Abstract
Aim
Abdominal migraine is rare in adults resulting in a lack of evidence-based treatment recommendations. Treatment therefore pragmatically follows the guidelines for migraine with and without aura. Here, we present the first report of a patient with abdominal migraine successfully treated with three different drugs targeting calcitonin gene-related peptide (CGRP).
Methods
A 68-year-old woman was referred to our headache center with suspected late-onset abdominal migraine. After extensive diagnostics, the diagnosis was confirmed based on the International Headache Society diagnostic criteria and guideline-compliant treatment was initiated.
Results
Before treatment initiation, the patient had suffered from 9 to 17 stereotypical episodes per month that lasted about 12 h and included moderate to severe abdominal pain, diarrhea, nausea, and vomiting for over 20 years. Earlier treatment comprised several acute and preventive drugs without success. Finally, she received attack treatment with rimegepant resulting in pain freedom after 2 h and preventive treatment with eptinezumab and fremanezumab resulting in 61% and 78% reduction of the attack frequency, respectively.
Conclusion
Calcitonin gene-related peptide is a crucial factor for the development of abdominal migraine and CGRP-targeting drugs may be a treatment option for these patients.
This is a visual representation of the abstract.
Introduction
The International Headache Society (IHS) classifies abdominal migraine as a periodic syndrome of childhood characterized by moderate to severe midline abdominal pain, vasomotor symptoms, nausea, vomiting, a duration of 2–72 h, and normality between episodes. 1 Its prevalence in children has been estimated at up to 4% 2 with frequent remission in adulthood and frequent conversion to classic migraine instead. 3 Thus, abdominal migraine is rare in adults resulting in a lack of evidence-based treatment recommendations. Analgesics, triptans, and antiemetics may be useful in the treatment of attacks; valproic acid and dihydroergotamine have been used successfully in the treatment of refractory attacks. 4 Pizotifen, propranolol, cyproheptadine, and flunarizine have been shown to be effective as preventive medications. 4 Currently, the treatment of abdominal migraine in all age groups pragmatically follows the same basic principles as for episodic and chronic migraine.
More recently, drugs targeting the neuropeptide calcitonin gene-related peptide (CGRP) and its receptor have been introduced as a new treatment option for migraine.5,6 Calcitonin gene-related peptide is involved in the induction of migraine headache via the trigeminovascular system. 7 In addition, CGRP has multiple physiological functions in the gastrointestinal (GI) tract. 8 However, the effect of drugs targeting CGRP and its receptor in the treatment of abdominal migraine is unknown. We present here a patient with abdominal migraine who was successfully treated with drugs targeting CGRP and its receptor.
Methods and results
Patient information
A 68-year-old female retired healthcare worker was referred to our tertiary headache center at the Odense University Hospital for suspected treatment-resistant abdominal migraine. Her past medical history was unremarkable except for bilateral total hip replacements and previous surgery for lumbar spondylolisthesis with chronic postoperative neuropathic pain requiring treatment with pregabalin.
She reported two types of pain:
Type 1 pain was headache attacks mostly on the right side, severe throbbing, lasting 6–24 h, accompanied by nausea, sometimes vomiting, sensitivity to light and noise, aggravated by physical exertion, and totally invalidating without treatment. They had first occurred before puberty, increased to 2–3 attacks/week during adolescence, and decreased to 1–2 attacks/month after menopause. Previously, she had experienced visual aura (flickering vision and zigzagging phenomena) that slowly spread over 30–60 min and preceded the headache. So far, treatment has consisted of attack treatment with nonsteroidal anti-inflammatory drugs (diclofenac, acetylsalicylic acid/codeine) and antiemetics with insufficient effect. She had never received any preventive treatment. The diagnosis episodic migraine with and without aura was made according to the IHS. 1
Type 2 pain had started at the age of 44 and always occurred during sleep, typically 1–1.5 h after falling asleep, often around 1:30 am, sometimes during her afternoon nap. The frequency of the pain attacks increased slowly without changing the phenotype. For the first 10 years, attacks occurred 2–3 times/month, then twice a week, and, at the time of referral, every other day. The attacks were stereotypical, beginning with a strange dream (nightmare), followed by sudden awakening, heart palpitations, and sweating. Then, she experienced sensory disturbances and pain that gradually spread from the left side of her face to the left arm and leg over 30–45 min, with increasing abdominal pain on the left side of the abdomen, supplemented after 2–3 h by several bouts of diarrhea, nausea, and vomiting that lasted for the next 4–6 h. About 12 h after awakening, her symptoms disappeared, but she was exhausted and had to rest for the next 24 h. During the period with bouts of diarrhea, nausea, and vomiting, she sometimes also experienced a mild left-sided headache, which she mentioned only when asked.
Clinical findings and diagnostic assessment
The diagnostic work-up included a normal neurological examination, electrocardiogram, and blood tests (including hematology, liver, gallbladder, and renal function) except for mild dyslipidemia (within age-related expectations). Magnetic resonance imaging (MRI) of the cerebrum and posterior fossa revealed cerebellar sequelae of lacunar infarction and a bilateral anterior inferior cerebellar artery loop type 1. Carotid and vertebral ultrasound, 7-day Holter monitoring, echocardiography, endocrinological diagnostics, abdominal MRI, and contrast-enhanced abdominal computed tomography were normal. Complementary 24-h electroencephalogram monitoring and polysomnography were unremarkable except for sleep apnea; continuous positive airway pressure treatment improved her sleep quality but neither the frequency nor the severity of the nocturnal attacks.
Based on the clinical symptoms (at least five attacks, moderate to severe abdominal pain, dull or “just sore” pain quality, nausea, vomiting, anorexia, duration of 2–72 h, normality between episodes) and the diagnostic findings, the diagnosis of (late onset) abdominal migraine in a patient with preexisting migraine with and without aura was made according to the IHS. 1
Therapeutic intervention
For treatment of attacks, she had tried diclofenac/tolfenamic acid/naproxen (good effect, but unsuitable for long-term daily use), codeine (improved diarrhea), sumatriptan/eletriptan/rizatriptan (no effect) and finally rimegepant, which resulted in pain freedom after 2 h without side effects. She had tried numerous migraine preventive medications at the highest tolerated doses, which were discontinued due to either lack of effect (candesartan, propranolol, lisinopril, lamotrigine) or side effects (topiramate, amitriptyline, imipramine, baclofen). As a last resort, the patient received eptinezumab (100 mg, intravenously every three months) and fremanezumab (225 mg, subcutaneously every month) (Figure 1(a)). As the patient's MRI of the brain and the posterior fossa showed cerebellar sequelae of a lacunar infarction, the decision to treat the patient with CGRP-targeting drugs was made as case-by-case decision based on the absence of cardiovascular risk factors, normal Holter monitoring, and ultrasound suggesting a clinically silent microvascular lesion in an otherwise healthy patient. The initial treatment with eptinezumab was switched to fremanezumab due to significant wearing-off after the first infusion. Three months later, treatment with fremanezumab was switched back to eptinezumab due to an allergic reaction at the injection site (swelling). The second change in therapy resulted in a one-month break (administrative reasons). Eptinezumab reduced the number of moderate to severe abdominal migraine attacks from an average of 9.3 attacks/month at baseline by 82%, bringing the average number of attacks to 1.7 attacks/month before the break. After the break, eptinezumab reduced baseline migraine attacks by 46%, bringing the average number of attacks to 5.0 attacks/month, without any side effects. Fremanezumab reduced the number of moderate to severe abdominal migraine attacks from an average of 9.3 attacks/month at baseline by 78% to an average of 2.0 attacks/month. During the break, attack frequency increased to baseline values. Eptinezumab reduced the number of moderate to severe abdominal migraine attacks by 61% to an average of 3.6 attacks/month over the whole treatment period (before and after the break; Figure 1(a)). Interestingly, eptinezumab reduced the frequency of abdominal migraine attacks independent of attack severity, whereas fremanezumab showed a reduction of moderate-to-severe abdominal migraine attacks but was less effective in reducing the mild abdominal migraine attacks (Figure 1(a)).
Treatment schedule. (a and b) The patient received eptinezumab (100 mg intravenously every 3rd month) in October 2023. Due to significant wearing-off with pain freedom until mid-December 2023, when abdominal migraine relapsed more and more frequently, treatment was switched from eptinezumab to fremanezumab (225 mg, subcutaneously, once a month). The patient received fremanezumab treatment from January 2024 to April 2024, when treatment was switched back to eptinezumab due to an allergic reaction at the injection site (swelling). The change in therapy resulted in a one-month break (administrative reasons). Since September 2024, due to the recommendations of the Danish Medicines Council, attack frequency is only recorded for one month every six months. (a) Number of moderate to severe abdominal migraine attacks per month (black curve), number of all abdominal migraine attacks per month (mild, moderate, and severe; orange curve). (b) Number of all migraine with aura attacks per month (mild, moderate, and severe); because of the low number of attacks, the patient did not consequently register attack severity; therefore, we show the total number of monthly attacks. During the entire period, in which we treated the patient, she only had migraines with aura.
Moreover, eptinezumab decreased the number of migraines with aura from an average of 2.3 attacks/month at baseline by 87% to 0.3 attacks/month (before the break) and by 67% to 0.75 attacks/month (after the break). Eptinezumab decreased attack frequency by 75% to an average of 0.57 attacks/month over the whole treatment period (before and after the break). Fremanezumab decreased the number of all attacks by 57% to an average of 1.0 attacks/month (Figure 1(b)). Moreover, the patient experienced a significant reduction of attack severity from moderate to severe before treatment to mild to moderate since the beginning of the anti-CGRP treatment. Hence, she also experienced a reduction of migraine disability as she was no longer invalidated by migraine attacks.
Timeline of therapeutic interventions
A timeline of therapeutic interventions is provided in Figure 1.
Follow-up and outcomes
Since September 2024, the frequency of attacks has only been recorded for one month every six months, according to the recommendations of the Danish Medicines Council. When she was called at the end of February 2025, she reported about stable conditions since September 2024 without any side effects.
Discussion
We present here of a patient with abdominal migraine who was successfully treated with drugs targeting CGRP and its receptor, both gepants and anti-CGRP antibodies.
Abdominal migraine is a rare disorder in adults and must be differentiated from other disorders such as irritable bowel syndrome, functional dyspepsia, epilepsy, sleep disorder, phaeochromocytoma, neuroendocrine tumor, porphyria, or endometriosis.
While the migraine-initiating effect of CGRP via the trigeminovascular system and its physiological functions in the GI system including motility, secretion, and immune functions are well described,7,8 its involvement in the pathophysiology of abdominal migraine remains unclear. Calcitonin gene-related peptide infusions caused GI hyperactivity including severe abdominal pain, diarrhea, and nausea 9 and CGRP antagonism induced constipation 10 in humans. Sumatriptan, which has been shown to inhibit CGRP release, 9 attenuated GI hyperactivity in a patient with irritable bowel syndrome. 11 Calcitonin gene-related peptide has been implicated in the development of visceral hyperalgesia, and CGRP receptor antagonists accordingly suppressed acetic acid–induced abdominal cramps in rats. 12 The pathophysiology of abdominal migraine is poorly understood, but the enteric nervous system, gut–brain axis, gut microbiota, variations in small intestine permeability, and genetic factors are thought to play an important role in abdominal migraine. 13
Treatment of abdominal migraine with anti-CGRP antibodies followed the same course as described for migraine with and without aura. We observed wearing-off eight weeks after eptinezumab infusion 14 and decreased efficacy after drug holidays as described in patients with migraine with and without aura. 15
In conclusion, our case report indicates that CGRP is a crucial factor for the development of abdominal migraine. Moreover, the treatment with both gepants and anti-CGRP antibodies was immediately effective and may represent an additional treatment option for patients with abdominal migraine. However, patients should be selected carefully and after detailed diagnostics to avoid misdiagnosis and to ensure appropriate use of the CGRP-targeting drugs.
Clinical implications
Drugs targeting CGRP and its receptor were successfully used to treat abdominal migraine.
Calcitonin gene-related peptide is involved in the pathogenesis of abdominal migraine.
Footnotes
Abbreviations
Declaration of conflicting interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
Informed consent
The patient has given written informed consent.
Patient perspective
The patient had a very poor quality of life for many years. She was very happy about the success of the treatment, which gave her “a new life,” as she said.
