Rizatriptan & Frovatriptan

Addition to the List

Peer Feedback:

“You only have one trirptan on there for migraine. That is not right. Migraine is a huge problem. What about adding rizatriptan (waferr, well tolerated) and frovatriptan (long acting)”

Literature Review Question:

What is the most efficacious and tolerable triptan for the treatment of migraine?

Literature Search:
eCPS - Neurologic Disorders: Headache in Adults
CPG via CMA
Pubmed – “triptan AND migraine AND comparison AND meta-analysis/review”

Triptan Meta-analysis (2014)

Table 2 presents the treatment rankings for all unadjusted and adjusted analysis for each outcome.

In conclusion, our study displays a hierarchy of treatment effects offered by the currently available triptans. Eletriptan appears to offer consistently the largest treatment efficacy at two and 24 hours. Rizatriptan appears to offer the second most favorable treatment outcome at two hours, but does not maintain the same degree of efficacy at 24 hours’ efficacy. Zolmitriptan and high-dose sumatriptan offer the third highest chance of pain-free response and headache response, and appear to maintain their efficacy at 24 hours. Clinicians will want to target a triptan that balances efficacy, tolerability, and costs for their patients.

Clinical implications

  • The relative efficacy of all triptans for the abortive treatment of migraine has remained uncertain as most randomized trials have compared the available triptans to placebo.
  • A multiple treatment comparison meta-analysis combining placebo and head-to-head trials was used to establish which triptan has the highest odds of producing favorable relief outcomes.
  • Eletriptan consistently has the highest odds of producing two-hour pain relief, two-hour headache response, 24-hour sustained pain relief, and 24-hour sustained headache response.
  • Rizatriptan, zolmitriptan, and high-dose (100 mg) sumatriptan also appear effective at two hours, whereas only zolmitriptan and high-dose sumatriptan appear to maintain their efficacy at 24 hours.

Thorlund, Kristian, et al. "Comparative efficacy of triptans for the abortive treatment of migraine: A multiple treatment comparison meta-analysis."Cephalalgia34.4 (2014): 258-267.

Canadian Guidelines for Migraine (2013)

Note: Guidelines split in to multiple parts, will only include relevant sections.

There are relatively few randomized, controlled, head-tohead trials comparing triptans to each other. Most head-to-head trials compare oral sumatriptan to one of the other triptans, and have utilized the 2-h headache response as a primary efficacy measure (2 h pain-free response is a preferred endpoint in clinical trials). 9

Although all seven triptans available in Canada show significant efficacy and good tolerability, and the differences between them are relatively small, head-to-head trials do support the presence of some differences. Unfortunately, comparison trials do not exist for all the triptans, and there are concerns that the results of some of them may have been affected by encapsulation. Based on available trials, it is possible to draw some conclusions, recognizing that the response of the individual patient to a specific triptan cannot be predicted, and as has often been said, the differences among patients appear greater than the differences among the triptans themselves. These studies were relatively small with limited power to detect differences, however, and should therefore be interpreted with caution.

  • Rizatriptan (10 mg) does tend to provide faster headache relief compared to a number of other oral triptans, and better relief of nausea than sumatriptan.
  • Eletriptan (40 mg) may show a greater sustained 24 hour response rate than sumatriptan, due at least in part to a relatively low headache recurrence rate.
  • Almotriptan (12.5 mg) tends to show a lower adverse event rate than some other triptans (zolmitriptan and sumatriptan).
  • Naratriptan and frovatriptan tend to have a slower onset of action and, therefore, a lower response rate at early time points after treatment, although in the direct comparison trials (see Table 4), frovatriptan (2.5 mg) appears to show similar efficacy at 2 h compared to several other triptans.

Recommendations (triptans)

  1. Strong recommendation, high quality evidence: Triptans (almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan, and zolmitriptan) are recommended for the acute treatment of migraine attacks that are likely to become moderate or severe.
  2. Strong recommendation, moderate quality evidence: If a patient does not respond well to one triptan or tolerates it poorly, other triptans should be tried over time in subsequent attacks. It is recommended that patients wait 24 hours before trying another triptan.

Although the triptans are chemically related drugs, in clinical practice it is a common experience that some patients will prefer one triptan to another. This may relate to a perceived difference in efficacy, differences in the side effects experienced, or both. Which triptan a patient will prefer cannot be predicted. It is generally accepted that the differences between patients are greater than the differences between triptans, and no one triptan is superior to the others for all patients. With regard to individual patients this has led to the adage that the best triptan “is the one that works best for the patient”. The different triptans do have different pharmacokinetic properties, and also to some extent show differences in side effects. Triptan choice can therefore be tailored to some extent to the individual patient. Rapidity of pain relief, the probability of pain relief, the probability of headache recurrence, and the probability of adverse events all are potential contributors to how satisfactory the patient’s response will be to any given triptan. 17,27,28

Expert Consensus

  1. It should be recognized that the response of an individual patient to a specific triptan cannot be predicted with accuracy. Patients with a less than optimal response to their current triptan should be encouraged to try several other triptans in different migraine attacks to determine if they will obtain better relief.
  2. Patients should be encouraged to take their triptan early in their attacks while pain is still mild, although caution may need to be exercised in patients with frequent attacks to avoid medication overuse.
  3. For severe migraine attacks with early vomiting, the use of subcutaneous sumatriptan 6 mg should be considered. Zolmitriptan nasal spray 5 mg may be an alternative choice for some patients. These formulations should also be considered for all patients with severe nausea, particularly those who have nausea early in their attacks, and for attacks not responsive to oral triptan medications.
  4. For patients with moderate or severe migraine attacks who require triptan therapy, and whose attacks build up rapidly in intensity, rizatriptan 10 mg tablets, eletriptan 40 mg tablets, zolmitriptan 5 mg nasal spray, and sumatriptan 6 mg SC injection should be considered.
  5. For patients with moderate or severe attacks who experience side effects on other triptans, almotriptan should be considered.
  6. For patients who experience frequent headache recurrence on triptan therapy, the use of eletriptan or frovatriptan should be considered, or the addition of naproxen sodium to the patient’s current triptan.
  7. For patients with nausea or vomiting who require an additional anti-emetic, metoclopramide, domperidone, or if necessary, prochlorperazine can be considered, to be taken with the triptan or triptan-NSAID combination.

Worthington, Irene, et al. "Canadian Headache Society Guideline: Acute drug therapy for migraine headache."The Canadian Journal of Neurological Sciences40.S3 (2013): S1-S3.

Triptans Meta-analysis (2002)

S = Sumatriptan, N = Naratriptan, R = Rizatriptan, E = Eletriptan, A = Almotriptan

Differences among the oral triptans at optimal doses may seem relatively small, but are clinically relevant for individual patients, i.e. provide clinically relevantly higher likelihood of success. For example, compared with sumatriptan 100 mg, rizatriptan 10 mg provides clinically significantly higher rates for response (60% for sumatriptan vs. 70% vs. rizatriptan =+17% relative improvement), pain free (29% vs. 40% =+38%) and sustained pain free (20% vs. 25% =+25%). Similarly, eletriptan 80 mg provides clinically significantly higher rates for response (60% vs. 66% =+10%) and sustained pain free (20% vs. 25% =+25%). Finally, almotriptan 12.5 mg provides clinically significantly higher rates for pain free (29% vs. 36% =+24%) and sustained pain free (20% vs. 26% =+30%) and a clinically significantly lower risk of AEs (33% for sumatriptan vs. 14% for almotriptan =x57%), although this latter advantage may have been exaggerated by the inclusion of different study populations (see above).

Note: This was included to show estimates of non-response of first attempted triptan.

Ferrari, M. D., et al. "Triptans (serotonin, 5‐HT1B/1D agonists) in migraine: detailed results and methods of a meta‐analysis of 53 trials."Cephalalgia22.8 (2002): 633-658.

eCPS (2015)

The triptans currently available to abort migraine include almotriptan, eletriptan, frovatriptan, naratriptan, rizatriptan, sumatriptan and zolmitriptan. All act on serotonin (5-HT) subclass 1B and 1D receptors, on extracerebral blood vessels and neurons respectively. The supposed mechanism of action is prevention of neurogenically sterile inflammatory responses around vessels and vasoconstriction. The newer agents may alter pain transmission centrally at the level of the trigeminal nucleus of the medulla, an action that may or may not have clinical benefits.

Overall, there is now good evidence that the available triptans are efficacious, generally well tolerated and safe.7Meta-analyses reveal that differences among the triptans are relatively small, but may be clinically meaningful to patients.8,9,10However, the benefits in individual patients may vary, as may patient preference for specific formulations (injection, nasal spray, tablets or fast-melt tablets).11

Subcutaneous sumatriptan has the fastest onset of action and remains the most efficacious triptan for a severemigraineattack. It is also useful in an acute cluster headache. There are few trials comparing triptans to each other. Rizatriptan may provide faster relief than a number of other oral triptans.6Almotriptan may have fewer adverse effects.6Naratriptan has a slow onset of action with maximal efficacy at 4 hours, lower headache recurrence rate and near placebo rates of side effects. Naratriptan may be best for moderately severemigraineattacks and for individuals who have low tolerance for side effects or high pain recurrence rates.

All triptans are contraindicated in patients with cardiac disorders, sustained hypertension, basilar and hemiplegicmigraine.

To avoid medication-overuse headache, triptans should be used less than 10 days per month.

Efficacy has been demonstrated for the short-term use (5–7 days, starting 2 days before menses) offrovatriptan2.5 mg po once to twice daily, to preventmenstrually associatedmigraine.25Perimenstrual use ofnaratriptan1 mg po BID orzolmitriptan2.5 mg po BID-TID may also be effective in this setting.14,26,27

Triptansare generally avoided as well (in pregnancy), although evidence is beginning to support a lack of additional risk to the mother or fetus, particularly with sumatriptan. Also avoid vasoconstricting agents such as ergots and triptans in the postpartum period because of a possible increased risk of postpartum stroke or angiopathy.Sumatriptanhas been studied more than other triptans in lactation and is considered compatible with breastfeeding, although it is prudent to avoid vasoconstricting agents in the initial postpartum period; other triptans should be used with caution.

Medication / Uses / Contraindications (CI), drug interactions (DI) or cautions / Adverse Effects
(common and severe) / Initial dose; typical dose / Monitoring
eletriptan / migraine / CI: coronary artery disease, WPW syndrome, uncontrolled HTN, TIA or stroke, peripheral vascular disease DI: SSRIs, SNRIs, TCAs, MAOIs (serotonin syndrome), ketoconazole, itraconazole, nefazodone, troleandomycin, clarithromycin, ritonavir, or nelfinavir / asthenia, dizziness, somnolence, nausea, headache, paresthesia, dry mouth, chest tightness/pain/pressure / 20mg; 20mg one time a day
Drug / Dosage / Adverse Effects / Drug Interactions / Comments / Costa
ALL TRIPTANS / N/A / All triptans:Chest discomfort, fatigue, dizziness, paresthesias, drowsiness, nausea, throat symptoms. / All triptans:Do not use with ergotamine-containing products. Caution with SSRIs or SNRIs (increased risk of serotonin syndrome). Do not use a triptan within24 hafter another triptan. / All triptans:do not use ifanycardiac-like symptoms; contraindicated in ischemic heart disease, sustained hypertension, pregnancy, basilar or hemiplegicmigraine; use less than10 days/monthto avoid medication-overuse headache.
Second dose not likely to be effective if first dose provided no relief. / N/A
almotriptan
Axert,generics / Oral:6.25–12.5mg; if headache returns after initial relief, may repeat in2 h;maximum 2 doses/24 h / Almotriptan:Do not use with MAOIs. Inhibitors of CYP3A4 (e.g., cimetidine, clarithromycin, efavirenz, erythromycin, grapefruit juice, itraconazole, ketoconazole and ritonavir) may increase bioavailability of almotriptan. / $$
eletriptan
Relpax,generics / Oral:20–40 mg; if headache returns after initial relief from20 mgdose, may take an additional20 mgin2 h;maximum 40 mg/24 h / Eletriptan:Contraindicated within 72 h of potent CYP3A4 inhibitors (e.g., clarithromycin, itraconazole, ketoconazole, nelfinavir, ritonavir). / $$
frovatriptan
Frova,generics / Oral: 2.5 mg; if headache recurs after initial relief, may repeat in4–24 h; maximum 5 mg/24 h / Frovatriptan:Oral contraceptives and propranolol may increase frovatriptan serum concentrations by 30–60%. / $$$
naratriptan
Amerge,
generics / Oral:1–2.5 mg; if headache returns after initial relief, may repeat dose in 4 h; maximum5 mg/24 h / Naratriptan may have a lower incidence of side effects than other triptans. / $$
rizatriptan
Maxalt,Maxalt RPD,generics / Oral:5–10 mg; if headache returns after initial relief, may repeat dose in 2 h; maximum20 mg/24 h / Rizatriptan:Do not use with MAOIs. Use with caution in patients taking propranolol (increased bioavailability of rizatriptan). / Rizatriptan:fastmelt wafers can be taken without water. / $$
sumatriptan
Imitrex,Imitrex DF,generics / Oral:25–100 mg; if headache returns after initial relief, may repeat in2 h;maximum 200 mg/24 h
Injectable:6 mgsc; may repeat in1 h;maximum 2injections/24 h
Nasal spray:5–20 mgintranasally; may repeat in 2 h; maximum40 mg/24 h / Nasal spray: taste disturbance, nausea. / Sumatriptan:Do not use with MAOIs. / Sumatriptan nasal spray:faster onset than with oral formulations. / Oral:$$
SC:$$$$$
Nasal:$$$
zolmitriptan
Zomig,Zomig Rapimelt,Zomig Nasal Spray,generics / Oral:2.5–5 mg; may repeat in 2 h; maximum10 mg/24 h
Nasal Spray: 2.5 mg or5 mg;may repeat in 2 h; maximum10 mg/24 h / Zolmitriptan: Do not use with MAOIs. Maximum dose of zolmitriptan5 mg/24 hif also on fluvoxamine or cimetidine. / Zolmitriptan:orally dispersible tablets can be taken without water; nasal spray available as 2.5 mg or 5 mg per dose. / $$

Legend: $ < $5$$ 5–10 $$$ 10–20$$$$ 20–30 $$$$$ 30–40
Neurologic Disorders: Headache in Adults; R. Allan Purdy, MD, FRCPC, FACP, FAHS; Date of Revision: February 2015