Naratriptan is as effective as sumatriptan for the treatment of migraine attacks when used properly. A mini-review

Background Naratriptan, marketed in a low oral dose of 2.5 mg, is generally regarded as a less-effective triptan with a slower onset of action than most other triptans in the treatment of migraine attacks. In this review, naratriptan will be compared with sumatriptan, the standard triptan. Methods Papers on pharmacodynamics and pharmacokinetics and results from comparative clinical trials with oral and subcutaneous naratriptan versus other triptans were retrieved from PubMed. Results Naratriptan and sumatriptan have similar effects in relevant animal models. In a randomized controlled trial, oral naratriptan 2.5 mg is less effective than oral sumatriptan 100 mg after both 2 h and 4 h. In contrast, oral naratriptan 10 mg has a similar time-effect curve as oral sumatriptan 100 mg, in both its steepness and the efficacy at 2 h and 4 h. Subcutaneous naratriptan 10 mg (88% pain free at 2 h) was in one trial superior to subcutaneous sumatriptan 6 mg (55% pain free at 2 h). Conclusion Naratriptan was marketed for the treatment of migraine attacks as the “gentle triptan” in a low oral dose of 2.5 mg, a dose with no more adverse events than placebo. This low dose results in the slow onset of action and low efficacy of oral naratriptan, but in high doses oral naratriptan is similar to oral sumatriptan. Based on one randomized controlled trial, subcutaneous naratriptan has probably the greatest effect of any triptan.

A phase 1 randomized study of hemodynamic effects and pharmacokinetic interactions during concomitant use of rimegepant and sumatriptan in healthy adults

Objective: This randomized, partially-blinded, placebo-controlled study evaluated hemodynamic effects, pharmacokinetic interactions, and safety of concomitant administration of oral rimegepant and subcutaneous sumatriptan. Methods: Healthy non-smokers aged ≥18 and ≤40 years (men) or ≥18 and ≤50 years (women) were enrolled. On Day 1, subjects received 12 mg of sumatriptan as 2 subcutaneous 6 mg injections separated by 1 hour. From Days 2 to 4, subjects received rimegepant or placebo once daily (randomized 6 to 1, rimegepant to placebo). On Day 5, subjects received rimegepant or placebo, followed 2 hours later by 2 subcutaneous 6 mg injections of sumatriptan, separated by 1 hour. Sumatriptan was administered at the same times as on Day 1. Results: All 42 dosed subjects were analyzed. There were no significant differences in the time-weighted average of mean arterial pressure, diastolic blood pressure, or systolic blood pressure between treatment with rimegepant + sumatriptan and sumatriptan alone. Co-administration of rimegepant and sumatriptan had no effect on the pharmacokinetics of either drug. Overall, 93% (39/42) of subjects experienced ≥1 adverse event; injection site reaction was most common (60% [29/42]). Conclusions: Concomitant administration of oral rimegepant and subcutaneous sumatriptan to healthy adults was without hemodynamic or pharmacokinetic interaction and was safe and well tolerated.

Cluster Headache: Opportunities for Pharmacists to Improve Care

Cluster headache (CH) is a primary headache (PH) disorder characterized by recurrent attacks of severe/extremely severe unilateral pain and associated symptoms. While less prevalent than other PHs such as migraine, CH impact is substantial given the agonizing pain, negative effect on daily productivity, impaired mental health, and increased costs. Cluster headache is not optimally treated and few clinical trials are available to model therapy, especially dosing and administration. Pharmacists are well positioned to help prescribers and CH individuals with several key opportunities. Subcutaneous sumatriptan (SC SM) lower than the FDA-approved 6 mg per attack, specifically 2 mg and 3 mg, can be considered; literature describes these doses’ benefits. Moreover, lower doses may improve patient access to this treatment-of-choice. Despite the SC SM’s FDA-approved dose limit of 12 mg per 24 hours, the maximum CH dose has not been examined; this limit merits reevaluation since literature and clinical experience illustrate treatment exceeding this limit. Oxygen therapy for CH remains unfamiliar to, and under-utilized by, clinicians and CH individuals. Pharmacists can facilitate prescribing, distribution, and administration of oxygen via education. Patient education for the various CH medication devices, including oxygen, is paramount. Narcotics remain widely prescribed for CH, without supporting evidence, but with considerable abuse and diversion risks. Pharmacists are positioned to help guard against narcotic usage and to direct care toward medications endorsed by CH guidelines. Since the optimal method to initiate and discontinue drugs which may decrease CH attacks’ remains unknown, pharmacists can educate clinicians and individuals with CH to make fully informed decisions.

Cluster headache not responsive to sumatriptan: A retrospective study

Introduction Subcutaneous sumatriptan, a 5HT1B/1D agonist, is the most effective drug in cluster headache acute treatment. About 25% of the patients do not respond to subcutaneous sumatriptan; the reasons for this are unknown. In this study, we compare clinical characteristics of cluster headache patients responding and non-responding to subcutaneous sumatriptan. Methods We retrospectively investigated the clinical records of 277 cluster headache patients. Patients reporting repeated satisfactory response to subcutaneous sumatriptan within 15 minutes were considered responders. Results Of 206 cluster headache patients who had used subcutaneous sumatriptan (mean age 45.6, 16% females, 48% chronic), 91% were responders, and 9% non-responders. Compared to responders, non-responders had longer and more frequent attacks: 60 (median; IQR 38–90) vs. 100 (60–120) minutes ( p = 0.028), 4 (2.5–5) vs. 3 (2–4) attacks/day ( p = 0.024). No other difference was found. Conclusions In cluster headache attacks with long duration and high frequency, pain mechanisms not involving 5HT1B/1D receptors may play a more relevant role.

Cluster headache

Cluster headache is a primary headache disorder characterized by attacks of severe-to-very severe unilateral pain, located in the orbital, supraorbital, and/or temporal regions, with ipsilateral autonomic symptoms and/or restlessness. By definition, cluster headache attacks last between 15 and 180 minutes. Based on the temporal course, cluster headache can be categorized into episodic and chronic. A subdivision can also be made in primary and secondary chronic and secondary episodic. The cause of cluster headache is unknown, but probably the hypothalamus, trigeminal sensory system, some cranial blood vessels, and the autonomic nervous system are involved. A combination of acute (oxygen inhalation and/or subcutaneous sumatriptan) and prophylactic (first choice verapamil) treatment is usually necessary. For treatment-resistant patients, some experimental invasive options exist.

Subcutaneous sumatriptan reduces cilostazol induced headache in migraine patients

Objectives The authors have previously tried to develop a model for the testing of novel drug candidates for migraine, using the headache and migraine provoking agent cilostazol. Previous studies have used sumatriptan tablets as the validating drug, but they were not sufficiently effective. In this study we test the effect of subcutaneous sumatriptan on cilostazol induced headache in patients with migraine without aura. Method Thirty patients with migraine without aura received 200 mg cilostazol on two different study days. The induced headache was treated with subcutaneous sumatriptan in a randomized, double-blind cross-over design. The patients filled out a self-reported headache questionnaire until 12 h after cilostazol. Results All 30 patients experienced headache (range 3–10) on both study days and the headache fulfilled the criteria for a migraine-like attack in 73% on the sumatriptan day and in 77% on the placebo day. Sumatriptan injection reduced the headache score 2 h after treatment ( p = 0.003). The difference between headache intensity on the sumatriptan day and the placebo day was significant at both 2 h ( p = 0.01) and 4 h ( p = 0.0007) after treatment. Conclusion Subcutaneous sumatriptan reduces cilostazol induced headache in migraine patients. The cilostazol model may be useful as a tool to test the potential of new anti-migraine drugs. Trial registration: The study is registered on clinicaltrials.gov (NCT03422796).

Changes in the gene expression profile during spontaneous migraine attacks

ObjectiveMigraine occurs in clearly defined attacks and thus lends itself to investigate changes during and outside attack. Gene expression fluctuates according to environmental and endogenous events and therefore is likely to reveal changes during a migraine attack. We examined the hypothesis that changes in RNA expression during and outside of a spontaneous migraine attack exist which are specific to the migraine attack.MethodsWe collected blood samples from 27 migraine patients during an attack, two hours after treatment with subcutaneous sumatriptan, on a headache-free day and after a cold pressor test. All patients were deeply phenotyped, including headache characteristics and treatment effect during the sampling. RNA-Sequencing, genotyping, and steroid profiling was performed on all samples. RNA-Sequences were analyzed at gene level (differential expression analysis) and at network level, and we integrated transcriptomic and genomic data.ResultsWe found 29 differentially expressed (DE) genes between ‘attack’ and ‘after treatment’, after subtracting non-migraine specific genes, i.e. genes related to a general pain/stress response. DE genes were functioning in fatty acid oxidation, signaling pathways and immune-related pathways. Network analysis revealed molecular mechanisms affected by change in gene interactions during the migraine attack, e.g. ‘ion transmembrane transport’ and ‘response to stress’. Integration of genomic and transcriptomic data revealed pathways related to sumatriptan treatment, i.e. ‘5HT1 type receptor mediated signaling pathway’.InterpretationUsing a paired-sample design, we uniquely investigated intra-individual changes in the gene expression during a migraine attack. We revealed both genes and pathway potentially involved in the pathophysiology of migraine.

Subcutaneous sumatriptan: association with decreases in postoperative pain and opioid use after elective cranial surgery

OBJECTIVESumatriptan, a serotonin receptor agonist, has been used in the management of primary headache disorders and has been shown to affect trigeminal dural afferents. There is limited literature on the safety and efficacy of sumatriptan for postcraniotomy pain management. This study aimed to identify whether subcutaneous sumatriptan is a safe and efficacious pain management strategy after elective craniotomy.METHODSThe authors retrospectively reviewed patients who underwent supratentorial or suboccipital craniotomy between 2016 and 2019 that was performed by a single provider at a single institution to identify patients given subcutaneous sumatriptan in the postoperative period. Pain scores and intravenous and oral opioid use were compared in patients with (n = 15) and without (n = 45) sumatriptan administration.RESULTSPatients with and without sumatriptan administration had no significant differences in baseline characteristics or surgery type. There were no sumatriptan-related complications. The average pain score decreased from 3.9 to 1.3 within 1 hour after sumatriptan administration (p = 0.014). In both adult and pediatric patients there was decreased postoperative pain (adults: pain score of 1.1 vs 7.1, p < 0.001; pediatric: 1.1 vs 3.9, p = 0.007) within the first 48 hours. There were decreases in intravenous opioid use, length of intravenous opioid use, maximum dose of intravenous opioid used, oral opioid use, length of oral opioid use, and maximum dose of oral opioid used in both adult and pediatric patients.CONCLUSIONSThe authors identified subcutaneous sumatriptan as a safe and efficacious tool for postoperative pain management after craniotomy. Large multicenter randomized controlled studies are needed to further evaluate the specific role of sumatriptan in postoperative pain management after craniotomy.

Ultra-rapid brain uptake of subcutaneous sumatriptan in the rat: Implication for cluster headache treatment

Background In spite of the substantial therapeutic efficacy of triptans, their site of action is still debated. Subcutaneous sumatriptan is the most efficacious symptomatic treatment for cluster headache (CH) patients, showing therapeutic onset within a few minutes after injection even in migraine patients. However, whether subcutaneous sumatriptan is able to reach the CNS within this short time frame is currently unknown. Methods Here, by means of liquid chromatography/mass spectrometry, we investigated peripheral and brain distribution of subcutaneous sumatriptan soon after injection in rats at a dose equivalent to that used in patients. Tissue sumatriptan contents were compared to those of oxazepam, a prototypical lipophilic, neuroactive drug. Results We report that sumatriptan accumulated within brain regions of relevance to migraine and CH pathogenesis such as the hypothalamus and the brainstem as soon as 1 and 5 minutes after injection. Notably, sumatriptan brain distribution was faster than that of oxazepam, reaching concentrations exceeding its reported binding affinity for 5HT1B/D receptors, and in the range of those able to inhibit neurotransmitter release in vivo. Conclusion Our findings indicate that sumatriptan distributes within the CNS soon after injection, and are in line with prompt pain relief by parenteral sumatriptan in CH patients.

Subcutaneous sumatriptan for the treatment of postcraniotomy pain (SUPS trial): protocol for a randomised double-blinded placebo controlled trial

IntroductionPostcraniotomy pain protocols use opioids, which are considered suboptimal analgesia following this procedure. Multimodal analgesia components are sparse. Our null hypothesis states that sumatriptan is not different to placebo in addition to usual intravenous opioids, for the treatment of acute postcraniotomy pain.Methods and analysisThis is a prospective single-centre randomised double-blinded placebo-controlled phase III clinical trial comparing subcutaneous sumatriptan injection in the recovery area with placebo for the treatment of postcraniotomy pain. Eligible adult patients (18 years and older) undergoing craniotomy will be identified preoperatively. Both patient groups will receive a subcutaneous injection at a point where recovery-nursing staff would initiate the usual intravenous opioid analgesia as per standardised pain management protocol. In both groups, further pain management will be followed by the usual intravenous opioid administration. Primary outcome will consist of the difference in pain experienced by the two groups of patients in recovery area 60 min after the study drug administration. Postcraniotomy pain will be measured at regular intervals using the Visual Analogue Scale (VAS) in recovery area. The minimal clinically important difference of 10 mm on the VAS between the two groups will be considered as statistically significant. We will include selected clinical and patient-reported outcomes as secondary endpoints. Univariate regression will be conducted on each one of the clinically plausible potential confounders. We will enrol a total 136 patients, with the study duration of 2 years. This trial will commence recruitment on the 1 July 2019.Ethics and disseminationThis trial protocol has achieved approval by the Austin Health Research Committee, HREC/17/Austin/596. This trial was prospectively registered with Australian New Zealand Clinical Trials Registry on the 10/05/2018 with a unique trial identifier U1111-1209-9072 and registration Number ACTRN12618000793213P. Findings of this study will be disseminated in peer-reviewed academic journals.Trial registration numberU1111-1209-9072, ACTRN12618000793213P