Amitriptyline (brand name “Elavil”) is a medication that was initially approved by the FDA in 1961 for the treatment of major depressive disorder. Due to its three-ring chemical structure, it is formally classified as a tricyclic antidepressant (TCA). Though not formally approved in the United States to treat conditions other than major depression, Amitriptyline is often administered as an off-label agent for the prevention of migraine headaches.
Scientific literature suggests that Amitriptyline’s efficacy as a migraine preventative may be on par with several FDA-approved antimigraine medications. In fact, the United States Headache Consortium Guidelines (published in 2000) documented Amitriptyline as having [letter grade] “A” quality evidence to support its usage for migraine prevention. It should also be noted that Amitriptyline is approved in the United Kingdom, Italy, and various European countries for migraine management.
For this reason, it is no surprise that medical professionals continue to prescribe Amitriptyline without hesitation to those who fail to attain relief from conventional pharmacological options. There’s really no debating whether Amitriptyline is effective for migraine headache prevention, however, there could be some debate as to whether it should be used as a treatment. While many individuals remain satisfied with their decision to use Amitriptyline for migraines, others end up regretting it.
How Amitriptyline May Treat Migraines (Mechanism of Action)
Amitriptyline is able to effectively prevent future migraine attacks and may also reduce their severity and/or duration. Though scientists understand how Amitriptyline functions as an antidepressant (via increasing extracellular monoamines), the mechanism(s) associated with its antimigraine effect are likely facilitated via modulation of voltage-gated sodium channels, thereby offsetting Cortical Spreading Depression (CSD). Since CSD (Cortical Spreading Depression) is implicated among many individuals with migraines, reducing it may be the principal therapeutic mechanism of Amitriptyline.
That said, it would be somewhat myopic to attribute the entire antimigraine mechanism of Amitriptyline to a single mechanism involving modulation of voltage-gated sodium channels. Other mechanisms of Amitriptyline that may contribute to migraine relief and/or prevention include: anti-inflammatory effects, serotonin receptor antagonism, H1 receptor antagonism, and NMDA modulation. It may be that a multitude of cumulative mechanisms facilitate its antimigraine effect.
Voltage-gated sodium channels: A chief mechanism by which Amitriptyline may attenuate migraines is via the modulation of voltage-gated sodium channels. A study by Yan et al. (2010) investigated the effects of Amitriptyline on cultured cortical neurons from rats. The impetus for the study by Yan et al. was to better understand the mechanism by which Amitriptyline facilitates its antimigraine effects.
Researchers noted that individuals with migraine headaches tend to exhibit cortical spreading depression (CSD) characterized as a wave of neuroelectrical hyperactivity succeeded by a wave of neuroelectrical hypoactivity. Markers of cortical spreading depression include abnormalities of calcium, sodium, and sodium-potassium ATP channels – and are seen among those who suffer from migraines. Results from the study discovered that Amitriptyline inhibited sodium channel current “(I(Na))” in a concentration-dependent (as opposed to voltage-dependent) manner.
It also modulated the activation of “I(Na)” to facilitate hyperpolarization. It appeared as though the expression of Na(V)1.1 and Na(V)1.6 sodium channels were inhibited to a greater extent than Na(V)1.2. Researchers concluded that a prominent mechanism by which Amitriptyline treats migraines is via reduction of cortical spreading depression (CSD). It accomplishes this principally via inhibition of “I(Na)” and mRNA expression of sodium channels.
The voltage-gated sodium channel modulation provided by Amitriptyline may reverse trigeminovascular nociceptive dysfunction among those with chronic migraine. While we cannot assume that this is the single mechanism by which Amitriptyline prevents migraines, it may be an important one. Moreover, this supports the idea that Amitriptyline’s antimigraine properties are mediated through distinct mechanisms from those associated with its antidepressant effect.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/20398637
- Source: http://www.ncbi.nlm.nih.gov/pubmed/24228717
- Source: http://www.ncbi.nlm.nih.gov/pubmed/24292897
Anti-inflammatory effect: Research has long highlighted links between neurogenic inflammation (NI) and migraine headaches. Neurogenic inflammation is associated with upregulated Calcitonin gene-related peptide (CGRP) stimulation from trigeminal neurons. The CGRP from trigeminal neurons stimulates a vasodilatory response through relaxation of vascular smooth muscle (within the wall of blood vessels).
Perhaps another critical mechanism by which Amitriptyline may treat migraines is via its anti-inflammatory effect. A study published in by Sadeghi et al. (2011) documented that Amitriptyline was capable of inhibiting carrageenan-induced inflammation in rats. Following its administration, Amitriptyline reduced the number of polymorphonuclear leukocytes (at sites of inflammation), as well as proinflammatory biomarkers IL-1B and TNF-alpha.
While it is important to avoid extrapolating these results to humans, a similar mechanism could occur. Assuming Amitriptyline is able to reduce proinflammatory cytokine production and/or neurogenic inflammation, it may indirectly inhibit trigeminal neuron CGRP stimulation. Moreover, it may prevent CGRP from inducing vasodilation, possibly a reason for which it is highly effective.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/21645506
5-HT receptor antagonism: Though most are familiar with Amitriptyline’s mechanism as a serotonin reuptake inhibitor, some may not be aware that it also acts as a serotonin receptor antagonist at numerous sites including: 5-HT2A, 5-HT2C, 5-HT3, 5-HT6, and 5-HT7. Despite the fact that serotonin receptor antagonism is not its primary mechanism of action, the antagonism of select 5-HT receptors may contribute to its antimigraine effect. Specifically, it could be that antagonism of 5-HT2, 5-HT3, and 5-HT7 receptors attenuate migraines.
- 5-HT3 receptors: A report by Ferrari (1991) discussed 5-HT3 receptor antagonists in migraine therapy. The 5-HT3 receptors mediate excitatory effects of serotonin and antagonism of these receptors prevent inflammatory-induced vascular pain. 5-HT3 antagonists are capable of inhibiting neurogenic dural inflammation within the trigeminal nerve, and therefor could be useful for migraine prevention.
- 5-HT2 receptors: A report by Mylecharane (1991) discussed the 5-HT2 antagonists as possible migraine treatments. Antagonizing the 5-HT2 receptors may increase vasoconstriction and ultimately offset vasodilation associated with migraines. The drug methysergide functions as a potent 5-HT2 receptor antagonist, possibly contributing to its therapeutic antimigraine efficacy. Amitriptyline acts as a 5-HT2A and 5-HT2C antagonist, possibly another mechanism by which it may reduce migraines.
- 5-HT7: Amitriptyline is also understood to act as an antagonist at the 5-HT7 receptor. Research shows that inhibition of the 5-HT7 receptor affects CGRP (Calcitonin gene-related peptide). Particularly, 5-HT7 antagonism reduces CGRP release in animal models and heightened CGRP is associated with neurogenic inflammation and migraines. Antagonism of the 5-HT7 receptors may be a minor mechanism by which the drug reduces migraines.
Histamine receptor antagonism: Amitriptyline is understood to function as a H1, H2, and H4 histamine receptor antagonist. It binds to these receptors and prevents activation resulting from endogenous histamine. A study published by Lassen et al. (1995) documents that administration of histamine was capable of causing migraine headaches, primarily by activating the H1 receptor site.
Activation of the H1 receptor sites facilitates the formation of nitric oxide, which in turn facilitates vasodilation and provokes migraine headaches. In their study, they noted that migraine patients receiving a H1 receptor antagonist attenuated headache and delayed migraine attacks resulting from histamine. Other research has noted histamine as potentially contributing significantly to the onset of migraines.
While conventional antihistamines are not considered effective as antimigraine agents, antagonists of H1 receptors (and possibly H2 receptors) can attenuate migraine severity. Amitriptyline acts upon H1 and H2 receptors as an antagonist to prevent histamine-induced receptor activation. One could speculate that its histaminergic effects play a role (even if a small one) in the treatment of migraines.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/7579128
- Source: http://www.ncbi.nlm.nih.gov/pubmed/24433203
NMDA modulation: Research suggests that Amitriptyline functions as a modest allosteric NMDA negative modulator. In other words, it binds allosterically to a site distinct from an NMDA receptor, but inhibits the effect of agonism on NMDA receptors. Other research suggests that it may act as an NMDA receptor antagonist, thereby inhibiting glutamatergic stimulation at the NMDA receptor sites.
Glutamate is thought to play a role in CSD (Cortical Spreading Depression), trigeminovascular activation, and central sensitization – each of which may cause migraines. Preliminary evidence indicates that glutamate-receptor (NMDA) antagonists are effective for the treatment of migraines in animal models. What’s more, case reports of humans with chronic migraines have documented unexpected migraine remission following administration of memantine – an NMDA receptor antagonist.
While the degree to which NMDA is modulated by Amitriptyline is not as significant as that associated with memantine, its NMDA modulation may contribute slightly to its antimigraine effect. That said, since the NMDA modulation is only modest, it is extremely unlikely that this is the only mechanism by which Amitriptyline treats migraines.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/12858134
- Source: http://www.ncbi.nlm.nih.gov/pubmed/18194287
- Source: http://www.ncbi.nlm.nih.gov/pubmed/7486155
Benefits of Amitriptyline for Migraines (Possibilities)
Below is a list of possible benefits to be attained from using Amitriptyline as an intervention for migraine prophylaxis. Perhaps the most notable benefit associated with using Amitriptyline for migraines is that it is supported by a multitude of well-designed studies. Other miscellaneous benefits include: low cost, mood enhancement, unique mechanism of action, and effectiveness in treating other headaches.
- All ages: While most research has discovered Amitriptyline to be safe and well-tolerated in adult populations, a select number studies have analyzed its efficacy among pediatric populations with unremitting headaches. When administered at a smaller dosage of approximately 1 mg/kg body weight (per day) to children, Amitriptyline is considered effective and well-tolerated over a long-term. Based on the available literature, Amitriptyline appears safe and effective across all individuals dealing with refractory migraines – regardless of age. Many other antimigraine drugs may be riskier than Amitriptyline when used in children.
- Allodynia: Though many antimigraine drugs successfully attenuate certain symptoms of migraine headaches, not all are able to reduce allodynia. Allodynia is a sensation of pain across the skin generated from modest tactile stimulation (e.g. light touch). The severity and frequency of migraine attacks experienced are directly correlated with occurrence of allodynia. Evidence from Amitriptyline studies shows that the drug is able to reduce allodynia significantly within 3 to 6 months of administration.
- Chronic tension-type headaches: Individuals with migraines may also experience chronic tension-type headaches. Chronic tension-type headaches are described as a band of pain across the forehead causing discomfort and sometimes fatigue. While most people can carry on working through chronic tension-type headaches, they may wish they could get some sort of relief. Multiple studies published in the 1990s have documented Amitriptyline’s efficacy in treating chronic tension-type headaches.
- Clinically effective prophylactic: There is relatively strong clinical evidence to support the usage of Amitriptyline for migraine prophylaxis. The United States Headache Consortium Guidelines published by Ramadan et al. (2000) note that it has excellent quality of evidence to support its efficacy, and thus, is considered a “Group 1” treatment. It is important to note that Amitriptyline is considered an approved migraine prophylactic in the United Kingdom, Italy, and various countries outside of the United States.
- Low cost: Due to the fact that Amitriptyline hit the market in the 1960s, the patent for its brand name formulation “Elavil” has long been expired. As a result of the expired patent, the drug is manufactured as generic Amitriptyline for an extremely low cost. In fact, most pharmacies will issue a 30-day supply of the drug for under $10 and some for under $5. If you’re using Amitriptyline for migraine prophylaxis, you need not worry about whether you’ll be able to afford it.
- Migraine subtypes: Scientific researchers have attempted to elucidate specific types (or models) of migraines and have determined that Amitriptyline is more effective for certain migraine subtypes than other medications. Some research suggests that Amitriptyline is most effective for “Type D” migraines characterized by: no triggers, resembles tension-type headache, and possible muscular component. Other studies have confirmed that Amitriptyline is most effective for migraines without discernable triggers. Additionally, later research documented Amitriptyline as being most effective among those suffering from short-duration/high-frequency migraines, as well as migraines that occur with “short warning” (as opposed to “long warning”).
- Minimize acute medication usage: Those suffering from frequently-occurring migraines often utilize acute agents designed to shorten migraine attacks and/or reduce migraine pain. The problem with many of these interventions (such as Fioricet for migraines) is that they can be overused and in some cases addictive. Overuse of acute interventions is associated with worse long-term outcomes (e.g. exacerbation of migraines). Since Amitriptyline reduces the frequency of migraines, acute medicinal options won’t need to be used as often – which could improve long-term success in migraine management.
- Mood enhancement: The fact that Amitriptyline functions principally as an SNRI (serotonin-norepinephrine reuptake inhibitor) means that it holds the potential to enhance mood. The mechanism by which it enhances mood is likely independent from that by which it prevents migraines. In any regard, individuals suffering from mild to moderate depression may derive benefit from Amitriptyline’s ability to increase extracellular concentrations of monoamines – especially at high doses. Essentially the drug could be used to treat depression while simultaneously preventing migraines.
- Insomnia: Since Amitriptyline can often cause drowsiness as a side effect, it is recommended to be administered at night. Should an individual suffer from migraines with comorbid insomnia, Amitriptyline may effectively treat the insomnia by inducing drowsiness, while simultaneously preventing migraines. In fact, treating insomnia may be one critical factor by which Amitriptyline indirectly decreases migraines. Poor sleep hygiene and insomnia are understood to directly cause migraines in certain individuals. By reducing insomnia, a person’s migraines may be prevented.
- Psychiatric comorbidities: Individuals diagnosed with comorbid psychiatric conditions (in addition to migraines) may derive significant benefit from Amitriptyline. As was already mentioned, Amitriptyline has potential to enhance mood by attenuating depression, as well as decreasing insomnia. Research shows that it may also be helpful for those suffering from certain types of ADHD, anxiety disorders, and eating disorders.
- Unique mechanism of action: Among those diagnosed with refractory migraines, Amitriptyline may be a great option. It has a unique mechanism of action compared to most antimigraine agents in that it inhibits reuptake of serotonin and norepinephrine. Additionally, the drug affects histamine, acetylcholine, glutamate, and reduces inflammation. For some individuals, particularly those with “Type D” migraines, this mechanism may be more effective than other options.
Drawbacks of Amitriptyline for Migraines (Possibilities)
There may be some drawbacks associated with using Amitriptyline as a migraine prophylactic. Perhaps the most significant major drawback is that daily administration is required and the drug remains in systemic circulation for an entire 24-hour period. Should a person end up taking Amitriptyline to prevent migraines, he/she will be under the constant (perhaps unwanted) influence of an exogenous chemical. Other drawbacks associated with using Amitriptyline for migraines include: side effects, lack of efficacy (for some), and withdrawal symptoms upon cessation.
- Daily administration: Those taking Amitriptyline as a migraine preventative will need to take the drug everyday to maintain efficacy. For some patients, it may be difficult to remember to take a pill every single day. Forgetting to take Amitriptyline just one or two days can result in a backlash of severe effects such as: nausea, dizziness, anxiety, etc. Some individuals may dislike the fact that they’re taking a drug every single day and are constantly under its influence – especially over a long-term.
- Lack of immediate effect: Some studies suggest that Amitriptyline may take weeks or months to fully “kick in” and for users to reap its migraine prophylactic effect. In other words, you may end up taking Amitriptyline for a month or two before you start to notice that it reduces the frequency of your migraines. Evidence indicates that for maximal preventative benefit, it’ll need to be administered for up to 3 months. Since other treatment options for migraine prophylaxis appear to reduce migraine frequency quicker than Amitriptyline (e.g. beta blockers), these other agents may be preferred.
- Long-term effects: The long-term effects associated with Amitriptyline are relatively unknown and subject to interindividual variation. Though the literature suggests that Amitriptyline is likely safe over a long-term, the effects resulting from years or decades of usage are unclear. It is known that antidepressants alter connectivity in a matter of hours, and likely continue to modulate connections with each day they are ingested. One may speculate that the long-term effects of Amitriptyline may be unfavorable in certain users.
- Off-label: In the United States, Amitriptyline is regarded as an off-label treatment for migraines, meaning it has not been approved by the FDA. This means that the FDA hasn’t seen enough solid evidence to support the recommendation of Amitriptyline for migraine prophylaxis. In theory, individuals should respond better to other first-line, established treatments by comparison.
- Prophylaxis-only: Though most professionals understand that Amitriptyline is likely only effective in reducing the number of migraine attacks that occur (as a prophylactic), some patients may expect it to treat migraines if administered acutely during an attack. We know that Amitriptyline administration during a migraine attack won’t stop the pain or shorten the duration. The fact that it only functions as a prophylactic agent may be perceived as unfavorable by some individuals.
- Ineffective: While Amitriptyline is clearly a highly-effective prophylactic for certain users, others may find it completely ineffective. Studies have documented Amitriptyline as being less effective among those experiencing migraines with specific triggers, “long warnings,” and/or severe depression. Another reason Amitriptyline may be completely useless for some individuals is that it is metabolized by CYP2D6 and CYP2C19 isoenzymes. Polymorphisms in the genes coding for these enzymes may lead to poor or ultrarapid metabolism – each of which may reduce Amitriptyline efficacy. Those who want to estimate how they’re likely to respond to Amitriptyline should get their genes sequenced (or use GeneSight).
- Overdose: Compared to other antimigraine interventions and various antidepressants, Amitriptyline is associated with greater toxicity. As a result, assuming a person were to deliberately (or even unintentionally) administer an abnormally high (supratherapeutic) dose of Amitriptyline, it could result in serious adverse reactions and/or death. The British National Formulary has documented Amitriptyline as being especially dangerous in cases of overdose, hence a major reason why it is not commonly used as a first-line antidepressant.
- Side effects: Common side effects of Amitriptyline include drowsiness, dry mouth, and headache. Many individuals also complain about the fact that Amitriptyline causes weight gain, leading to significant increases in body weight when administered over an extended duration. Additionally, even among those taking the drug for migraine prophylaxis, it could induce mood swings or cause suicidality and depression (in some people). As a result of its disconcerting side effect profile, it may not be an appealing antimigraine option.
- Superior interventions: There are many antimigraine medications that have been approved by the FDA as a result of robust evidence to support their efficacy. A substantial number of these mediations may be of superior efficacy for migraine management than Amitriptyline. Additionally, these medications often provoke significantly fewer unwanted side effects compared to Amitriptyline – making them favorable treatment options.
- Tolerance: It is possible that some individuals may notice a decline in efficacy of Amitriptyline over an extended duration. Someone who’s been taking the drug for several years may find that migraine attacks return to normal pre-treatment frequency. This is likely due to the fact that a user’s physiology has become tolerant to daily Amitriptyline administration. To maintain the efficacy of Amitriptyline over a long-term, the dosage may need to be increased. However, when dosage is increased, side effects (and adverse reactions) also tend to increase. (Read more: “Why Antidepressants Stop Working”).
- Withdrawal symptoms: Assuming you’ve been taking Amitriptyline for awhile to prevent migraines, but want to discontinue, you may be in for a challenging situation. Discontinuing the drug, especially abruptly, can induce hellacious Amitriptyline withdrawal symptoms. These discontinuation symptoms may last months and can include: anxiety, depression, mood swings, increased migraine frequency, insomnia, etc. Many people that have stopped Amitriptyline end up regretting their decision to ever take it in the first place as a result of these discontinuation symptoms.
Amitriptyline for Migraines (Review of Evidence)
If you’re taking Amitriptyline for migraines or considering it as a potential intervention, it may be helpful to examine published studies that sought to determine its antimigraine efficacy. Keep in mind that not all studies incorporate robust designs, and therefore may lack clinical relevance. Reports documenting the antimigraine effects of Amitriptyline date back to the 1970s and most evidence suggests that it is a highly effective antimigraine medication.
2015: A Comparative Effectiveness Meta-Analysis of Drugs for the Prophylaxis of Migraine Headache.
A meta-analysis published by Jackson et al. (2015) compared the efficacy and side effect profiles of various medications designed for migraine headaches. All data were collected independently from sources such as PubMed, EMBASE, and Cochrane Trial Registry. The quality of that data was then analyzed with JADAD and Cochrane Risk of Bias instruments.
Inclusion criteria for this meta-analysis was randomized controlled trials (RCTs) of at least 4-weeks duration conducted among adults with migraine headaches. It should be mentioned that all data collected was published prior to mid-May 2014. Results indicated that Amitriptyline was considered a drug with 3+ trials that was more effective than a placebo for episodic migraines.
The network meta-analysis noted that Amitriptyline was superior in antimigraine efficacy to various other agents such as Propranolol, Prozac and Topamax. Amitriptyline appears to have solid evidence to support its efficacy as an intervention for migraines. Moreover, there’s minor evidence indicating that it may be of superior efficacy to various other agents.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/26172390
2013: Efficacy of amitriptyline, pizotifen and propranolol in the prevention of migraine.
An intervention study was conducted by Israil et al. (2013) at Mymensingh Medical College Hospital (MMCH) from January 2006 to December 2007 to compare the efficacy of Amitriptyline, Pizotifen, and Propranolol for the prevention of migraines. Researchers assessed 90 cases of migraine that met inclusion guidelines. Results from their comparative analysis revealed that all 3 interventions reduced the duration, frequency, and severity of migraine attacks.
There were no significant differences in efficacy among the agents when compared. This suggests that Amitriptyline is an effective agent for migraine prevention. Additionally, the tolerability and adverse effect profiles were considered similar among the 3 interventions.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/23416816
2013: Allodynia in migraine: clinical observation and role of prophylactic therapy.
Researchers Misra et al. (2013) investigated prophylactic therapy among patients with migraine, specifically assessing the effect of therapy in treating allodynia. Allodynia is characterized as experiencing pain from a non-painful stimulation of the skin such as light touch. Many individuals with migraines suffer from migraine-related allodynia.
For their study, a total of 448 patients with migraines (in accordance with International Headache Society criteria) were recruited. Participants were asked about whether they suffered from allodynia, as well as details regarding the allodynia such as its type and severity. A total of 277 participants received either Amitriptyline (25-50 mg/day) or Divalproate (500-750 mg/day) – side effects were documented.
Over 70% of all participants suffered from allodynia the following subtypes: static mechanical (90%), dynamic (89%), and thermal (17%). Results indicated that Amitriptyline (and Divalproate) significantly reduced frequency and severity of allodynia after 3 and 6 months of treatment – compared to baseline. This provides evidence that in addition to treating migraine headaches, Amitriptyline is able to alleviate migraine-related allodynia.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/23328330
2012: Nonpharmacologic treatment of migraine with low-dose propranolol or amitriptyline.
Pediatric migraine sufferers are recommended to utilize non-pharmacological interventions to treat migraines. In many cases, pharmacological interventions are considered risky and may affect brain development and/or provoke unwanted side effects. A study conducted by Eidlitz-Markus et al. (2012) investigated the combination of non-pharmacological interventions along with low-dose Amitriptyline or Propranolol for cases of severe pediatric migraine headaches.
Researchers compiled medical files from 118 patients (average age ~12.5), each of whom was treated with non-pharmacological interventions. Of these children, 25 were administered low-dose Amitriptyline (average = 0.26 mg/kg/day) and 93 were administered low-dose Propranolol (average = 0.4 mg/kg/day). Among 80% of individuals, headache frequency decreased by over 50% per month as a result of low-dose adjunct pharmacology.
It was concluded that low-dose Amitriptyline and Propranolol are effective for migraine reduction among children. Propranolol is preferred over Amitriptyline among pediatrics due to its safety and side effect profile. Nonetheless, this data suggests Amitriptyline (in small doses) is effective as an antimigraine intervention among children when combined with non-pharmacology interventions.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/22633628
2011: Amitriptyline in the prophylactic treatment of migraine and chronic daily headache.
A report by Couch (2011) documented the efficacy of Amitriptyline compared to a placebo for the treatment of intermittent migraines (IM) and chronic daily headaches (CDH). Couch notes that Amitriptyline is among the most popular pharmacological interventions for migraines, yet there are few placebo-controlled studies to support its usage. The study discussed by Couch took had taken place over a period of 20 weeks between the years 1976 and 1979 – results were previously unpublished.
Patients recruited for the study had a history of migraine headaches in accordance with the 1962 Ad Hoc Committee report, and all had reported a minimum of 2 headaches per month. The study was organized into a 4-week baseline phase (Period A) which involved administering a placebo (b.i.d.) for 1 week, placebo (t.i.d.) for 1 week, and placebo (q.i.d.) for the remaining 2 weeks. Any individuals from the “Period A” reporting 2 or more migraine headaches were then enlisted for “Period B” and randomized to receive either: Amitriptyline (25 mg) or a placebo; all placebo pills looked identical to the Amitriptyline pills.
Period B took place for an additional 4 weeks and dosing frequency was the exact same as Period A. Thereafter, patients continued dosing with a 12-week maintenance phase known as “Period C.” Patients were instructed to track headache occurrence with a calendar, as well as note the frequency of headaches (per month), severity of headaches, and duration of headaches (hours).
A total of 391 patients were recruited for Period A and 338 of those patients fit inclusion criteria for Period B. A total of 255 patients completed 12 weeks of the study, 210 completed 16 weeks, and 186 completed the full 20-week duration. Results indicated that headache frequency had significantly improved among those receiving Amitriptyline compared to a placebo after 8 weeks.
However, at week 12, 16, and 20 – there was no significant difference between the efficacy of Amitriptyline and placebo for headache frequency reduction. It was mentioned that the reasoning for this lack of statistical significance of Amitriptyline over the placebo in later weeks may have been due to a potent placebo response; many patients appeared to benefit significantly from the placebo. Although such a significant placebo response isn’t common, it can happen in placebo-controlled studies.
Both the Amitriptyline and the placebo groups reported over a 50% decrease in headache frequency (P < .01). That said, neither the Amitriptyline nor placebo reduced headache severity or duration at any period of the study. The author documented a trend for Amitriptyline’s superiority over the placebo after 12 weeks and 20 weeks – but the statistical significance was lacking.
In conclusion, it appears as though Amitriptyline may be efficacious in reducing migraine frequency over a short-term (8 weeks). Since the results were not statistically significant over a longer-term, we cannot assume that Amitriptyline provided continued benefit, however, the placebo response was abnormally significant (P < .01) – suggesting that both reduced headache frequency. Perhaps if the study were repeated in the future, and the placebo response were eliminated, Amitriptyline would’ve remained statistically more effective throughout the longer-term of 20 weeks.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/21070231
2009: Topiramate versus amitriptyline in migraine prevention: a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority trial in adult migraineurs.
A 26-week trial conducted by Dodick et al. (2009) compared the efficacy and tolerability of popular antimigraine agent Topamax with that of Amitriptyline for the management of episodic migraines. Researchers organized a multicenter, randomized, double-blinded, double-dummy, parallel-group design with a total of 331 adult participants. Participants with 3-12 migraines per month were set at random to receive either Topamax or Amitriptyline at equipotent 25 mg/day doses.
Dosages were titrated up to 100 mg per day for both agents. Efficacy of each drug was determined based on change from pre-treatment baseline in average number of migraine episodes. Secondary measures were collected to determine rate of days with migraine, rate of days with non-migraine headaches, rate of antimigraine medication usage, migraine duration, and migraine severity.
Various common migraine symptoms such as hypersensitivity to light and sound, as well as nausea – were also recorded, along with quality of life (as measured by The Migraine-Specific Quality of Life Questionnaire). Of the 331 patients, a total of 172 received Topamax and 159 received Amitriptyline. Results indicated that both Topamax and Amitriptyline were effective in reducing the number of migraine episodes per month, but comparatively, neither was more effective than the other in terms of improving primary or secondary measures.
However, results noted that there were some advantages associated with using Topamax compared to Amitriptyline for migraine management, namely: improved functional disability during migraines, improvements on select measures of the MSQ (emotional function, role function-restrictive, role function-preventative), and body weight (it resulted in weight loss of 2.4 kg). (Read more: “Topamax for Weight Loss“). Researchers concluded that although Topamax and Amitriptyline were equally effective in monthly migraine reduction, the Topamax was advantageous for improving quality of life.
Though this report provides evidence that Amitriptyline is able to effectively reduce the number of migraines per month in a large sample over an extended duration (26 weeks), other agents may promote superior quality of life by comparison. Nonetheless, this study bolsters support for Amitriptyline usage among those who wish to reduce the frequency of migraine attacks.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/19393844
2004: Venlafaxine versus amitriptyline in the prophylactic treatment of migraine: randomized, double-blind, crossover study.
A randomized, double-blinded, crossover trial conducted by Bulut (2004) assessed the efficacy of Amitriptyline compared to Effexor (an SNRI antidepressant) for the treatment of migraine headaches (with or without aura). In the study, several intolerable side effects were reported among those taking Amitriptyline including: excessive sleepiness, cognitive deficits, and orthostatic hypotension – causing 5 patients to discontinue. Just one patient discontinued Effexor as a result of an adverse reaction involving nausea and vomiting.
After an initial run-in period, a total of 52 patients were assigned at random to receive Amitriptyline or Effexor for a duration of 12 weeks. Thereafter, a 4-week washout phase resulted in patients discontinuing medication to eliminate the respective drugs from systemic circulation. Following this washout phase, patients were administered the opposite drug (to what they initially received) for another 12 weeks.
Results indicated that both agents were effective for migraine prevention, as well as for the attenuation of migraine-related pain. It was noted that side effects associated with Effexor were favorable compared to those associated with Amitriptyline. Authors concluded that since both medications appear equally efficacious, and Effexor provoked fewer unwanted side effects – Effexor may be slightly favorable over Amitriptyline.
It should be noted that this study provides more evidence demonstrating the efficacy of Amitriptyline for migraine prophylaxis. While Effexor may provoke more side effects, significant conclusions in terms of tolerability are difficult to draw from a small-scale study of 52 participants. Nevertheless, certain tolerability issues associated with Amitriptyline should be considered by practitioners and patients.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/15567552
2000: A comparative efficiency of amitriptyline, fluoxetine and maprotiline in prevention of migraine in attack-free period.
A study conducted in Russia by Amelin et al. (2000) compared the efficacy of several agents for migraine prophylaxis. Between migraine attacks, researchers noted that highly effective antimigraine agents were antidepressants and beta-blockers. In a single-blind study, researchers compared the Amitriptyline 12.5-25 mg/day (a tricyclic antidepressant) with Prozac 10-20 mg/day (an SSRI) and Maprotiline 10-25 mg/day (a tetracyclic antidepressant).
The mechanisms of each agent slightly differ: Amitriptyline acts as mostly as a reuptake inhibitor of serotonin, norepinephrine, and as a 5-HT2 antagonist; Prozac acts mostly as a reuptake inhibitor of serotonin; and Maprotiline acts mostly as a selective norepinephrine reuptake inhibitor. Each were administered for a total of 12 weeks and 20 patients were assigned to each group.
Of the 60 patients, only 46 were able to complete the entire 12 weeks of prophylactic therapy. Among those that completed the study, a total of 14 received Amitriptyline, 16 received Prozac, and 16 received Maprotiline. Efficacy of each agent was determined based on a reduction in frequency of migraines during treatment by at least 50% compared to pre-treatment baseline. Significant efficacy was noted in 71% of Amitriptyline users, 56% of the Prozac users, and just 38% of the Maprotiline users.
Among responders, all agents were capable of reducing severity and duration of migraine attacks. Secondary assessments indicated that patients receiving Amitriptyline or Prozac experienced improvements in quality of life compared to the group receiving Maprotiline. Furthermore, only Amitriptyline and Prozac effectively prevented migraine attacks – whereas Maprotiline was deemed ineffective.
Judging by the 71% of responders in the Amitriptyline group (compared to 56% in the Prozac group and 38% in the Maprotiline group), it appears as though Amitriptyline may be more universally effective as a migraine prophylactic compared to other antidepressants. Furthermore, Amitriptyline was associated with improved quality of life among migraine sufferers, suggesting that it may simultaneously enhance mood. This single-blind study provides additional support for utilizing Amitriptyline for migraine prophylaxis.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/10983362
2000: Effectiveness of amitriptyline in the prophylactic management of childhood headaches.
While non-pharmacology is preferred over pharmacological treatments among pediatrics with headaches, sometimes non-pharmacology approaches fail to provide significant benefit. A study conducted by Hershey et al. (2000) sought to determine the efficacy of Amitriptyline administered at 1 mg/kg/day to children with unremitting headaches. Though Amitriptyline appeared efficacious among adults for migraine prophylaxis, its usage among children wasn’t well-documented.
For this reason, researchers organized a study with 279 children with problematic headaches. Since the adult dosage of Amitriptyline ranged from 10 mg to 150 mg, researchers speculated that an appropriate dosage for children was ~1 mg/kg/day. Prior to treatment, measures were collected including: frequency, severity, and duration of headaches.
Of the 279 children participating in the study, a total of 192 were administered Amitriptyline. Results indicated that over 80% of children perceived that they were functioning better while taking the drug compared to around 10% who perceived no significant change. Treatment with Amitriptyline reduced headache severity to 5.1 (from 6.84) and duration to 6.3 hours (from 11.5 hours). Additionally, there were no significant side effects noted by the children taking Amitriptyline nor their families.
Long-term follow-ups conducted between 156 and 415 days post-study indicated that children continued to benefit from Amitriptyline. Though not all children in this study had migraines, over 60% did have migraines, and 7.9% had migraine with aura. Based on these results, we can conclude that low-dose (1 mg/kg/day) Amitriptyline is effective and well-tolerated among children over a long-term for migraine prophylaxis and otherwise untreatable headaches.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/10940092
1998: The efficacy of spinal manipulation, amitriptyline and the combination of both therapies for the prophylaxis of migraine headache.
In the late 1990s, a study conducted by Nelson et al. (1998) analyzed the efficacy of Amitriptyline, spinal manipulation, and/or a combination of interventions for migraine prophylaxis. Researchers noted that upwards of 11 million adults in the U.S. are afflicted with migraine headaches and efficacy of various interventions need to be determined. Amitriptyline is a pharmacological treatment that appears effective as a migraine prophylactic.
Additionally, some speculate that the non-pharmacological intervention of spinal manipulation is an effective antimigraine therapy. Spinal manipulation therapy involves moving and/or jolting joints, massage, exercise, and physical therapy with the intent of decreasing pressure, reducing inflammation, and enhancing nerve function. To gauge efficacy of these interventions, researchers organized a randomized, parallel-group study with 218 participants for a term of 12 weeks.
A 4-week baseline period examined pre-intervention headache pain based on a headache index score. Thereafter, participants were assigned to receive Amitriptyline, spinal manipulation therapy, or a combination of Amitriptyline plus spinal manipulation therapy for 8 weeks. Outcomes were further analyzed for an additional 4-week period following the 8 weeks of therapy.
Among all 3 groups, significant improvement was noted in all primary and secondary measures. Headache index scores were reduced 49% among the Amitriptyline group, 40% among the spinal manipulation group, and 41% among the Amitriptyline plus spinal manipulation group. After the additional 4-week post-intervention follow-up, reduction in headache index scores from baseline were: 24% for Amitriptyline, 42% for spinal manipulation, and 25% for the combination therapy (Amitriptyline plus spinal manipulation).
Researchers concluded that there are no significant advantages to be attained from combining Amitriptyline and spinal manipulation for migraine treatment. Spinal manipulation may be favorable over Amitriptyline in terms of tolerability and sustained efficacy. That said, this study provides further evidence suggesting that Amitriptyline is a therapeutic pharmacologic option for those with migraines.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/9798179
1995: Spinal manipulation vs. amitriptyline for the treatment of chronic tension-type headaches: a randomized clinical trial.
Like the above study, an earlier study by Boline et al. (1995) compared spinal manipulation therapy to Amitriptyline for the treatment of chronic tension-type headaches. For this study, a total of 156 patients were recruited, each of whom had been formally diagnosed with chronic tension-type headaches. Patients were assigned at random to receive either spinal manipulation therapy or Amitriptyline for 6 weeks.
A baseline phase of 2 weeks recorded pre-treatment headache intensity, frequency, over-the-counter medication usage, and health status. These same measures were reassessed at a post-treatment follow-up phase 4-weeks after the interventions. During the study, it was noted that a total of 19 patients dropped out from the Amitriptyline group and 5 from the spinal manipulation group.
While receiving treatment, both groups experienced significant improvement in primary outcome measures (intensity, frequency, over-the-counter mediation usage, and health status). However, after the 4-week post-treatment follow-up, only the group receiving the spinal manipulation therapy maintained symptomatic improvement whereas the Amitriptyline users did not. This finding isn’t surprising given that systemic circulation of Amitriptyline is required for benefit, whereas spinal manipulation yields ongoing benefit between sessions.
In terms of tolerability, 46 patients receiving Amitriptyline noted unwanted side effects (drowsiness, dry mouth, and weight gain), whereas only 3 patients receiving spinal manipulation reported unwanted side effects (neck soreness and stiffness). Results of this study support the usage of Amitriptyline and spinal manipulation as interventions for chronic tension-type headaches.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/7790794
1994: Amitriptyline in therapy of chronic tension headache.
A placebo-controlled, double-blinded study conducted by Göbel et al. (1994) examined the efficacy of Amitriptyline 75 mg (slow-release) among those experiencing chronic tension-type headaches. Various headache parameters were measured prior to treatment including: EMG activity, suppression of temporal muscle activity, contingent negative variation (CNV), as well as experimental pain sensitivity. All study participants had a history of refractory headaches spanning over years.
Results indicated that among individuals receiving Amitriptyline (75 mg/day), daily headache duration had significantly reduced within 3 weeks of treatment compared to the placebo. After 6 weeks of treatment, headache duration remained significantly reduced among the Amitriptyline group compared to the placebo. Amitriptyline didn’t have any major influence on headache parameters such as: EMG activity, suppression of temporal muscle activity, contingent negative variation (CNV), or experimental pain sensitivity
It was discovered that sensitivity to suprathreshold experimental pain had decreased as a result of Amitriptyline usage. Among those with chronic tension-type headaches, Amitriptyline appears to facilitate significant symptomatic improvement by reducing daily headache duration. Though this study didn’t specifically investigate Amitriptyline for migraines, it shows that Amitriptyline appears useful for managing other types of headaches.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/7808565
1993: Propranolol and amitriptyline in prophylaxis of migraine. Pharmacokinetic and therapeutic effects.
Researchers Ziegler et al. (1993) investigated the efficacy of Propranolol (a beta blocker) and Amitriptyline (an antidepressant) for the prevention of migraine headaches. For the study, 30 patients with a history of frequent migraine headaches were recruited and were assigned to treatment with each drug and a placebo in a randomized manner. Treatment took place in 3-month modules, meaning each patient received Propranolol for 3 months, Amitriptyline for 3 months, and placebo for 3 months – but the order was unpredictable.
To assess efficacy of each intervention, headache scores were recorded at pre-treatment baseline, as well as after each month of treatment. Responses to medication were determined based on changes in frequency, duration, and/or severity of migraines. Results indicated that Amitriptyline significantly reduced severity, frequency, and duration of migraine attacks.
Comparatively, Propranolol only reduced severity of migraine attacks. Interestingly, Amitriptyline efficacy was correlated with female sex, as well as baseline migraines of shorter duration and higher frequency. On the other hand, Propranolol seemed to be a better option for migraines of longest duration.
In any regard, this suggests that Amitriptyline is capable of improving various aspects of migraines including: severity, frequency, and duration. From this research it can be speculated that female users may derive greater benefit from Amitriptyline than males. Additionally, Amitriptyline appears to be a more effective all-around antimigraine agent compared to Propranolol.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/8352668
1987: Migraine prophylaxis. A comparison of propranolol and amitriptyline.
A comparative study published by Ziegler et al. (1987) assessed the efficacy of Amitriptyline versus Propranolol for migraine prophylaxis. A total of 30 patients with migraine headaches were recruited by researchers to participate in the study. The study was considered double-blinded, placebo-controlled, and implemented a crossover design.
To determine efficacy of Amitriptyline and Propranolol, researchers instructed the 30 patients to record headache data in daily diaries. From these daily headache diaries, researchers were able to come up with “headache scores” to gauge responsiveness to medicinal interventions. Secondary measures were collected from each patient and included the Zung and Hamilton Depression tests, as well as Spielberger test for Anxiety.
Results indicated that both Amitriptyline and Propranolol were superior in efficacy to a placebo, but neither agent was of greater efficacy compared to the other. Furthermore, the antimigraine efficacy of each agent was not associated with significant decreases in depressive or anxious symptoms. In conclusion, this provides more evidence to support the pharmacological usage of Amitriptyline as an antimigraine agent.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/3579659
1979: Amitriptyline in migraine prophylaxis.
A study by Couch and Hassanein (1979) was among the first controlled-trials to investigate the therapeutic value of Amitriptyline as a migraine prophylactic. This study recruited 100 patients and assigned them to receive a placebo for a 4-week baseline period. Thereafter, the 100 patients were randomized to receive Amitriptyline (47 individuals) or placebo (53 individuals) for an additional 4 to 8-week term.
Both the Amitriptyline (25 mg tablets) and placebo were administered up to 4 times per day. Results indicated that Amitriptyline was significantly more effective than the placebo for migraine prophylaxis. Researchers noted that Amitriptyline benefitted both non-depressed and depressed individuals and concluded that Amitriptyline is an effective antimigraine intervention.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/508127
1978: The treatment of migraine and tension headaches with amitriptyline.
In 1978, a French researcher named Pluvinage investigated Amitriptyline for the treatment of migraine and tension headaches. He assessed the efficacy of Amitriptyline among 100 patients for over a full year which included: 26 cases of migraine and 74 cases of tension headaches. It was noted that Amitriptyline provided excellent to fair relief in 17 persons with migraines, and Dihydroergotamine provided the same degree of relief in 16 persons with migraines.
The combination of Amitriptyline plus Dihydroergotamine was of “excellent” efficacy in 21 patients. Amitriptyline also alleviated 53 cases of tension headaches and 56 with the adjunct administration of Dihydroergotamine. This study provided some initial evidence to suggest that Amitriptyline, even when used as a standalone agent, may improve symptoms among those with migraine headaches.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/213837
1976: Amitriptyline in the prophylaxis of migraine. Effectiveness and relationship of antimigraine and antidepressant effects.
A study by Couch et al. (1976) investigated Amitriptyline as an antimigraine agent. This study recruited 110 individuals that had been diagnosed with severe migraine. Results suggested that Amitriptyline administration reduced migraine symptoms by at least 50% among 72% of patients and by more than 80% in 57% of patients. Among the 31 individuals that failed to derive at least 50% symptomatic reduction from Amitriptyline, almost zero response was observed.
This suggests that non-responders to Amitriptyline may exhibit distinctive pathoetiological underpinnings from responders. In addition to its efficacy as a migraine prophylactic, it also slightly improved depressive symptoms among those experiencing depression at the time of the study. Researchers concluded that Amitriptyline appears effective for the prevention of migraines, but the mechanisms by which it treats migraines differ from those by which it ameliorates depression.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/943066
1973: Amitriptyline in migraine prophylaxis. Changes in pattern of attacks during a controlled clinical trial.
Among the earliest published studies investigating Amitriptyline as a migraine prophylactic was conducted by Gomersall and Stuart (1973). They set-up a double-blind, controlled trial with a crossover design that incorporated 26 volunteer participants (each suffering from migraines). Of the 26 participants, 20 completed the trial.
A total of 16 participants (of the 20 completers) experienced fewer migraine attacks on Amitriptyline compared to the placebo. Researchers noted that Amitriptyline was most effective in attenuating migraine attacks that occurred with “short warning” and without identifiable triggers. Amitriptyline appeared less effective among those experiencing migraines with “long warning” and triggered by fatigue.
It was concluded that dosages between 10 mg and 60 mg administered nightly provided sufficient relief. Though this wasn’t a large-scale trial, it shows that Amitriptyline may be effective for certain migraine subtypes – particularly those with “short warning” and no triggers.
- Source: http://www.ncbi.nlm.nih.gov/pubmed/4731336
Limitations associated with research of Amitriptyline for Migraines
In terms of using Amitriptyline for migraine prophylaxis, there aren’t many limitations associated with the research. Some may argue that there needs to be more randomized-controlled trials with larger sample sizes published before Amitriptyline can be recommended as an antimigraine intervention. Additionally, there could be a bit more data regarding long-term outcomes (safety, efficacy, dosing, etc.) of migraine patients treated with Amitriptyline.
- Long-term outcomes: There have been some studies published that took place over a long-term (e.g. 26 weeks) and found Amitriptyline to be an effective, well-tolerated antimigraine intervention. Another study among pediatric patients noted that low-dose Amitriptyline reduced headache frequency and wasn’t associated with any adverse effects over a long-term. However, some could argue that its safety, efficacy, and number of dosage adjustments – warrant further research among long-term users.
- Migraine subtypes: Some research indicates that Amitriptyline may be more effective in preventing migraines of certain subtype compared to others. Several studies have documented Amitriptyline as being an effective agent for migraines associated with lack of triggers, muscular components, “short warning” periods prior to onset, as well as short-duration/high-frequency migraines. This means that Amitriptyline may only be helpful for preventing certain types of migraines and not others. Further research is warranted to determine whether Amitriptyline is more useful for specific types of migraines and perhaps of limited usefulness for others.
- Study designs: To better determine the efficacy of Amitriptyline for migraine prophylaxis, newer randomized controlled trials (RCTs) would be useful, especially with larger sample sizes. It could be argued that there already are enough large-scale, randomized controlled-trials to justify the usage of Amitriptyline for migraines, but not in the eyes of the FDA. Other countries such as the United Kingdom have approved Amitriptyline for migraine prevention, believing the currently-available evidence from existing designs is sufficient.
Verdict: Amitriptyline is clinically effective for the prevention of migraines
Based on the scientific literature, there’s ample evidence suggesting Amitriptyline is effective for the prevention of migraine headaches. It appears to be effective in all age groups ranging from adults to pediatrics and is considered well-tolerated when taken at night. As was already mentioned several times, the United States Headache Consortium Guidelines acknowledged Amitriptyline as having “Grade A” evidence to support its administration for migraine prophylaxis.
There’s minor evidence to suggest that Amitriptyline may not only reduce frequency of migraines (via preventative mechanisms), but also attenuate severity and shorten attack duration. The extent to which Amitriptyline is able to inhibit migraine-related pain and shorten duration remains unclear and warrants further investigation. Most professionals would not consider Amitriptyline to be effective if a migraine is already-occurring.
The main goals of migraine prophylaxis are to decrease migraine attack frequency, severity, and overall disability. Since Amitriptyline reduces attack frequency to a clinically significant extent, it may help minimize usage of acute antimigraine agents (e.g. Fioricet), that when overused, could lead to rebound migraine attacks. Medication overuse is a big problem among migraine suffers, and for many, Amitriptyline may help minimize need for acute (possibly addictive) interventions.
Although there are clearly some potential drawbacks associated with using Amitriptyline, these are unlikely significant when used at low doses. At higher doses, side effects such as drowsiness, weight gain, etc. – may become more of a concern. In summary, professionals are justified in using Amitriptyline as a first-line intervention among those who wish to prevent migraine attacks and/or address mixed migraine with tension-type headaches.
Have you tried Amitriptyline for migraines?
If you’ve taken Amitriptyline for migraine prophylaxis, feel free to share your experience in the comments section below. To help others get a better understanding of your situation, include details such as: types of migraines you deal with, dosage of Amitriptyline you take, whether you use any other medications (or supplements), and/or suffer from comorbid medical conditions. Mention whether you’ve found Amitriptyline to be an effective antimigraine intervention or relatively useless.
As an antimigraine agent, would you say Amitriptyline is most effective for attenuating the: frequency, severity, and/or duration of your migraines? If you’ve previously tested other antimigraine agents, share whether you believe Amitriptyline is more, less, or equally effective. If you had to rate the efficacy of Amitriptyline as a migraine prophylactic on a scale of 1 to 10 (with 10 being most effective), what rating would you assign it?
Overall, the evidence supports clinical usage of Amitriptyline for migraine prophylaxis. Though a subset of users may experience intolerable adverse effects (e.g. drowsiness, dry mouth, weight gain, etc.) or fail to respond to Amitriptyline, in many users, its antimigraine effects are clinically significant. In summary, those who fail to derive adequate benefit from first-line antimigraine agents may wish to test the off-label therapeutic potential of Amitriptyline.