Daridorexant in patients with primary headaches and chronic insomnia: An observational study

Abstract

Aim

There is an unquestionable, clinical and pathophysiological, relationship between sleep and primary headaches. We explored the effect of daridorexant, a novel dual orexin receptor antagonist, in patients with primary chronic headache and chronic insomnia.

Methods

Retrospective chart review of patients with primary chronic headache and insomnia who had started treatment with daridorexant 50 mg for their sleep disorder. Headaches were assessed using a calendar and sleep quality using the Patient Global Impression of Change (PGIC) scale (1 no benefit–7 absolute response).

Results

We included 12 patients (10 women; ages 36–72 years). In 6 (50%) patients, insomnia improved (PGIC ≥ 5); mean PGIC being 4.9. In contrast, only one patient (8.3%) experienced a response (≥50% reduction) in their headaches. Mild adverse events were seen in two patients.

Conclusions

In patients with primary chronic headaches, daridorexant improved the subjective quality of sleep in half of the patients but had no clear effect on the frequency or intensity of chronic headaches.

Graphical abstract

This is a visual representation of the abstract.

Introduction

Daridorexant, a dual antagonist of orexin 1 and 2 receptors without the tolerance or dependence of benzodiazepines, has recently been marketed in Europe and is among the recommended drugs recommended for the treatment of chronic insomnia. Orexin neuropeptides, which are mainly expressed in the hypothalamus, stabilize wakefulness through activation orexin 1 and 2 receptors. Dual orexin receptor antagonist, such as daridorexant, inhibit these orexin receptors which promote wakefulness.^1,2 The relationship between sleep and primary headaches is intimate and bidirectional. As an example, insomnia is the main factor associated with the chronicity of primary headaches. On the other hand, sleep is able to abort a migraine attack, and it is well-known than cluster headaches are directly related to sleep.^3,4 Although a specific analgesic effect of dual orexin receptor antagonists has not been demonstrated, ⁵ orexin neuropeptides seem to play a role in nociception, at least in animal models, where they are able to modulate responses of the trigemino-vascular system to dural stimulation.^6,7 Therefore, it seems logical to consider testing a potential effect of this drug able to restore a physiological sleep in chronic insomnia and primary headaches. Our aim has been to explore the effect of daridorexant in patients with a history of chronic insomnia.

Patients and methods

We retrospectively reviewed the clinical charts of patients with primary headache and chronic insomnia who, as part of our routine clinical practice, had started treatment with 50 mg of daridorexant as a single nightly dose. Headache and insomnia diagnosis followed current criteria.^8,9 All these patients had failed at least to benzodiazepines, low doses of amitriptyline and trazodone. Within the first quarter, we assessed potential efficacy on headache using a diary. We excluded subjects with a change in their migraine preventive treatment during treatment with daridorexant. Response required a 50% decrease in monthly headache days. Insomnia was evaluated subjectively using the Patient Global Impression of Change (PGIC) scale (1 no benefit–7 absolute response). ¹⁰ Emergent adverse events were also recorded.

Results

We included a total of 12 patients (10 women). Their ages ranged from 36 to 72 years (mean 53.9 ± 15.0, median 53.5). Mean ± SD insomnia duration was 4.6 ± 3.5 years (median 3; range 1–10). All had been treated with trazodone, low doses of amitriptyline and benzodiazepines. Eight patients had used at least two different benzodiazepines. All patients met criteria for resistant primary headache ¹¹ : six for chronic migraine and analgesic overuse, four for high-frequency episodic migraine, and two for new daily persistent headache. Chronic migraine patients had also failed to onabotulinumtoxinA and at least one anti-CGRP monoclonal antibody. Six patients had concomitant anxiety-depression syndrome and one restless legs syndrome. No patient had sleep apnea. Insomnia and migraine chronification coincided in time in three patients, while insomnia preceded migraine impairment in four patients and appeared after migraine chronification in five patients.

In 6 patients (50%) their chronic insomnia subjectively improved (PGIC ≥ 5); the mean PGIC score in the whole series being 4.9 (range 4–6). According to headache calendar, one patient (8.3%) exhibited either 50% or 30% response in both frequency and intensity of her headaches; the remaining patients did not shown >30% in frequency, severity or in acute symptomatic consumption of their headaches. Mild adverse events (somnolence and nightmares) were reported by 2 patients (16.7%).

Discussion

This is the first study to analyze the effectiveness in daily clinical practice of daridorexant, a novel dual orexin receptor antagonist, in patients with both chronic primary headache and chronic insomnia. We could summarize our findings by saying that daridorexant did improve, as expected, the subjective quality of sleep in half of the patients with chronic insomnia refractory to standard treatments, but that, at least in the short term, daridorexant did not improve the frequency of chronic headaches in most patients. These results are consistent with the only controlled clinical trial published to date in migraine, which failed to demonstrate a significant effect over placebo of another dual orexin antagonist, filorexant, in migraine prevention.^10,11 This controlled clinical trial investigated the response to filorexant in patients with episodic migraine, not specifically insomnia. Therefore, it seemed logical to test dual orexin antagonists in patients with chronic primary headache and refractory insomnia. Our results, however, indicate that these drugs do not have a direct effect on primary headaches, as in other conditions with chronic pain. ⁵ Our data must be interpreted as very preliminary since they are retrospective, not controlled, the number of included patients is low, our follow-up is short and also we included only very chronic patients resistant for treatment of both insomnia and headache.

On the other hand, our experience regarding the efficacy of this orexin receptor antagonist in chronic insomnia is consistent with that from controlled clinical trials, ¹ and, although only half of the cases improved with daridorexant, it must be taken into account that our patients were highly complex and had not responded adequately to the drugs we use in clinical practice for the treatment of chronic insomnia in patients with headaches. As in controlled clinical trials, daridorexant tolerability was excellent, with a low percentage of side effects that were considered mild. ¹ Unlike what happened with insomnia, most patients did not see their headaches improved with daridorexant. Although these negative results should be interpreted with caution because we would need more patients with a less refractory profile and longer follow-up, the apparent ineffectiveness of daridorexant in headaches would indicate that, despite the fact that we know that they largely share the anatomical structures involved in their pathophysiology,^3,4 we should treat both symptoms, headache and insomnia, separately. We must emphasize, however, the importance of achieving good quality sleep, especially in patients with chronic headaches. This is not only because we know that sleep is the main factor associated with the chronic nature of migraine ³ but also because good quality sleep is associated with improved functioning of the glymphatic system, which is responsible for clearing our brain of debris, including molecules such as calcitonin gene-related peptide, the main culprit of migraine pain.^12,13

Clinical implications

Antagonism on orexin receptors, although improves sleep quality, does not seem to exert a preventive action for headaches in patients with both chronic primary headache and insomnia.

In clinical practice, chronic headache and insomnia should be treated separately.