Scope decisions recorded for the next curator. The chest and central nervous system sensations node hangs off the trigger rather than off the vasoconstriction node: the pooled trial data establish the rates but report no mechanism, and the conventional coronary attribution for triptan chest symptoms is contested, so no vascular parentage is asserted. The migraine-progression node is deliberately narrow -- the cited review found progression on triptans only in patients already having headache on 10 to 14 days a month and not overall, and the node says so, because a blanket class-chronification claim is not what the source supports. The CGRP-release arm carries two evidence items of different kinds on purpose: the trigeminal-stimulation experiment is the mechanistic one and is model-organism evidence, while the human arm is a correlation between peptide normalisation and headache relief, not a demonstration of sequence. Familial_Hemiplegic_Migraine is not wired as a conformer although it is a migraine entry: its own management is avoidance of vasoconstricting agents, and a disease that withholds a drug class is not an instance of that class's mechanism. Its relation to this module is the adverse branch, not the therapeutic one.
5-HT1B/1D Receptor Agonist Occupancy
trigger
A triptan binds and activates 5-HT1B and 5-HT1D receptors. The class is selective for these subtypes, and the two receptors sit in different places -- 5-HT1B on the smooth muscle of cranial extracerebral vessels, 5-HT1D presynaptically on trigeminal sensory terminals -- which is why one drug produces two mechanisms rather than one.
Used by disorders
Migraine
as Triptan Occupancy of Meningeal and Trigeminal 5-HT1B/1D Receptors
Downstream
-
Cranial Extracerebral Vasoconstriction via 5-HT1B
-
Presynaptic Inhibition of Trigeminal Neuropeptide Release via 5-HT1D
-
Chest and Central Nervous System Sensations on Triptan Therapy
-
Migraine Progression on Frequent Triptan Use in High-Frequency Headache
Show evidence (2 references)
"the development of sumatriptan and second generation triptans in the 1990's led to discover that these drugs produce selective cranial extracerebral vasoconstriction (via 5-HT1B receptors) and inhibition of the trigeminovascular system responses implicated in migraine (via 5-HT1D/5-HT1F receptors)."
Establishes that the class acts through 5-HT1B and 5-HT1D, and that the two receptors carry the two separate mechanisms this node feeds.
"The triptans, selective serotonin 5-HT(1B/1D) agonists, are very effective acute migraine drugs with a well- developed scientific rationale."
Names the receptor selectivity that makes this node receptor-specific rather than a generic serotonergic one.
Presynaptic Inhibition of Trigeminal Neuropeptide Release via 5-HT1D
effector
Agonist occupancy of 5-HT1D receptors on trigeminal sensory terminals suppresses release of calcitonin gene-related peptide and the other vasoactive neuropeptides those terminals discharge during an attack. This is the non-vascular half of the class's action, and it is the half the later CGRP-directed drugs target further downstream.
Downstream
-
Interruption of Trigeminovascular Nociceptive Signalling
Show evidence (2 references)
"Trigeminal ganglion stimulation at a frequency of 5 per second also led to a release into the cranial circulation of calcitonin gene-related peptide (CGRP), with the level rising from 67 +/- 3 to 82 +/- 5 pmol/liter on the side of stimulation. These increases were also markedly antagonized by..."
The mechanistic demonstration: trigeminal stimulation releases CGRP, and sumatriptan blocks that release.
"inhibition of the trigeminovascular system responses implicated in migraine (via 5-HT1D/5-HT1F receptors)"
Attributes the trigeminovascular-inhibition arm to 5-HT1D, which is the receptor bound on this node.
Interruption of Trigeminovascular Nociceptive Signalling
central effector
The two arms converge: the dilated extracerebral vessels constrict and the trigeminal terminals stop discharging neuropeptide, so the trigeminovascular response that sustains the attack is interrupted. This is the step the therapeutic endpoint runs through, and it is the key conformance target for an entry that models the mechanism rather than the drug.
Downstream
-
Headache Response and Sustained Pain Freedom
Show evidence (2 references)
"Stimulation of the trigeminal ganglion led to a frequency-dependent increase in cerebral blood flow, with a mean maximum of 43 +/- 9% at a stimulus frequency of 20 per second. There was a marked reduction in these responses by some 50% after administration of either sumatriptan or dihydroergotamine."
Shows the trigeminovascular response itself being halved by the drug, which is the convergent step rather than either arm alone.
"In 7 of 8 patients responding to subcutaneous sumatriptan administration, elevated CGRP levels (60 +/- 8 pmol/liter) were normalized, with the headache being relieved (40 +/- 8 pmol/liter)."
The human counterpart, which is a correlation between peptide normalisation and headache relief rather than a demonstration of sequence; graded INDIRECT for that reason.
Headache Response and Sustained Pain Freedom
consequence
The clinical endpoints the class is prescribed for, and the honest size of them: a majority get headache response by two hours, under a third are pain free at two hours, and only a fifth are pain free at two hours and stay that way through twenty-four. The attrition between those three numbers is part of this node, because a module that recorded only the response rate would overstate the class.
Show evidence (2 references)
"Mean results for 100 mg sumatriptan were 59% (95% CI 57-60) for 2 h headache response (improvement from moderate or severe to mild or no pain); 29% (27-30) for 2 h pain free (improvement to no pain); 20% (18-21) for sustained pain free"
The three graded endpoints, pooled across the trial set, including the attrition between them.
"INTERPRETATION: At marketed doses, all oral triptans were effective and well tolerated."
The pooled verdict on the class as a whole rather than on one agent.
Coronary and Systemic Vasoconstriction Contraindicating Use in Vascular Disease
adverse effect
The 5-HT1B receptor is not confined to cranial extracerebral vessels, so the constrictor action reaches the coronary and other systemic beds. The consequence is a hard contraindication in established vascular disease, which excludes a substantial share of the patients who need acute treatment and is the clinical gap the non-vasoconstrictor classes were developed to fill.
Show evidence (2 references)
"a number of patients do not respond well to the triptans and are contraindicated in patients with cardiovascular pathologies."
States the contraindication that this node exists to carry.
"This mini-review outlines further developments in the design of novel (non-vasoconstrictor) antimigraine treatments acting via 5-HT receptors"
Supports reading the vasoconstrictor liability as the specific problem the successor classes were designed around, rather than as an incidental adverse effect.
Chest and Central Nervous System Sensations on Triptan Therapy
adverse effect
Chest tightness or pressure, and central nervous system effects such as dizziness, paraesthesia and somnolence, are the characteristic tolerability cost of the class. Both are placebo-subtracted in the pooled data, so the rates are attributable to the drug; the chest rate is small in absolute terms and the central one several times larger. No vascular parentage is asserted for the chest symptoms: see the module notes.
Show evidence (1 reference)
"placebo-subtracted proportions for patients with at least one adverse event (AE) were 13% (8-18), for at least one central nervous system AE 6% (3-9), and for at least one chest AE 1.9% (1.0-2.7)."
The placebo-subtracted rates for both symptom groups, which is what makes them attributable to the drug rather than to the attack.
Migraine Progression on Frequent Triptan Use in High-Frequency Headache
adverse effect
Frequent use of acute treatment is the most-cited risk factor for episodic migraine becoming chronic, but the class-specific picture is narrower than that framing suggests. Triptans were associated with progression only in patients already having migraine on ten to fourteen days a month, and not in the cohort overall; opioids and barbiturates were associated with progression at lower exposure thresholds. This node asserts the conditional finding and no more.
Show evidence (2 references)
"Triptans induced migraine progression in those with high frequency of migraine at baseline (10-14 days per month), but not overall."
The exact conditional claim this node makes, including the negative half.
"high frequency of headaches seems to be a risk factor for chronic migraine regardless of medication exposure."
Supports attributing the risk primarily to baseline headache frequency rather than to the drug class, which is why this node is scoped to the high-frequency stratum.
Oral Triptan Therapy for Acute Migraine
Platform:
Small molecule
Sumatriptan, rizatriptan, zolmitriptan, eletriptan, almotriptan, naratriptan and frovatriptan, taken at the onset of an attack as migraine-specific acute treatment.
Evidence: 2
Subcutaneous Sumatriptan for Severe Attacks
Platform:
Small molecule
Parenteral sumatriptan, used where an oral agent is too slow or cannot be kept down.
Evidence: 1