pain modulatory responses to external stressors. Solstrand Dahlberg et al. [56] found increased PAG connectivity with the primary somatosensory cortex (face representation) and pain expectancy areas (e.g., supplementary motor area) in interictal migraineurs with higher attack frequency compared to HVs, alongside reduced connectivity between the PAG and the prefrontal cortex, a key region in the descending pain modulatory system. Disease duration and attack frequency have also been found to correlate with reduced PAG-putamen connectivity and basal ganglia morphological changes in migraineurs [56,57,58]. Given the basal ganglia’s role in modulating acute and chronic pain and analgesic responses [59], their diminished engagement may reflect another manifestation of impaired pain modulatory system in migraine.

Our findings suggest that the pathophysiological mechanisms of chronic migraine may differ between patients with and without MOH. In chronic migraine with MOH, the absent or reduced offset analgesia phenomenon in most, but not all, subjects (similar to interictal episodic migraine) suggest additional mechanisms beyond dysfunction of endogenous pain control, such as central sensitization, cortical hyperexcitability, and neurogenic inflammation [60]. Subjects with chronic migraine with MOH show increased sensitization of somatosensory cortical evoked responses and potentiation to repetitive non-painful stimuli [61]. In contrast, subjects with chronic migraine without MOH exhibit initial sensitization but no response potentiation with repeated stimulation [62, 63]. Recent neurophysiological evidence showed that central neuronal circuits are highly sensitized at both thalamocortical and cortical levels in subjects with chronic migraine with MOH, likely as a direct consequence of persistent administration of analgesics [64]. Indeed, according to studies on rodents, persistent administration of various classes of analgesics causes central sensitization [65, 66], leading to increased activation of the SpV [67] and enhancing susceptibility to evoked cortical spreading depression [67,68,69,70]. In addition, the mechanisms underlying offset analgesia may provide further insights. Offset analgesia primarily depends on A-delta fibers, while C-fibers are more closely associated with central sensitization [19, 71]. This distinction could explain why no differences in offset analgesia responses were found between subjects with migraine assessed interictally (in which central sensitization may be not as strong as in chronic migraine patients) and subjects with chronic migraine associated to MOH, despite their distinct phenotypes. This might, in fact, be due to the presence of distinct pathophysiological mechanisms in the latter group of subjects, such as central sensitization, which are not adequately assessed by the offset analgesia paradigm.

The correlation between Δconstant-offset values and ASC12 and NPRS scores suggests that an imbalance between descending antinociceptive and pronociceptive mechanisms may enhance central sensitization, amplifying pain signaling [72, 73]. Central sensitization, a key factor in cutaneous allodynia, is more common in chronic migraine with MOH than in episodic migraine and is a predictor of migraine chronification [71, 74, 75]. Dysfunction in the RVM, leading to prevailing descending facilitation, is considered crucial for allodynia development [65, 76]. Supporting this, RVM inactivation with bupivacaine blocked cephalic and extracephalic allodynia induced by inflammatory mediators in rat models [76].

The present study has several limitations. First, we acknowledge the relatively small sample sizes of the preictal, ictal, postictal, and chronic migraine without MOH cohorts, as well as the absence of longitudinal assessments. The cross-sectional design limits our ability to track individual changes across different migraine phases, preventing definitive conclusions regarding the modulation of offset analgesia responses over time. While our findings suggest potential variations in endogenous pain control mechanisms across the migraine cycle, these remain speculative and require confirmation through longitudinal studies with larger cohorts to establish a clearer causal relationship. Furthermore, while our data indicate predominant group differences, individual variability should be considered when interpreting the findings. In the interpretation of the findings regarding subjects with chronic migraine, caution is required because they were assessed only during a phase of non-exacerbated pain, which may not be easily distinguishable from preictal or postictal phases. In the absence of a consensus identification and definition of the different phases of pain during chronic migraine, the selection of a pain intensity > 6 at the NRS scale to identify an ongoing pain exacerbation seemed the best trade-off based on clinical evidence. A potential confounder could be the unbalanced gender proportion of the participants, which is however reflecting the higher prevalence of migraine in females. Of note, our control sample was matched for gender to mitigate the confounding effects of this discrepancy. Additionally, we cannot exclude the possibility that prophylactic medications could have affected the offset analgesia phenomenon in chronic migraine subjects. Nevertheless, it is unlikely that these medications significantly affected our findings, as fewer than half of the patients were on stable prophylactic therapy with a single drug from various classes, and they still satisfied the diagnostic criteria for chronic migraine, suggesting that the therapy was not effective. Moreover, current evidence does not support the notion that centrally acting drugs, including serotonin-noradrenaline reuptake inhibitors, antiepileptic drugs and beta blockers, could modulate offset analgesia [77, 78]. Furthermore, our experimental paradigm did not include the assessment of offset analgesia outside the trigeminal area, which could have provided additional insights. It is worth noting, however, that in a previous study assessing offset analgesia in subjects with migraine [4], the authors failed to detect significant differences between subjects with migraine evaluated interictally and healthy controls when offset analgesia was assessed in an extratrigeminal area (forearm). Finally, the experimental paradigm of offset analgesia may capture only dysfunctional aspects related to endogenous pain control underlying the processing of dynamic painful stimuli. A combined approach using different paradigms, including more sensitive tests for identifying central sensitization phenomena, should be applied in future studies to gain a more comprehensive understanding.

In conclusion, our results provide an opportunity to connect preclinical and clinical findings regarding the functioning of descending pain modulation systems in different migraine phenotypes. Future longitudinal studies will have to examine how changes in the offset analgesia phenomenon relate to clinical progression and response to prophylactic treatments, to clarify its potential as a biomarker. Understanding the mechanisms underlying alterations in the offset analgesia phenomenon in migraine may ultimately pave the way for the development of new pharmacological or non-pharmacological therapeutic approaches.

Data availability

Raw data used in this study are available in the Zenodo repository at 10.5281/zenodo.12742349.

References

  1. Cosentino G, Fierro B, Vigneri S, Talamanca S, Paladino P, Baschi R et al (2014) Cyclical changes of cortical excitability and metaplasticity in migraine: evidence from a repetitive transcranial magnetic stimulation study. Pain 155:1070–1078

    Article  PubMed  Google Scholar 

  2. Peng KP, May A (2019) Migraine understood as a sensory threshold disease. Pain 160:1494–1501

    Article  PubMed  Google Scholar 

  3. Schulte LH, May A (2016) The migraine generator revisited: continuous scanning of the migraine cycle over 30 days and three spontaneous attacks. Brain 139:1987–1993

    Article  PubMed  Google Scholar 

  4. Szikszay TM, Adamczyk WM, Carvalho GF, May A, Luedtke K (2020) Offset analgesia: somatotopic endogenous pain modulation in migraine. Pain 161:557–564

    Article  PubMed  Google Scholar 

  5. Tassorelli C, Greco R, Silberstein SD (2019) The endocannabinoid system in migraine: from bench to pharmacy and back. Curr Opin Neurol 32:405–412

    Article  CAS  PubMed  Google Scholar 

  6. Coppola G, Di Clemente L, Fumal A, Magis D, De Pasqua V, Pierelli F et al (2007) Inhibition of the nociceptive R2 Blink reflex after supraorbital or index finger stimulation is normal in migraine without aura between attacks. Inhibition of the nociceptive R2 Blink reflex after supraorbital or index finger stimulation is normal in migraine without aura between attacks. Cephalalgia 27:803–808

    Article  CAS  PubMed  Google Scholar 

  7. Kisler LB, Granovsky Y, Coghill RC, Sprecher E, Manor D, Yarnitsky D et al (2018) Do patients with interictal migraine modulate pain differently from healthy controls? A psychophysical and brain imaging study. Pain 159:2667–2677

    Article  PubMed  Google Scholar 

  8. Mungoven TJ, Marciszewski KK, Macefield VG, Macey PM, Henderson LA, Meylakh N (2022) Alterations in pain processing circuitries in episodic migraine. J Headache Pain 23:9

    Article  PubMed  PubMed Central  Google Scholar 

  9. Perrotta A, Serrao M, Sandrini G, Burstein R, Sances G, Rossi P et al (2010) Sensitisation of spinal cord pain processing in medication overuse headache involves supraspinal pain control. Cephalalgia 30:272–284

    Article  CAS  PubMed  Google Scholar 

  10. Teepker M, Kunz M, Peters M, Kundermann B, Schepelmann K, Lautenbacher S (2014) Endogenous pain Inhibition during menstrual cycle in migraine. Eur J Pain 18:989–998

    Article  CAS  PubMed  Google Scholar 

  11. de Tommaso M, Losito L, Difruscolo O, Sardaro M, Libro G, Guido M et al (2005) Capsaicin failed in suppressing cortical processing of CO 2 laser pain in migraine patients. Neurosci Lett 384:150–155

    Article  PubMed  Google Scholar 

  12. de Tommaso M, Difruscolo O, Sardaro M, Libro G, Pecoraro C, Serpino C et al (2007) Effects of remote cutaneous pain on trigeminal laser-evoked potentials in migraine patients. J Headache Pain 2007;8:167–74

  13. Guy N, Voisin D, Mulliez A, Clavelou P, Dallel R (2018) Medication overuse reinstates conditioned pain modulation in women with migraine. Cephalalgia 38:1148–1158

    Article  PubMed  Google Scholar 

  14. Sandrini G, Rossi P, Milanov I, Serrao M, Cecchini AP, Nappi G (2006) Abnormal modulatory influence of diffuse noxious inhibitory controls in migraine and chronic tension-type headache patients. Cephalalgia 26:782–789

    Article  CAS  PubMed  Google Scholar 

  15. Grill JD, Coghill RC (2002) Transient analgesia evoked by noxious stimulus offset. J Neurophysiol 87:2205–2208

    Article  PubMed  Google Scholar 

  16. Zhang S, Li T, Kobinata H, Ikeda E, Ota T, Kurata J (2018) Attenuation of offset analgesia is associated with suppression of descending pain modulatory and reward systems in patients with chronic pain. Mol Pain 14:1744806918767512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Kurata J (2018) Neural mechanisms of offset analgesia. Adv Exp Med Biol 1099:141–146

    Article  CAS  PubMed  Google Scholar 

  18. Nahman-Averbuch H, Martucci KT, Granovsky Y, Weissman-Fogel I, Yarnitsky D, Coghill RC (2014) Distinct brain mechanisms support Spatial vs Temporal filtering of nociceptive information. Pain 155:2491–2501

    Article  PubMed  PubMed Central  Google Scholar 

  19. Latremoliere A, Woolf CJ (2009) Central sensitization: a generator of pain hypersensitivity by central neural plasticity. J Pain 10(9):895–926

    Article  PubMed  PubMed Central  Google Scholar 

  20. Ligato D, Petersen KK, Morch CD, Arendt-Nielsen L (2018) Offset analgesia: the role of peripheral and central mechanisms. Eur J Pain 22:142–149

    Article  CAS  PubMed  Google Scholar 

  21. Martucci KT, Yelle MD, Coghill RC (2012) Differential effects of experimental central sensitization on the time-course and magnitude of offset analgesia. Pain 153(2):463–472

    Article  PubMed  Google Scholar 

  22. Petre B, Tetreault P, Mathur VA, Schurgin MW, Chiao JY, Huang L et al (2017) A central mechanism enhances pain perception of noxious thermal stimulus changes. Sci Rep 7:3894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Derbyshire SW, Osborn J (2009) Offset analgesia is mediated by activation in the region of the periaqueductal grey and rostral ventromedial medulla. NeuroImage 47:1002–1006

    Article  CAS  PubMed  Google Scholar 

  24. Sprenger C, Stenmans P, Tinnermann A, Buchel C (2018) Evidence for a spinal involvement in Temporal pain contrast enhancement. NeuroImage 183:788–799

    Article  PubMed  Google Scholar 

  25. Yelle MD, Rogers JM, Coghill RC (2008) Offset analgesia: a Temporal contrast mechanism for nociceptive information. Pain 134:174–186

    Article  PubMed  Google Scholar 

  26. Cecchi GA, Huang L, Hashmi JA, Baliki M, Centeno MV, Rish I et al (2012) Predictive dynamics of human pain perception. PLoS Comput Biol 8:e1002719

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Alter BJ, Santosa H, Nguyen QH, Huppert TJ, Wasan AD (2022) Offset analgesia is associated with opposing modulation of medial versus dorsolateral prefrontal cortex activations: A functional near-infrared spectroscopy study. Mol Pain 18:17448069221074991

    Article  PubMed  PubMed Central  Google Scholar 

  28. Yelle MD, Oshiro Y, Kraft RA, Coghill RC (2009) Temporal filtering of nociceptive information by dynamic activation of endogenous pain modulatory systems. J Neurosci 29:10264–10271

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. May A (2017) Understanding migraine as a cycling brain syndrome: reviewing the evidence from functional imaging. Neurol Sci 38(Suppl 1):125–130

    Article  PubMed  Google Scholar 

  30. Goadsby PJ, Evers S (2020) International classification of headache Disorders- ICHD-4 alpha. Cephalalgia 40:887–888

    Article  PubMed  Google Scholar 

  31. Headache Classification Committee of the International Headache Society (IHS) (2018) The International Classification of Headache Disorders, 3rd edition. Cephalalgia. 38:1-211

  32. Peng KP, May A (2020) Redefining migraine phases - a suggestion based on clinical, physiological, and functional imaging evidence. Cephalalgia 40:866–870

    Article  PubMed  PubMed Central  Google Scholar 

  33. Toigo E, Pellot E, Lyons H, McAllister P, Taylor M (2024) Patient self rated pain: headache versus migraine a retrospective chart review. Head Face Med 20:63

    Article  PubMed  PubMed Central  Google Scholar 

  34. Vollert J, Trewartha N, Kemkowski D, Cremer AF, Zahn PK, Segelcke D, Pogatzki-Zahn EM (2022) Conditioned pain modulation and offset analgesia: influence of sex, sex hormone levels and menstrual cycle on the magnitude and retest reliability in healthy participants. Eur J Pain 26(9):1938–1949

    Article  PubMed  Google Scholar 

  35. Nahman-Averbuch H, Shefi T, Schneider VJ 2nd, Li D, Ding L, King CD et al (2018) Quantitative sensory testing in patients with migraine: a systematic review and meta-analysis. Pain 159:1202–1223

    Article  PubMed  Google Scholar 

  36. Cosentino G, Antoniazzi E, Bonomi L, Cavigioli C, D’Agostino M et al (2023) Age-, gender- and body site-specific reference values of thermal quantitative sensory testing in the Italian population using the Q-sense device. Neurol Sci 44(12):4481–4489

    Article  PubMed  PubMed Central  Google Scholar 

  37. Rolke R, Baron R, Maier C, Tölle TR, Treede -DR, Beyer A et al (2006) Quantitative sensory testing in the German research network on neuropathic pain (DFNS): standardized protocol and reference values. Pain 123:231–243

    Article  CAS  PubMed  Google Scholar 

  38. Yarnitsky D, Sprecher E (1994) Thermal testing: normative data and repeatability for various test algorithms. J Neurol Sci 125(1):39–45

    Article  CAS  PubMed  Google Scholar 

  39. Reulen JP, Lansbergen MD, Verstraete E, Spaans F (2003) Comparison of thermal threshold tests to assess small nerve fiber function: limits vs. levels. Clin Neurophysiol 114(3):556–563

    Article  CAS  PubMed  Google Scholar 

  40. Nahman-Averbuch H, Callahan D, Darken R, Haroutounian S (2023) Harnessing the conditioned pain modulation response in migraine diagnosis, outcome prediction, and treatment-A narrative review. Headache 63:1167–1177

    Article  PubMed  Google Scholar 

  41. Olesen J, Burstein R, Ashina M, Tfelt-Hansen P (2009) Origin of pain in migraine: evidence for peripheral sensitisation. Lancet Neurol 8:679–690

    Article  PubMed  Google Scholar 

  42. Akerman S, Holland PR, Goadsby PJ (2011) Diencephalic and brainstem mechanisms in migraine. Nat Rev Neurosci 12:570–584

    Article  CAS  PubMed  Google Scholar 

  43. Russo A, Silvestro M, Tedeschi G, Tessitore A (2017) Physiopathology of migraine: what have we learned from functional imaging?? Curr Neurol Neurosci Rep 17:95

    Article  PubMed  Google Scholar 

  44. Knight YE, Goadsby PJ (2001) The periaqueductal grey matter modulates trigeminovascular input: a role in migraine? Neuroscience 106:793–800

    Article  CAS  PubMed  Google Scholar 

  45. Knight YE, Bartsch T, Kaube H, Goadsby PJ (2002) P/Q-type calcium-channel Blockade in the periaqueductal Gray facilitates trigeminal nociception: a functional genetic link for migraine? J Neurosci 22(5):RC213

    Article  PubMed  PubMed Central  Google Scholar 

  46. Fields HL, Bry J, Hentall I, Zorman G (1983) The activity of neurons in the rostral medulla of the rat during withdrawal from noxious heat. J Neurosci 3:2545–2552

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Fields H (2004) State-dependent opioid control of pain. Nat Rev Neurosci 5:565–575

    Article  CAS  PubMed  Google Scholar 

  48. Hellman KM, Mason P (2012) Opioids disrupt pro-nociceptive modulation mediated by Raphe Magnus. J Neurosci 32:13668–13678

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Salas R, Ramirez K, Vanegas H, Vazquez E (2016) Activity correlations between on-like and off-like cells of the rostral ventromedial medulla and simultaneously recorded wide-dynamic-range neurons of the spinal dorsal Horn in rats. Brain Res 1652:103–110

    Article  CAS  PubMed  Google Scholar 

  50. Peng KP, May A (2018) Quantitative sensory testing in migraine patients must be phase-specific. Pain 159(11):2414–2416

    Article  PubMed  Google Scholar 

  51. Marciszewski KK, Meylakh N, Di Pietro F, Mills EP, Macefield VG, Macey PM et al (2018) Changes in brainstem pain modulation circuitry function over the migraine cycle. J Neurosci 38:10479–10488

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tillu DV, Gebhart GF, Sluka KA (2008) Descending facilitatory pathways from the RVM initiate and maintain bilateral hyperalgesia after muscle insult. Pain 136:331–339

    Article  CAS  PubMed  Google Scholar 

  53. Julien N, Goffaux P, Arsenault P, Marchand S (2005) Widespread pain in fibromyalgia is related to a deficit of endogenous pain Inhibition. Pain 114:295–302

    Article  PubMed  Google Scholar 

  54. Borsook D, Maleki N, Becerra L, McEwen B (2012) Understanding migraine through the lens of maladaptive stress responses: a model disease of allostatic load. Neuron 73:219–234

    Article  CAS  PubMed  Google Scholar 

  55. Maleki N, Becerra L, Borsook D (2012) Migraine: maladaptive brain responses to stress. Headache 52(Suppl 2):102–106

    Article  PubMed  PubMed Central  Google Scholar 

  56. Solstrand Dahlberg L, Linnman CN, Lee D, Burstein R, Becerra L, Borsook D (2018) Responsivity of periaqueductal Gray connectivity is related to headache frequency in episodic migraine. Front Neurol 9:61

    Article  PubMed  PubMed Central  Google Scholar 

  57. Chen Z, Chen X, Liu M, Liu S, Ma L, Yu S (2017) Disrupted functional connectivity of periaqueductal Gray subregions in episodic migraine. J Headache Pain 18:36

    Article  PubMed  PubMed Central  Google Scholar 

  58. Maleki N, Becerra L, Nutile L, Pendse G, Brawn J, Bigal M et al (2011) Migraine attacks the basal ganglia. Mol Pain 7:71

    Article  PubMed  PubMed Central  Google Scholar 

  59. Borsook D, Upadhyay J, Chudler EH, Becerra L (2010) A key role of the basal ganglia in pain and analgesia–insights gained through human functional imaging. Mol Pain 6:27

    Article  PubMed  PubMed Central  Google Scholar 

  60. Schwedt TJ (2014) Chronic migraine. BMJ 348:g1416

    Article  PubMed  Google Scholar 

  61. Coppola G, Currà A, Di Lorenzo C, Parisi V, Gorini M, Sava SL et al (2010) Abnormal cortical responses to somatosensory stimulation in medication-overuse headache. BMC Neurol 10:126

    Article  PubMed  PubMed Central  Google Scholar 

  62. Coppola G, Di Lorenzo C, Schoenen J, Pierelli F (2013) Habituation and sensitization in primary headaches. J Headache Pain 14:65

    Article  PubMed  PubMed Central  Google Scholar 

  63. Schoenen J (2011) Is chronic migraine a never-ending migraine attack? Pain 152:239–240

    Article  PubMed  Google Scholar 

  64. Sebastianelli G, Casillo F, Abagnale C, Renzo AD, Cioffi E, Parisi V et al (2023) Central sensitization mechanisms in chronic migraine with medication overuse headache: a study of thalamocortical activation and lateral cortical Inhibition. Cephalalgia 43:3331024231202240

    Article  PubMed  Google Scholar 

  65. De Felice M, Ossipov MH, Porreca F (2011) Persistent medication-induced neural adaptations, descending facilitation, and medication overuse headache. Curr Opin Neurol 24(3):193–196

    Article  PubMed  PubMed Central  Google Scholar 

  66. Potewiratnanond P, le Grand SM, Srikiatkhachorn A, Supronsinchai W (2019) Altered activity in the nucleus Raphe Magnus underlies cortical hyperexcitability and facilitates trigeminal nociception in a rat model of medication overuse headache. BMC Neurosci 20:54

    Article  PubMed  PubMed Central  Google Scholar 

  67. Green AL, Gu P, De Felice M, Dodick D, Ossipov MH, Porreca F (2014) Increased susceptibility to cortical spreading depression in an animal model of medication-overuse headache. Cephalalgia 34:594–604

    Article  PubMed  Google Scholar 

  68. Becerra L, Bishop J, Barmettler G, Xie Y, Navratilova E, Porreca F et al (2016) Triptans disrupt brain networks and promote stress-induced CSD-like responses in cortical and subcortical areas. J Neurophysiol 115:208–217

    Article  CAS  PubMed  Google Scholar 

  69. Sun-Edelstein C, Rapoport AM, Rattanawong W, Srikiatkhachorn A (2021) The evolution of medication overuse headache: history, pathophysiology and clinical update. CNS Drugs 35:545–565

    Article  PubMed  Google Scholar 

  70. Supornsilpchai W, le Grand SM, Srikiatkhachorn A (2010) Cortical hyperexcitability and mechanism of medication-overuse headache. Cephalalgia 30:1101–1109

    Article  PubMed  Google Scholar 

  71. Luebke L, von Selle J, Adamczyk WM, Knorr MJ, Carvalho GF, Gouverneur Pet al et al (2024) Differential effects of thermal stimuli in eliciting Temporal contrast enhancement: A psychophysical study. J Pain 25(1):228–237

    Article  PubMed  Google Scholar 

  72. De Felice M, Porreca F (2009) Opiate-induced persistent pronociceptive trigeminal neural adaptations: potential relevance to opiate-induced medication overuse headache. Cephalalgia 29:1277–1284

    Article  PubMed  PubMed Central  Google Scholar 

  73. De Felice M, Ossipov MH, Wang R, Dussor G, Lai J, Meng ID et al (2010) Triptan-induced enhancement of neuronal nitric oxide synthase in trigeminal ganglion dural afferents underlies increased responsiveness to potential migraine triggers. Brain 133(Pt 8):2475–2488

    Article  PubMed  PubMed Central  Google Scholar 

  74. Bigal ME, Lipton RB (2008) Excessive acute migraine medication use and migraine progression. Neurology 71:1821–1828

    Article  CAS  PubMed  Google Scholar 

  75. Bigal ME, Lipton RB (2009) Excessive opioid use and the development of chronic migraine. Pain 142:179–182

    Article  CAS  PubMed  Google Scholar 

  76. Edelmayer RM, Vanderah TW, Majuta L, Zhang ET, Fioravanti B, De Felice M et al (2009) Medullary pain facilitating neurons mediate allodynia in headache-related pain. Ann Neurol 65:184–193

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Larsen DB, Uth XJ, Arendt-Nielsen L, Petersen KK (2021) Modulation of offset analgesia in patients with chronic pain and healthy subjects - a systematic review and meta-analysis. Scand J Pain 22:14–25

    Article  PubMed  Google Scholar 

  78. Niesters M, Hoitsma E, Sarton E, Aarts L, Dahan A (2011) Offset analgesia in neuropathic pain patients and effect of treatment with morphine and ketamine. Anesthesiology 115:1063–1071

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Elena Ballante for her assistance with the statistical analysis and study design.

Funding

This study was supported by the Italian Ministry of Health (Ricerca Corrente 2025–2027).

Author information

Authors and Affiliations

  1. Department of Brain and Behavioral Sciences, University of Pavia, Via Bassi 21, 27100, Pavia, Italy

    Giuseppe Cosentino, Roberto De Icco & Cristina Tassorelli

  2. Translational Neurophysiology Research Section, IRCCS Mondino Foundation, 27100, Pavia, Italy

    Giuseppe Cosentino, Elisa Antoniazzi, Camilla Cavigioli & Massimiliano Todisco

  3. Headache Science and Neurorehabilitation Center, IRCCS Mondino Foundation, 27100, Pavia, Italy

    Elena Guaschino, Natascia Ghiotto, Roberto De Icco & Cristina Tassorelli

  4. Department of Health Science and Technology, Center for Pain and Neuroplasticity (CNAP), School of Medicine, SMI, Aalborg University, Aalborg, 9220, Denmark

    Matteo Castaldo

  5. Clinical Psychophysiology and Clinical Neuropsychology Labs, Parma University, 43121, Parma, Italy

    Matteo Castaldo

Authors
  1. Giuseppe Cosentino
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Elisa Antoniazzi
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Camilla Cavigioli
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Elena Guaschino
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Natascia Ghiotto
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Matteo Castaldo
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Massimiliano Todisco
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Roberto De Icco
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Cristina Tassorelli
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

GC conceived the study and drafted the protocol, which were subsequently refined in meetings of the investigators. EA, C., EG, and NG were responsible for the performance of the study under the supervision of CT, MT, RD, and MC. EA and CC contributed to data management. GC carried out the statistical analysis. GC drafted the manuscript. All authors reviewed and approved the final version of the manuscript.

Corresponding author

Correspondence to Giuseppe Cosentino.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Cosentino, G., Antoniazzi, E., Cavigioli, C. et al. Offset analgesia as a marker of dysfunctional pain modulation in episodic and chronic migraine. J Headache Pain 26, 50 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s10194-025-01995-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s10194-025-01995-4

Keywords

The Journal of Headache and Pain

ISSN: 1129-2377

Contact us