A study of migraine‐like headache caused by topical aryl hydrocarbon receptor agonist tapinarof

Tapinarof is an aryl hydrocarbon receptor (AHR) agonist. One-percent cream of tapinarof was approved for treatment of atopic dermatitis; however, headaches were observed in 16% of patients after using tapinarof in a clinical trial.1 The mechanism underlying these headaches remains unknown. Herein, we report two cases in which tapinarof was associated with headache and cases in which it was not. Written informed consent was obtained from these two patients and their guardians for the examination and reporting of these cases. Research Ethics Committee, Faculty of Pharmacy and Research Institute of Pharmaceutical Sciences, Musashino University (Tokyo, Japan). Case 1 involved a 14-year-old boy with a history of migraine. Headaches had been occurring approximately once every 2 months since the patient was around 11 years old. When a typhoon was approaching, the frequency tended to increase. The pain was of moderate intensity, and although he had never sought medical care for his headaches, the patient occasionally took oral analgesics. Both of his parents also had a history of migraine. Before starting tapinarof treatment, the patient had been using betamethasone valerate ointment and clobetasone butyrate ointment. His atopic dermatitis was characterized by an Investigator's Global Assessment (IGA) score of 3, an Eczema Area and Severity Index (EASI) score of 7.2, and involvement of approximately 70% of the body surface area (%BSA). The patient applied tapinarof at 9 p.m. and went to bed thereafter. At 5 a.m., he was awakened due to a headache, which lasted for approximately 8 h. The pain was bilateral occipital, pulsating, and of moderate intensity, and it worsened with routine activity. The patient felt nauseated during this first episode following tapinarof application; however, photophobia, phonophobia, and aura were not present. On the day after the first application, the patient applied tapinarof only to his feet, and no headache was reported. Thereafter, the daily use of tapinarof did not trigger any headaches, and his atopic dermatitis improved within about 1 month. After approximately 9 months of use, we asked the patient again about any episode of headaches. He reported intermittent discontinuation of tapinarof when his skin condition improved. Headaches occurred when tapinarof was resumed after being withheld for 1 week or longer. He also reported two previous episodes of headache following the resumption of tapinarof after such interruptions. The characteristics of these headaches were consistent across episodes. The overall frequency of headache episodes did not change significantly before and after tapinarof initiation. However, after starting tapinarof, the patient did not report headaches associated with approaching typhoons during the observation period. The patient had been using topical tapinarof intermittently during the 9 months following treatment initiation but was no longer using it at the time of the 9-month visit. To assess the extent of systemic absorption, we instructed him to collect a urine sample the morning after the next application. He then applied tapinarof to his shoulders, back, and abdomen, and a urine sample was collected the following morning. The patient again experienced headache after applying the medication. The urinary tapinarof concentration was 10.2 nM. Tapinarof concentrations were measured using liquid chromatography/tandem mass spectrometry. Case 2 involved a 14-year-old boy whose mother had a history of migraine. He had no personal history of headaches. His atopic dermatitis was characterized by an IGA score of 3, an EASI score of 14.4, and involvement of approximately 90% of the BSA. Before initiating tapinarof therapy, the patient had used betamethasone valerate ointment and clobetasone butyrate ointment. Tapinarof was applied to his back and the areas behind his knees, and it was found to be effective. No headaches occurred during tapinarof therapy. After 11 months of continued treatment, a urine sample was collected the morning after tapinarof application. At that time, tapinarof had been applied behind the knees. The urinary tapinarof concentration was 2.18 nM. Concerning medication-induced headaches, the ICHD-3 lists phosphodiesterase inhibitor-induced headache and provides diagnostic criteria (8.1.2), and under headache due to the occasional use of medications other than headache medications, lists atropine, digitalis, disulfiram, hydralazine, imipramine, nicotine, nifedipine, nimodipine, and sildenafil.2 Based on the ICHD-3 classification, a tapinarof-induced headache may be categorized as a headache attributed to the occasional use of non-headache medication. In this study, case 1 developed a headache approximately 8 h after topical tapinarof application, longer than that reported for some orally administered medications. Two possible reasons for this are as follows: (1) patients applied the medication topically at night and then fell asleep, experiencing pain the next morning; and (2) topical application takes time to absorb. Although only two cases were included in this study, we detected tapinarof in urine samples taken the morning after use. Tapinarof is thought to be absorbed transdermally, reach the central nervous system via the bloodstream, and potentially contribute to headache development. Of the two patients in whom tapinarof was detected in the urine, one (case 1) had experienced headache due to tapinarof. In this patient, the headache recurred after a 1-week suspension of tapinarof and subsequent resumption of tapinarof. This indicates a probable link between the headache and tapinarof. Tapinarof, an AHR agonist, is used to treat atopic dermatitis and psoriasis vulgaris. Metabolites of the kynurenine pathway are important endogenous ligands of the AHR, and AHR signaling has been implicated in neuroimmune mechanisms relevant to migraine pathophysiology.3 Previous studies have suggested that AHR activation modulates inflammatory responses and neural excitability through immune regulatory pathways. In an animal study by Yang et al., the AHR agonist 2-(1'-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) alleviated migraine-like pain behaviors in rats, accompanied by activation of AHR signaling and improvement in the imbalance of regulatory T cell (Treg) and T-helper 17 cell (Th17)–related transcription factors and inflammatory mediators.4 These findings indicate that AHR-related pathways can influence migraine-related mechanisms. In the present human case–based study, migraine-like headaches were observed following topical administration of tapinarof, a chemically and pharmacologically distinct AHR agonist. Importantly, the biological effects of AHR activation are highly ligand-dependent, and different AHR agonists may induce divergent downstream immune and neural responses. Therefore, the apparent discrepancy between the migraine-attenuating effects observed in the animal model using ITE and the headache occurrence observed in our cases with tapinarof may reflect ligand-specific differences in AHR signaling rather than a contradiction in the role of AHR itself. Although immunological parameters such as Treg/Th17 balance were not directly evaluated in this study, our findings suggest that ligand-specific AHR activation may variably influence neuroimmune pathways associated with migraine. Other AHR-related mechanisms, including modulation of neuroinflammatory signaling and interactions with kynurenine pathway metabolites, may also contribute to headache occurrence. Further studies are warranted to clarify the mechanisms by which distinct AHR agonists affect headache-related pathways in humans. Toshiyuki Hikita: Conceptualization; investigation; data curation; writing – original draft. Toshiyuki Kudo: Formal analysis; validation; writing – review and editing. Yasuko Ogawa: Formal analysis; validation. Natsue Nakamoto: Data curation; investigation. Kiyomi Ito: Conceptualization; writing – review and editing; supervision; project administration. The authors thank the participating investigators, patients, and their families, as well as colleagues involved in the conduct of the study. No funding was received for this study. Toshiyuki Hikita, Toshiyuki Kudo, Yasuko Ogawa, Natsue Nakamoto, and Kiyomi Ito have no conflicts of interest to disclose. The data that support the findings of this study are proprietary and are not publicly available. The data may be made available upon reasonable request.