Researchers Investigate Whether SREP Can Determine Central Sensitization Among Patients With EM

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Findings suggest that including slowly repeated evoked pain (SREP) in quantitative sensory testing protocols may enhance assessments of altered pain modulation in different pain conditions.

Study results published in Scientific Reports provide evidence for slowly repeated evoked pain (SREP) as a possible central sensitization (CS) marker with potential clinical utility among patients with migraine. The findings also suggest including SREP in quantitative sensory testing (QST) protocols may enhance assessments of altered pain modulation in different pain conditions, researchers wrote.

Although the underlying mechanisms of migraine are not understood, experimental evidence of CS in migraineurs has been observed during and between attacks. CS, defined as “an amplification of pain responses, reflected in hypersensitivity, allodynia or hyperalgesia in response to peripheral inputs, that is produced by a central nervous system–related upregulation of ascending facilitatory pain pathways (bottom-up regulation) and/or an impairment of descending inhibitory pain mechanisms (top-down regulation),” has also been observed in patients with fibromyalgia.

There are several ways of measuring CS, including use of temporal summation of pain (TSP), which shows ascending pain facilitation believed to reflect the "wind-up" effect in the spinal cord, the authors explained. “Like TSP, SREP is a dynamic protocol that assesses changes in pain perception in response to repeated evoked pain stimuli, but with stimuli presented at a much lower frequency not believed to elicit TSP,” they said.

To test whether SREP sensitization provokes responses in migraineurs, examine SREP’s capacity to discriminate migraineurs from healthy individuals, and compare SREP pain responses to frequently used static (pain threshold and tolerance) and dynamic (TSP) evoked pain indices, the researchers recruited 40 Spanish female migraineurs without aura to participate in the study.


All participants were headache free for at least 48 hours prior to the study, reported having episodic migraine (EM), and were 18 to 30 years old. Based on age and body mass index, patients were matched with 40 healthy individuals serving as a control group. Participants completed the Present Pain Intensity index of the McGill Pain Questionnaire (PPI-MPQ), the catastrophizing subscale of the Coping Strategies Questionnaire, and the Hospital Anxiety and Depression Scale.

Participants first completed a clinical interview, then the SREP or TSP protocol, administered in a randomized-counterbalanced order, with a 5-minute rest period between each. Specifically, “SREP consisted of a series of 9 suprathreshold painful pressure stimuli of 5 second duration and a 30 second interstimulus interval. SREP sensitization was indexed by the increase in pain ratings across the stimuli.”

Analyses revealed:

  • SREP sensitization was observed in EM, but not in healthy individuals (P < .001)
  • SREP differentiated between EM and healthy individuals with up to 75% diagnostic accuracy
  • Pain threshold, pain tolerance, and TSP did not show significant discriminative ability
  • Only current clinical pain intensity (PPI-MPQ) correlated positively with the SREP index in patients with EM (R = 0.39; P = .013; Bonferroni adjusted P = .026), although the difference between groups was not statistically significant
  • An SREP index value of 0.5 was the most sensitive cut-off for detecting central pain sensitization when prioritizing diagnostic sensitivity (0.88)

Overall, the results point to a pattern of increasing subjective pain ratings during the SREP in patients with EM, but not in healthy controls. “Our current findings in EM patients are similar to the elevated SREP sensitization observed in fibromyalgia patients in our previous studies comparing fibromyalgia with both healthy individuals and rheumatoid arthritis patients as control conditions without CS,” the authors wrote.

Standard QST protocols currently include TSP as the sole CS index. The use of SREP as a dynamic evoked pain index in QST protocols may enhance assessment of pain modulation in these populations by determining bottom-up vs top-down CS processes.

“If SREP primarily reflects top-down CS mechanisms, patients with greater SREP sensitization may obtain greater benefit from therapies that may enhance descending inhibition, such as physical exercise, psychological interventions, and medications enhancing neurotransmitters involved in pain inhibition,” the researchers said.

Additional studies comparing SREP with a more standardized protocol for measuring pain could provide further information on the diagnostic utility of SREP sensitization. The narrow age range of participants, in addition to a relatively small, female-only sample size mark limitations to the study.


de la Coba P, Bruehl S, del Paso GAR. Slowly repeated evoked pain (SREP) as a central sensitization marker in episodic migraine patients. Sci Rep. Published online February 25, 2021. doi:10.1038/s41598-021-84157-1