Subcutaneous Sumatriptan Research Articles

Pharmacokinetics and tolerability of sumatriptan after single-dose administration of a fixed-dose combination tablet of sumatriptan/naproxen sodium 85/500 mg followed two hours later by subcutaneous sumatriptan 4- or 6-mg injection: A randomized, open-label, three-period crossover study in healthy volunteers

Background: Rescue medication options that are consistent with the product labeling for sumatriptan/ naproxen sodium (S/N) and that have been permitted in ≥1 clinical trial include the use of a second tablet of S/N, sumatriptan tablets (to a total daily dose of 200 mg), and naproxen sodium tablets (within the maximum limits recommended in the labeling). Sumatriptan subcutaneous (SC) injection might be especially useful as rescue medication mostly because of its rapid onset of activity. Objective: The aim of this study was to assess the pharmacokinetics and tolerability of sumatriptan SC used as rescue medication after the administration of oral S/N for the treatment of migraine. Methods: This randomized, open-label, 3-period crossover study compared the exposure to sumatriptan (Cmax and AUC to 14 hours after the administration of the second dose [AUC 0–14]) between 3 treatment regimens: an initial dose of S/N 85/500 mg followed 2 hours later by sumatriptan 4 or 6 mg SC (S/N + S4 and S/N + S6, respectively) (test), or sumatriptan 100 mg PO (2 tablets administered 2 hours apart) (S100 + S100) (reference). Healthy adults aged 18 to 55 years were randomly assigned to receive all 3 regimens in a randomized sequence. On day 1 of each treatment period, continuous cardiovascular monitoring (ECG telemetry), serial 12-lead ECG, and serial blood pressure (BP) measurements were conducted 1 hour before to 10 hours after the administration of the first dose. Blood samples for pharmacokinetic assessment were collected up to 14 hours after the administration of the first dose. Adverse events (AEs) were monitored from the time of consent until study completion. Participants returned to the clinic for pharmacokinetic blood sampling (for S/N + S4 and S/N + S6) and for tolerability assessment at 24, 48, and 72 hours after S/N administration. Results: A total of 30 healthy adults were randomized. Five withdrew prematurely (3, withdrawn consent; 1, AE; and 1, protocol deviation). Half of the subjects were men, the mean age was 27.8 years, and the mean weight was 79.3 kg (range, 54.6–100.8 kg). With S/N + S4, sumatriptan Cmax and AUC 0–14 did not exceed those with S100 + S100. Sumatriptan Cmax was 1.26-fold higher with S/N + S6 than with S100 + S100. Sumatriptan AUC 0–14 with S/N + S6 was not significantly greater than that with S100 + S100. Differences in serial BP measurements between the SC and S100 + S100 regimens were not statistically significant. The numbers of subjects in whom any AE was reported were 10 (37%) with S/N + S4, 14 (54%) with S/N + S6, and 13 (48%) with S100 + S100. Conclusions: Sumatriptan 4 and 6 mg SC administered 2 hours after an S/N tablet yielded sumatriptan exposure that did not exceed that of S100 + S100. Cmax with the S/N + S6 regimen was 1.26-fold higher than reference values. Both regimens were reasonably well tolerated. Randomized controlled trials are needed to test the efficacy and tolerability of these SC regimens. ClinicalTrials.gov identifier: NCT00875784.

Triptans for acute cluster headache.

Cluster headache is an uncommon, but severely painful and disabling condition, with rapid onset. Validated treatment options are limited, and first-line therapy includes inhaled oxygen. Alternative therapies such as intranasal lignocaine and ergotamine are not as commonly used and are less well studied. Triptans are successfully used to treat migraine attacks and, because of this, they may also be useful for cluster headache. To determine the efficacy and tolerability of triptans for the acute treatment of cluster headaches. We searched Cochrane CENTRAL, MEDLINE and EMBASE for studies through 22 January 2010. Randomised, double-blind, placebo-controlled studies of triptans for acute treatment of cluster headache episodes. Two review authors independently assessed study quality and extracted data. Numbers of participants with different levels of pain relief, requiring rescue medication and experiencing adverse events and headache-associated symptoms in treatment and control groups were used to calculate relative risk and numbers needed to treat (NNT) and harm (NNH). All six included studies used a single dose of triptan to treat an attack of moderate to severe pain intensity. In total 231 participants received zolmitriptan 5 mg, 223 received zolmitriptan 10 mg, 131 received sumatriptan 6 mg, 88 received sumatriptan 12 mg, and 326 received placebo. Zolmitriptan was administered either orally or intranasally, and sumatriptan either subcutaneously or intranasally.Overall, the triptans studied were better than placebo for headache relief and pain-free responses, with an NNT of 2.4 for 15 minute pain relief with subcutaneous sumatriptan 6 mg (75% with sumatriptan and 32% with placebo), and 2.8 for 30 minute pain relief with intranasal zolmitriptan 10 mg (62% with zolmitriptan and 26% with placebo). Fewer participants need rescue medication with triptan than with placebo, but more experienced adverse events. Zolmitriptan and sumatriptan are effective in the acute treatment of cluster headaches and may provide a useful treatment option, potentially offering convenience over oxygen therapy and a better safety and tolerability profile than ergotamine. Non-oral routes of administration are likely to provide better and more rapid responses.

Subcutaneous Sumatriptan Pharmacokinetics: Delimiting the Monoamine Oxidase Inhibitor Effect

The absolute bioavailability of subcutaneous (s.c.) sumatriptan is 96-100%. The decay curve for plasma concentration after 6 mg s.c. sumatriptan (ie, after T(max) = about 0.2 hours) includes a large distribution component. Metabolism by monoamine oxidase-A (MAO-A) leads to about 40% of the s.c. dose appearing in the urine as the inactive indole acetic acid. Product labeling states that co-administration of an inhibitor of MAO-A (a MAOI-A) causes a 2-fold increase in sumatriptan plasma concentrations, and a 40% increase in elimination half-life. The objective of this study is to determine whether MAOI-A therapy should deter the use of 6 mg s.c. sumatriptan on pharmacokinetic grounds. Summary pharmacokinetic data were taken from the literature and from GlaxoSmithKline (GSK) study C92-050. Half-times were converted into rate constants, which were then used in a parsimonious compartmental model (needing only 3 simultaneous differential equations). Acceptance criteria for the model included observed plasma sumatriptan concentrations at T(max), 1, 2, and 10 hours post-dose. A set of 1000 concentration measurements at a resolution of 36 seconds was generated. The model was then perturbed with elimination constants observed during concomitant moclobemide administration, creating a second set of concentration measurements. The 2 sets were then plotted, examined for their differences, and integrated for a second time to obtain and compare areas under the curve (AUCs). The greatest absolute difference between the 2 sets of measurements was 2.85 ng/mL at t = 2.95 hours. A 2-fold difference between the 2 sets occurred only after t = 5.96 hours, when the concentration in the presence of the MAOI-A was 3.72 ng/mL (or <4% of C(max)). At t = 10 hours, the concentrations in both sets were <1 ng/mL (ie, below the lower limit of assay quantitation), and AUC(0-10h) was 97.4 and 117 ng.hour/mL in the absence and presence of the MAOI-A. There are no pharmacokinetic grounds to deter co-administration of an MAOI-A and subcutaneous sumatriptan. The dominance of the distribution phase and completeness of absorption of a 6 mg dose of s.c. sumatriptan explains the trivial effect size of the MAOI-A on plasma sumatriptan concentrations. Importantly, these findings should not be extrapolated to other routes of administration for sumatriptan.

Rapid absorption of sumatriptan powder and effects on glyceryl trinitrate model of headache following intranasal delivery using a novel bi-directional device

Abstract Objectives The aim was to investigate the pharmacokinetics of intranasal sumatriptan (administered using a novel bi-directional powder delivery device) and study its effects on quantitative electroencephalography in patients with migraine. The safety profiles of the two formulations were also compared. Methods The pharmacokinetics of intranasal sumatriptan (10 mg and 20 mg) administered using a novel breath-actuated bi-directional powder delivery device were compared with subcutaneous sumatriptan (6 mg), along with an investigation of their effects on the electroencephalogram (EEG) following glyceryl trinitrate (GTN) challenge in 12 patients with migraine using a randomized, three-way cross-over design. Key findings Following intranasal delivery, median tmax was 20 min with both doses compared with 10 min after the subcutaneous dose. Mean ± SD values for Cmax were 96 ± 25, 11 ± 7 and 16 ± 6 ng/ml for subcutaneous, intranasal 10 mg and intranasal 20 mg formulations, respectively. Values for area under the curve were also lower with the intranasal doses. Intranasal and subcutaneous sumatriptan induced similar EEG changes characterized by reduced theta-power and increased beta-power. The majority of study participants were free of pain according to the headache severity score with all treatments from 15 min through to 8 h post-dose. All treatments were well tolerated and there were no reports of bitter aftertaste after intranasal delivery. Sumatriptan was rapidly absorbed after intranasal administration using the new device. Using the GTN challenge, sumatriptan powder delivered intranasally at a dose of 20 mg by the new device had effects similar to those of subcutaneous sumatriptan on EEG and reported headache pain, despite much lower systemic exposure. Conclusions Administration of sumatriptan intranasally at doses of 10 mg and 20 mg by the breath actuated bi-directional powder delivery device results in rapid absorption. Delivery to target sites beyond the nasal valve induced a similar EEG profile to subcutaneous sumatriptan 6 mg and prevented migraine attacks in patients following GTN challenge. Intranasal administration of sumatriptan powder with the breath actuated bi-directional powder delivery device was well tolerated.

A Prospective, Randomized Trial of Intravenous Prochlorperazine Versus Subcutaneous Sumatriptan in Acute Migraine Therapy in the Emergency Department

Intravenous (IV) prochlorperazine with diphenhydramine is superior to subcutaneous sumatriptan in the treatment of migraine patients presenting to the emergency department (ED). In this randomized, double-blind, placebo-controlled trial, after providing written informed consent, patients presenting to the ED with a chief complaint of migraine received a 500-mL bolus of IV saline solution and either 10 mg prochlorperazine with 12.5 mg diphenhydramine IV plus saline solution placebo subcutaneously or saline solution placebo IV plus 6 mg sumatriptan subcutaneously. Pain intensity was assessed with 100-mm visual analog scales (visual analog scale at baseline and every 20 minutes for 80 minutes). The primary outcome was change in pain intensity from baseline to 80 minutes or time of ED discharge if subjects remained in the ED for fewer than 80 minutes after treatment. Sedation and nausea were assessed every 20 minutes with visual analog scale scales, and subjects were contacted within 72 hours to assess headache recurrence. Sixty-eight subjects entered the trial, with complete data for 66 subjects. Baseline pain scores were similar for the prochlorperazine/diphenhydramine and sumatriptan groups (76 versus 71 mm). Mean reductions in pain intensity at 80 minutes or time of ED discharge were 73 mm for the prochlorperazine/diphenhydramine group and 50 mm for those receiving sumatriptan (mean difference 23 mm; 95% confidence interval 11 to 36 mm). Sedation, nausea, and headache recurrence rates were similar. IV prochlorperazine with diphenhydramine is superior to subcutaneous sumatriptan in the treatment of migraine.

Is there an inherent limit to the efficacy of calcitonin gene-related peptide receptor antagonists in the acute treatment of migraine? A comment

Calcitonin gene-related peptide (CGRP) receptor antagonists are a new treatment principle in acute migraine attacks. Intravenous olcegepant 2.5 mg resulted in 66% headache relief after 2 h, whereas subcutaneous sumatriptan resulted in 81–92% headache relief after 2 h. The intrinsic activity of a parenteral triptan, a 5HT1B/1D receptor agonist, is thus higher than the maximum effect of the parenteral CGRP receptor antagonist olcegepant. For the orally bioavailable CGRP antagonist telcagepant 300 mg, the headache relief was only 55% in one phase III study. These results indicate that CGRP receptor antagonism results in success in the acute treatment of migraine in only a certain fraction of the patients.

Rapid absorption of sumatriptan powder and effects on glyceryl trinitrate model of headache following intranasal delivery using a novel bi-directional device

The aim was to investigate the pharmacokinetics of intranasal sumatriptan (administered using a novel bi-directional powder delivery device) and study its effects on quantitative electroencephalography in patients with migraine. The safety profiles of the two formulations were also compared. The pharmacokinetics of intranasal sumatriptan (10 mg and 20 mg) administered using a novel breath-actuated bi-directional powder delivery device were compared with subcutaneous sumatriptan (6 mg), along with an investigation of their effects on the electroencephalogram (EEG) following glyceryl trinitrate (GTN) challenge in 12 patients with migraine using a randomized, three-way cross-over design. Following intranasal delivery, median t(max) was 20 min with both doses compared with 10 min after the subcutaneous dose. Mean +/- SD values for C(max) were 96 +/- 25, 11 +/- 7 and 16 +/- 6 ng/ml for subcutaneous, intranasal 10 mg and intranasal 20 mg formulations, respectively. Values for area under the curve were also lower with the intranasal doses. Intranasal and subcutaneous sumatriptan induced similar EEG changes characterized by reduced theta-power and increased beta-power. The majority of study participants were free of pain according to the headache severity score with all treatments from 15 min through to 8 h post-dose. All treatments were well tolerated and there were no reports of bitter aftertaste after intranasal delivery. Sumatriptan was rapidly absorbed after intranasal administration using the new device. Using the GTN challenge, sumatriptan powder delivered intranasally at a dose of 20 mg by the new device had effects similar to those of subcutaneous sumatriptan on EEG and reported headache pain, despite much lower systemic exposure. Administration of sumatriptan intranasally at doses of 10 mg and 20 mg by the breath actuated bi-directional powder delivery device results in rapid absorption. Delivery to target sites beyond the nasal valve induced a similar EEG profile to subcutaneous sumatriptan 6 mg and prevented migraine attacks in patients following GTN challenge. Intranasal administration of sumatriptan powder with the breath actuated bi-directional powder delivery device was well tolerated.

Calcitonin gene-related peptide (CGRP) levels during glyceryl trinitrate (GTN)-induced headache in healthy volunteers

The role of nitric oxide (NO) in migraine has been studied in the experimental glyceryl trinitrate (GTN)-infusion headache model. We hypothesized that GTN-induced headache may activate the trigeminovascular system and be associated with increased levels of sensory neuropeptides, including calcitonin gene-related peptide (CGRP). CGRP, vasoactive intestinal peptide (VIP), neuropeptide Y (NPY) and somatostatin plasma levels were measured before and after placebo/sumatriptan injection and during GTN-induced headache. Following a double-blind randomized cross-over design, 10 healthy volunteers received subcutaneous sumatriptan 6 mg or placebo. This was succeeded by 20 min of GTN (0.12 µg kg(-1) min(-1)) infusion. At baseline no subject reported headache (using verbal rating scale from 0 to 10) and the jugular CGRP-like immunoreactivity (-LI) level was 18.6 ± 2.5 pmol/l. After a 20-min intravenous infusion of GTN 0.12 µg kg(-1) min(-1), median peak headache intensity was 4 (range 2-6) (P < 0.05), while jugular CGRP-LI levels were unchanged (19.0 ± 2.8 pmol/l; P > 0.05). There were no changes in VIP-, NPY- or somatostatin-LI. In conclusion, the NO donor GTN appears not to induce headache via immediate CGRP release.

EFNS guideline on the drug treatment of migraine – revised report of an EFNS task force

Migraine is one of the most frequent disabling neurological conditions with a major impact on the patients' quality of life. To give evidence-based or expert recommendations for the different drug treatment procedures in the particular migraine syndromes based on a literature search and the consensus of an expert panel. All available medical reference systems were screened for the range of clinical studies on migraine with and without aura and on migraine-like syndromes. The findings in these studies were evaluated according to the recommendations of the European Federation of Neurological Societies (EFNS) resulting in level A, B, or C recommendations and good practice points. For the acute treatment of migraine attacks, oral non-steroidal antiinflammatory drug (NSAID) and triptans are recommended. The administration should follow the concept of stratified treatment. Before intake of NSAID and triptans, oral metoclopramide or domperidone is recommended. In very severe attacks, intravenous acetylsalicylic acid or subcutaneous sumatriptan are drugs of first choice. Status migrainosus can be treated by cortoicosteroids, although this is not universally held to be helpful, or dihydroergotamine. For the prophylaxis of migraine, betablockers (propranolol and metoprolol) flunarizine, valproic acid, and topiramate are drugs of first choice. Drugs of second choice for migraine prophylaxis include amitriptyline, naproxen, petasites, and bisoprolol.

Acute Myocardial Infarction With Sumatriptan: A Case Report and Review of the Literature

We report a case of myocardial infarction associated with the use of sumatriptan and review the literature regarding similar cases. A 54-year-old woman with a history of migraine without aura, mild arterial hypertension, depression, and no history of coronary artery disease was admitted to our hospital for acute myocardial infarction, 30 minutes after using 6 mg of subcutaneous sumatriptan. Coronary angiography performed several days later revealed a normal coronary arterial system. Although at discharge the patient was advised to permanently avoid triptans, she continued the use of oral sumatriptan at low dosage (25-50 mg) without any problems.

Treatment of Cluster Headache in Pregnancy and Lactation

Cluster headache is a rare disorder in women, but has a serious impact on the affected woman's life, especially on family planning. Women with cluster headache who are pregnant need special support, including the expertise of an experienced headache centre, an experienced gynaecologist and possibly a teratology information centre. The patient should be seen through all stages of the pregnancy. A detailed briefing about the risks and safety of various treatment options is mandatory. In general, both the number of medications and the dosage should be kept as low as possible. Preferred treatments include oxygen, subcutaneous or intranasal sumatriptan for acute pain and verapamil and prednisone/prednisolone as preventatives. If there is a compelling reason to treat the patient with another preventative, gabapentin is the drug of choice. While breastfeeding, oxygen, sumatriptan and lidocaine for acute pain and prednisone/prednisolone, verapamil, and lithium as preventatives are the drugs of choice. As the individual pharmacokinetics differ substantially, adverse drug effects should be considered if unexplained symptoms occur in the newborn.

Sumatriptan does not change calcitonin gene-related peptide in the cephalic and extracephalic circulation in healthy volunteers

Triptans are effective and well tolerated in acute migraine management but their exact mechanism of action is still debated. Triptans might exert their antimigraine effect by reducing the levels of circulating calcitonin gene-related peptide (CGRP). To examine this question, we examined whether sumatriptan modulate the baseline CGRP levels in vivo, under conditions without trigeminovascular system activation. We sampled blood from the internal and external jugular, the cubital veins, and the radial artery before and after administration of subcutaneous sumatriptan in 16 healthy volunteers. Repeated-measure ANOVA showed no interaction between catheter and time of sampling and thus no significant difference in CGRP between the four catheters (P = 0.75). CGRP did not change over time in the four compartments (P > 0.05). The relative changes in CGRP between baseline and maximal sumatriptan concentration did not differ between the four vascular compartments (P = 0.49). It was found that Sumatriptan did not change the levels of circulating CGRP in the intra or extracerebral circulation in healthy volunteers. This speaks against a direct CGRP-reducing effect of sumatriptan in vivo in humans when the trigemino vascular system is not activated.

Advances in Medical Management of Cluster Headache

Cluster headache is a rare but extremely disabling condition. For the acute treatment of cluster headache attacks, oxygen (100%) with a flow of at least 7l/minute, 6mg subcutaneous sumatriptan and 5mg zolmitriptan nasal spray are the drugs of first choice. Prophylaxis of cluster headache should be performed with verapamil in a daily dose of at least 240mg (maximum dose depends on efficacy and tolerability). Although no placebo-controlled trials are available, steroids are clearly effective in cluster headache. Methylprednisone (or equivalent corticosteroid) at least 100mg orally or up to 500mg intravenously per day over five days (then tapering down) is recommended. Methysergide, lithium and topiramate are recommended as drugs of second choice. Although in part promising, surgical procedures require further scientific evaluation before they can be recommended.

Advances in Medical Management of Cluster Headache

Cluster headache is a rare but extremely disabling condition. For the acute treatment of cluster headache attacks, oxygen (100%) with a flow of at least 7l/minute, 6mg subcutaneous sumatriptan, and 5mg zolmitriptan nasal spray are the drugs of first choice. Prophylaxis of cluster headache should be performed with verapamil in a daily dose of at least 240mg (maximum dose depends on efficacy and tolerability). Although no placebo-controlled trials are available, steroids are clearly effective in cluster headache. Methylprednisone (or equivalent corticosteroid) at least 100mg orally or up to 500mg intravenously per day over five days (then tapering down) is recommended. Methysergide, lithium, and topiramate are recommended as drugs of second choice. Although in part promising, surgical procedures require further scientific evaluation before they can be recommended.

Early Responses in Randomized Clinical Trials of Triptans in Acute Migraine Treatment. Are They Clinically Relevant? A Comment

One can question the clinical relevance of early headache responses after oral and intranasal triptans. Thus, for pain-free the early responses were significant but in absolute values they were only a few percentages: the therapeutic gains (TGs) were 1.8% (95% CI = 0.3-3%) for oral almotriptan 12.5 after 30 minutes and 1.0% (95% CI = 0-2%) after intranasal zolmitriptan 5 mg after 15 minutes. These results are compared with subcutaneous sumatriptan 6 mg which has TGs of 11% (95% CI = 7-15%) to 14% (95% CI = 11-17%) for pain-free after 30 minutes. Subcutaneous sumatriptan has a 2 times higher response rate than intranasal zolmitriptan and is 5 times more effective than oral almotriptan at these early time points. It is concluded that if a very early and clinically relevant effect is desired then the migraine patient should use the subcutaneous administration form of sumatriptan.

Sumatriptan Does Not Affect Arteriovenous Oxygen Differences in Jugular and Cubital Veins in Normal Human Subjects

Arteriovenous anastomoses (AVAs) may open up during migraine attacks. In studies with anaesthetized and bilaterally vagosympatectomized pigs, triptans reduce AVA blood flow and increase the arteriovenous O2 difference (AVDO2). To investigate whether subcutaneous sumatriptan 6 mg could induce changes in the AVDO2, we measured the AVDO2 in the external jugular vein in healthy subjects. We also measured the AVDO2 in the internal jugular and cubital veins. There were no changes in AVDO2 after subcutaneous sumatriptan, probably because AVA blood flow is limited in humans with an intact sympathetic nervous system.

Subcutaneous Sumatriptan Relieved Migraine‐Like Headache in Two Adolescents With Aseptic Meningitis

Sumatriptan was developed as an agent for the treatment of acute migraine. However, sumatriptan may alleviate not only migraine headache, but also headache of subarachnoid hemorrhage and meningitis. We report 2 patients whose migraine-like headache on presentation was relieved by subcutaneous sumatriptan. Later, both patients were diagnosed with aseptic meningitis.

Chronic Cluster-Like Headache Secondary to Prolactinoma: Uncommon Cephalalgia in Association with Brain Tumors

Headache is a common and disabling aspect of pituitary disease. Chronic and episodic migraine are the most common clinical syndromes of headaches related to pituitary tumors, although other types of headache, such as trigeminal autonomic cephalalgias (TACs), can also be present. TACs include short-lasting, unilateral neuralgiform headache attacks with conjunctival injection and tearing; paroxysmal hemicrania; and cluster headache. We report on a patient with a chronic cluster-like headache associated with a macroprolactinoma. Although cabergoline, pregabalin, and corticosteroids were not effective as preventive treatments, high-dose verapamil showed good efficacy. Morphine and octreotide were efficacious as abortive treatments for attacks, but pain was only partially responsive to oxygen and refractory to subcutaneous sumatriptan.

Alcohol and Cluster Headaches

Alcohol and Cluster Headaches

Subcutaneous Sumatriptan in an Adolescent With Acute Posttraumatic Headache

Acute posttraumatic headache is common and can evolve into chronic posttraumatic headache, which is associated with medication overuse and disability. However, there are few studies to guide treatment management of acute posttraumatic headache. We describe an adolescent with acute posttraumatic headache that did not respond to several initial medications but had rapid and sustained improvement in headache and associated migrainous features with subcutaneous sumatriptan.