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Nortriptyline For Migraines: An Alternative Prophylactic

Nortriptyline is a tricyclic antidepressant (TCA) that was initially FDA approved in 1964 (under the brand name “Pamelor”) for the treatment of major depression.  It is regarded as chemical successor to Amitriptyline based on the fact that Nortriptyline is Amitriptyline’s predominant psychoactive metabolite.  Since Nortriptyline has been on the market since the mid-1960s, researchers are aware that the drug may be therapeutic for numerous other medical conditions, including migraine headaches.

Although not commonly recommended as an antimigraine agent, Nortriptyline is sometimes prescribed off-label for migraine prophylaxis.  Individuals with recurrent migraine attacks that fail to derive benefit from conventional first-line prophylactic agents may end up testing Nortriptyline as an intervention.  On occasion, medical professionals may prescribe Nortriptyline to patients that exhibit abnormal metabolism of Amitriptyline as a result of polymorphisms encoding for CYP2C19 isoenzyme expression.

The United States Headache Consortium published a report in 2000 documenting Nortriptyline as a [letter-grade] “C” intervention for migraine prophylaxis.  This grading was based on the fact that impressions of the drug in clinical settings were favorable, indicating that most patients report improvement and it appears very effective.  That said, some patients and practitioners may be hesitant to pursue Nortriptyline as a migraine prophylactic based on the fact that there is limited scientific evidence to support its usage.

How Nortriptyline May Treat Migraines (Mechanisms of Action)

When used as a standalone intervention, Nortriptyline may be useful as a migraine prophylactic in a subset of individuals.  While we know its parent-drug Amitriptyline is highly effective as a migraine prophylactic, Nortriptyline appears to be less effective.  This could be based on the fact that it is a secondary amine (as opposed to a tertiary amine), modulates norepinephrine to a greater extent than serotonin, inhibits different voltage-gated sodium channels, and/or has less robust anti-inflammatory effects.

Nevertheless, since many individuals derive therapeutic relief from Nortriptyline, it is necessary to evaluate the numerous mechanisms by which it may prevent migraines.  Examples of mechanisms by which Nortriptyline may reduce the occurrence of migraines include: voltage-gated sodium channel inhibition, norepinephrine transporter inhibition, histamine receptor antagonism, NMDA receptor modulation, and serotonin receptor antagonism.  It is unclear as to whether certain mechanisms may contribute more to its antimigraine effect than others or if all contribute synergistically.

Voltage-gated sodium channels: A notable mechanism by which Nortriptyline may prevent migraines is by altering activity in voltage-gated sodium channels (e.g. Na(V)1.7).  Like other tricyclic antidepressants, Nortriptyline inhibits sodium channel activation in a concentration-dependent manner.  This inhibition is believed to directly attenuate the onset of cortical spreading depression (CSD), characterized as a sudden wave of neuroelectrical hypoactivity [often preceded by neuroelectrical hyperactivity].

It is well-documented that cortical spreading depression is associated with migraine attacks.  Since Nortriptyline may be able to effectively prevent cortical spreading depression resulting from sodium channel hyperactivity, users may experience less migraines.  Assuming the pathoetiological underpinnings of a particular individual’s migraines involve sodium channel dysfunction, the sodium channel inhibition provided by Nortriptyline may be especially useful.

What’s more, evidence indicates that voltage-gated sodium channel inhibition provided by Nortriptyline is capable of reducing pain.  Assuming users are able to derive an analgesic effect from this mechanism, Nortriptyline could [theoretically] decrease migraine-related pain.  Overall, it is likely that among responders to Nortriptyline for migraine prophylaxis, voltage-gated sodium channel modulation is a critical mechanism.

The drug Amitriptyline (closely related to Nortriptyline) is known to inhibit “I(Na)” and mRNA expression of sodium channels that cause cortical spreading depression.  Whether Nortriptyline acts similarly hasn’t been scientifically evaluated and remains unclear.  However, if there is a similar “I(Na)” and mRNA inhibitory effect provided by Nortriptyline, it may ameliorate dysfunction of trigeminovascular nociceptive processes.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/17175203
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24228717
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24292897

5-HT2A / 5-HT2C antagonism: Another possible mechanism that may be associated with the antimigraine effect of Nortriptyline is its 5-HT2A and 5-HT2C receptor antagonism.  Pharmacodynamic literature indicates that Nortriptyline binds with high affinity to both 5-HT2A and 5-HT2C receptor sites; its affinity is slightly greater for the former.  Some evidence suggests that 5-HT2 receptor antagonists may effectively prevent and/or treat migraines.

A report by Mylecharane (1991) documented the fact that various 5-HT2 receptor antagonists (e.g. cyproheptadine, methysergide, mianserin, pizotifen, etc.) are effective migraine prophylactics.  It is thought that antagonism at 5-HT2 receptor sites can modulate an array of processes including: CNS activity, cranial vasoconstriction, cranial capillary permeability, neuroendocrine activity, and platelet aggregation – each of which, or the sum of which, may prevent migraines.

Though antagonism of Nortriptyline on 5-HT2A receptors is slightly greater than its antagonism at 5-HT2C receptors, it may be 5-HT2C antagonism that plays a more critical role in migraine prevention.  This speculation comes from the fact that the drug Valdoxan (agomelatine) acts as a selective 5-HT2C receptor antagonist and appears efficacious in migraine management.  While Valdoxan functions predominantly as a melatonin receptor agonist (at MT1 and MT2 sites), its 5-HT2C antagonism cannot be dismissed as a mechanism implicated in migraine prevention.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/2045831
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/23503551

H1 receptor antagonism: Like most tricyclic antidepressants, Nortriptyline binds with substantial affinity to histamine receptors, particularly the H1 receptor site.  Upon binding to the H1 receptor site, it inhibits stimulation of the receptor from endogenously-secreted histamine.  Research conducted by Lassen et al. in the mid-1990s demonstrated that administration of exogenous histamine is capable of provoking migraine attacks.

Exogenous histamine was said to provoke migraines predominantly by stimulating H1 histamine receptors.  When the H1 receptors are stimulated by histamine, the formation of nitric oxide is upregulated and excessive vasodilation ensues to trigger a migraine.  In the aforestated study by Lassen et al. (1995), it was discovered that administration of an H1 receptor antagonist was able to decrease headache and delay histamine-induced migraine attacks.

Additional studies have noted that medications functioning as H1 antagonists such as cinnarizine and cyproheptadine appear to be effective migraine prophylactics.  Based on this finding, it is clear that H1 antagonists prevent nitric oxide formation (as induced by H1 stimulation), which leads to fewer migraine headaches.  Since Nortriptyline antagonizes the H1 receptor, its histaminergic modulation should be considered as a possible mechanism by which it treats migraines.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/7579128
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/24433203

Alpha-1 antagonist: Nortriptyline binds with moderate affinity to the alpha-1 adrenergic receptor and functions as an antagonist.  Its alpha-1 adrenergic antagonism may be another modality by which Nortriptyline is able to reduce migraine attacks.  A report published in 1997 by Vatz suggests that blocking the alpha-1 adrenergic receptors appears clinically effective for prophylaxis of migraine.

Vatz noted that alpha-1 adrenergic blockers terazosin or doxazosin were administered to 10 patients with migraine.  Of the 10 patients, 9 experienced reductions in migraine frequency and severity.  Although 10 patients is not a large sample size, it does provide some evidence suggesting that the mechanism of alpha-1 antagonism may facilitate an antimigraine effect.

Alpha-1 receptors mediate vasoconstriction processes resulting from norepinephrine and epinephrine.  It is unclear as to whether modulation of vasoconstriction contributes to the antimigraine effect associated with alpha-1 receptor blockade provided by Nortriptyline.  However, it could be that in a subset of individuals with unique neurophysiological migraine underpinnings (e.g. lack of vasodilation), alpha-1 antagonism may be useful.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/9074296
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/8073910

NMDA modulation: Some evidence suggests that Nortriptyline modulates NMDA (N-methyl-D-aspartate) to a modest extent as a negative allosteric modulator.  In other words, it binds to a distinct site [from the actual receptors] and inhibits NMDA receptor agonism (via negative allosteric modulation).  This evidence of Nortriptyline’s ability to function as a negative allosteric modulator of the NMDA receptor is based on work by McCaslin et al. (1992).

McCaslin and his team noted that administration of Nortriptyline is neuroprotective against NMDA-induced toxicity.  NMDA is an amino acid derivative that functions similarly to the excitatory neurotransmitter glutamate; excessive agonism from NMDA can be toxic.  Furthermore, overstimulation of NMDA receptors is capable of inducing the cortical spreading depression (CSD) which precedes migraines.

A study by Shatillo et al. (2015) noted that NMDA receptors are highly implicated in animal models of cortical spreading depression (CSD).  Additionally, researchers discovered that administration of an NMDA receptor antagonist prevented the onset of cortical spreading depression.  What’s more, human trials have shown that NMDA antagonists such as Namenda (memantine) are effective interventions for migraine.

Since migraines often occur as a result of cortical spreading depression, preventing it is often critical for successful migraine prophylaxis.  Though Nortriptyline isn’t a full receptor antagonist, the fact that it blunts NMDA receptor activation is clearly a mechanism by which it may prevent cortical spreading depression.  Prevention of cortical spreading depression via negative allosteric modulation of NMDA receptors may play a role in the facilitation of its antimigraine effect.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/1629716
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/25688928

Norepinephrine reuptake inhibition: Inhibiting the transporter of norepinephrine (NET) is the chief mechanism by which Nortriptyline functions, and may play an important role in the prevention of migraines.  Unlike its parent-drug Amitriptyline which principally inhibits serotonin transport (SERT), Nortriptyline prevents termination and recycling of norepinephrine.  This leads to greater concentrations of norepinephrine in the extracellular space (between neurons) and enhances cellular signaling.

Evidence dates back to the 1990s suggesting that dysfunctional transmission of norepinephrine may play a role in migraines.  A study by Martínez et al. (1993) investigated catecholamine concentrations in the plasma and cerebrospinal fluid among migraine sufferers compared to non-sufferers.  Researchers discovered that plasma concentrations of norepinephrine were substantially lower among those with “common” and “classic” migraines compared to the control group.

Specifically, results documented that norepinephrine within the plasma of migraine sufferers was 308.6 pg/ml (common migraine) and 378.3 pg/ml (classic migraine), whereas in non-sufferers it was 651.7 pg/ml.  Cerebrospinal fluid concentrations of norepinephrine were as follows: 59.1 pg/mg (common migraine) and 50.7 pg/ml (classic migraine) – compared to 73.1 pg/ml among healthy controls.  As a result of these differences, researchers posited that central sympathetic dysfunction, particularly chronic sympathetic hypoactivity, may provoke migraine attacks.

A report by Peroutka (2004) also suggested that migraine is caused by an imbalance of sympathetic co-transmitters, especially a depletion of sympathetic norepinephrine stores in the peripheral nervous system.  Though Nortriptyline may not significantly bolster peripheral norepinephrine concentrations, it may do so slightly or just enough to provide antimigraine effects.  That said, norepinephrine transporter inhibition may alter central concentrations of norepinephrine in such a way that it could exacerbate migraines for certain individuals.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/8410012
  • Source: http://www.ncbi.nlm.nih.gov/pubmed/14979884

Benefits of Nortriptyline for Migraines (Possibilities)

Included below is a list of speculative benefits associated with using Nortriptyline as a migraine prophylactic.  Since there isn’t much evidence to support Nortriptyline’s antimigraine efficacy, it’s benefits should be considered relatively limited.  Perhaps its most notable benefit is that it can sometimes be used among individuals that don’t respond to Amitriptyline due to CYP450 isoenzyme polymorphisms.  Other miscellaneous benefits associated with using Nortriptyline include: low cost, mood enhancement, treatment of psychiatric comorbidities, and reducing usage of acute antimigraine agents.

  • All age groups: Despite the fact that Nortriptyline is seldom prescribed to children, it is considered safe in pediatrics when used at low doses. Additionally, there are some reports suggesting that it is likely an effective antimigraine medication for pediatric populations.  Since not all medications can be utilized across all age groups with efficacy and tolerability, Nortriptyline may be perceived as advantageous compared to age-sensitive medications.
  • Amitriptyline alternative: Some individuals may be unable to properly metabolize Amitriptyline as a result of a genetic polymorphism encoding for CYP2C19. The CYP2C19 isoenzyme may be overexpressed (leading to ultrarapid metabolism) or underexpressed (leading to poor metabolism).  In these cases, the drug may fail to provide any therapeutic benefit and/or may provoke significant side effects.  Assuming the CYP2C19 polymorphism is a patient’s main problem, a switch to Nortriptyline may be useful due to the fact that it is related, yet doesn’t undergo CYP2C19 metabolism.
  • Clinical impressions: The United States Headache Consortium creates evidence-based guidelines for the treatment of migraine headache. The set of guidelines published in 2000 by Silberstein rated the clinical impressions associated with Nortriptyline as “+++.”  The “+++” signifies that medical professionals consider Nortriptyline to be very effective for migraine prophylaxis; most patients experience clinically significant improvement.  Because Nortriptyline hasn’t been extensively researched as a migraine prophylactic, clinical impressions are useful.
  • Chronic tension-type headaches: Individuals with migraines may also suffer from chronic tension-type headaches. These are characterized as headaches that occur on a daily basis and significantly impair functionality and/or compromise quality of life.  There is evidence suggesting that Nortriptyline (at doses up to 75 mg/day) can attenuate CTTH, especially when combined with stress reduction.  This could prove beneficial for those suffering from migraines plus CTTH.
  • Combination treatment: When administered as part of a combination treatment such as Nortriptyline plus Topamax or Propranolol, it is considered highly effective in migraine prophylaxis. While not everyone requires a dual-pharmacological approach to prevent migraines, those that fail to derive sufficient benefit from monotherapies usually respond to combination treatments.  It is also necessary to note that when combined with Topamax or Propranolol, there appear to be no significant interactions and/or increases in unwanted side effects.
  • Energy increase: Nortriptyline is referred to as a norepinephrine reuptake inhibitor, implying that it blocks the reabsorption of norepinephrine from the presynaptic neuron. This leads to increased concentrations of norepinephrine in the synaptic cleft and is thought to yield a stimulatory effect [by activating the sympathetic branch of the autonomic nervous system].  The stimulatory effect may significantly boost a person’s energy and offset fatigue.  Since fatigue is understood to be a potential cause of migraines, increasing energy could be therapeutic.  Additionally, most people enjoy an energy boost for working out, occupational output, and/or general tasks that necessitate completion.
  • Low cost: Assuming you find Nortriptyline to be an effective migraine prophylactic, a notable benefit is its extremely low cost. Due to the fact that Nortriptyline has been on the market since the 1960s, the patent for its brand name “Pamelor” formulation has expired.  Expiry of the patent has lead to generic manufacturing for extremely low prices.  A 30-day supply of Nortriptyline is unlikely to cost more than $20 – regardless of the dose.  In fact, most low-dose formats (e.g. 25 mg and under) may cost less than $5 for 30 pills.
  • Mood enhancement: While Nortriptyline functions as an antidepressant (meaning it is designed to prevent depression, not necessarily enhance mood), some individuals without depression may report mood improvements or enhanced well-being. Though not everyone is guaranteed to experience mood enhancement while taking Nortriptyline for migraine prophylaxis, it can occur.  Should you feel happier than usual, it may be that the modulation of neurotransmitters provided by Nortriptyline is making you feel “better than normal.”
  • Medical comorbidities: Nortriptyline is commonly prescribed for an array of psychiatric conditions such as major depression and panic disorder, but also numerous medical conditions such as neuropathic pain, nocturnal enuresis, and irritable bowel syndrome. Assuming you have another condition that can be treated by Nortriptyline, you may be able to get away with taking one pill to treat multiple conditions.  This may be advantageous over taking separate medications for each condition in that multiple drugs increases likelihood of interactions and/or side effects.
  • Reduce acute medication: Though Nortriptyline is regarded as a migraine prophylactic, it is considered useless for stopping an already-occurring migraine. Medical professionals often prescribe prophylactics along with acute medications to be used only during a migraine attack.  An example of an acute agent would be something like Fioricet for migraines – it is administered after a migraine has started and reduces both the pain and duration of attack.  However, it is known that chronic administration of acute medications is problematic in that users can become tolerant, report diminished efficacy, or even rebound migraines.  Since Nortriptyline may effectively reduce the number of migraines experienced through preventative mechanisms, acute medication usage can be minimized – leading to favorable long-term outcomes.
  • Refractory migraines: Individuals with refractory migraines may have tested a number of prophylactic medications without sufficient benefit. Since the causes of migraines are subject to interindividual neurophysiological variation, it is possible that Nortriptyline may work extremely well for a subset of those with unremitting migraine attacks.  In fact, some research suggests that combination treatment with Nortriptyline plus Topamax is highly effective for those who don’t respond to traditional monotherapy.
  • Unique mechanism of action: Nortriptyline provides a unique mechanism of action in that it modulates norepinephrine, serotonin, histamine, NMDA, and voltage-gated sodium channels. The fact that it functions distinctly from other antimigraine interventions (including Amitriptyline) may be favorable for a subset of individuals.  Not all individuals with migraines exhibit the same set of pathoetiological underpinnings and therefore may respond favorably to an atypical treatment like Nortriptyline.

Drawbacks of Nortriptyline for Migraines (Possibilities)

There are considerable drawbacks associated with using Nortriptyline as a migraine prophylactic, especially ahead of other options.  Perhaps the most significant drawback is that its efficacy for the prevention of migraines is not supported by robustly designed, randomized controlled trials.  Other drawbacks associated with usage of Nortriptyline as an antimigraine agent include: potential exacerbation of migraines, lack of immediate effect, non-responders (due to gene expression), and unwanted side effects.

  • Daily administration: Those taking Nortriptyline as a migraine prophylactic will be required to administer the drug every single day. Failure to administer the drug everyday (such as skipping a day) may trigger horrific acute withdrawal symptoms until the next dose is ingested.  Many people may also dislike the fact that their neurophysiology is constantly under the influence of Nortriptyline, ultimately overriding various [health-conducive] homeostatic processes.
  • Efficacy concerns: The efficacy of Nortriptyline for migraine prophylaxis remains unsubstantiated by science. In fact, some studies have shown that when administered as a standalone agent, it was ineffective for preventing migraines among sufferers.  Though its parent-drug Amitriptyline is a highly effective migraine prophylactic, the mechanism of Nortriptyline differs and for this reason, may be less effective or totally ineffective.
  • Lack of immediate effect: The prophylactic effects of Nortriptyline are not instantaneously attained after a single dose. Research has shown that tricyclic antidepressants may take between 1 and 3 months to exert their full migraine prophylactic effect.  This means that users may take Nortriptyline for over a month and get frustrated with the fact that it hasn’t reduced the frequency of migraine attacks.
  • Long-term outcomes: The outcomes of those that have used Nortriptyline for a long-term (e.g. years) for the prevention of migraines aren’t documented. Most studies investigating Nortriptyline’s efficacy were conducted in less than 3 months.  Therefore, is is unclear as to whether patients experience any unwanted adverse long-term effects and whether migraine reduction is sustained.
  • Mood swings: Although Nortriptyline can enhance mood and/or alleviate depression, not everyone notices emotional improvement. A subset of Nortriptyline users, even without a history of depression, may experience an increase in depression or suicidality as a result of the drug.  Some individuals may report agitation, anger, anxiety, and irritability after taking Nortriptyline for migraines.  Others may report a blunting of emotion or “flat affect” in that they feel zombie-like or (un)comfortably numb.
  • Non-responders: Though the drug’s efficacy for migraine prophylaxis hasn’t been confirmed, another problem is that some individuals may fail to respond as a result of genetic polymorphisms. Polymorphisms of genes encoding for CYP2D6 may affect the efficacy and tolerability of Nortriptyline.  A small percentage of individuals that are CYP2D6 ultrarapid metabolizers may derive zero therapeutic benefit from the drug due to the fact that it is metabolized too rapidly.  Those who are CYP2D6 poor metabolizers may also not respond well and may struggle with tolerability issues.  Most medical professionals should recommend testing services such as GeneSight to get a better understanding of individuals that are pharmacokinetically suited to take the drug vs. those who aren’t.
  • Off-label: As of current, Nortriptyline is solely approved in the United States for the treatment of major depressive disorders. Prescribing it as a migraine prophylactic is not supported by the FDA and certainly not supported by most literature.  Since it is an off-label intervention, patients receiving it may want to consider other options and/or may dislike the idea of taking it.
  • Overdose / Toxicity: A reason that tricyclic antidepressants are less commonly used than conventional antidepressants (e.g. SSRIs) is largely related to toxicity. It is easier to overdose and/or experience toxic effects from a drug like Nortriptyline than conventional treatments.  Deliberate overdose of Nortriptyline is more likely to result in adverse cardiac events, serotonin syndrome, and commonly results in death – especially if combined with alcohol.  This should be of concern among patients with a history of suicidal ideation and depression.
  • Prophylactic-only: There has been zero investigation determining whether Nortriptyline could be useful as an acute antimigraine intervention. For this reason, we must assume that the drug may only be effective for prophylaxis of migraine.  Even its parent-drug Amitriptyline is only utilized as a prophylactic and isn’t considered effective when administered during a migraine attack.  Among individuals that need symptomatic relief during a migraine, other options besides Nortriptyline will need to be used.
  • Side effects: A major reason why tricyclic antidepressants are less commonly used these days (compared to the past) is their side effect profiles. Nortriptyline antagonizes: H1 receptors which causes sedation, alpha-1 adrenergic receptors which causes low blood pressure, and muscarinic receptors which causes anticholinergic reactions (e.g. blurred vision, constipation, dry mouth, urinary retention, etc.).  In addition to the aforestated side effects, other common reactions include: increased appetite, tinnitus, and irregular heartbeat.
  • Superior interventions: In terms of migraine prophylaxis, we don’t even know whether Nortriptyline is legitimately effective. As a result of its unestablished clinical efficacy, we must conclude that there are superior, clinically-validated prophylactic interventions for migraine sufferers.  The United States Headache Consortium guidelines from 2000 suggests that Nortriptyline has “Grade C” evidence to support its usage but limited scientific strength to support this grade.
  • Tolerance: Assuming someone takes Nortriptyline (or any drug) for an extended duration, they may notice that it becomes ineffective. Many antidepressants stop working (including Nortriptyline) because a person’s neurophysiology has become tolerant to regular administration of that dose.  It is possible that, over time, Nortriptyline may cease to function at what was once an initially-effective dose for migraine prophylaxis.  Increasing the dose may be necessary, but also problematic in that side effects may become more severe and/or numerous.
  • Withdrawal symptoms: Although Nortriptyline may provide some antimigraine relief, not all individuals are willing to remain under the influence of a pharmaceutical drug for the entirety of their lives. Unfortunately, it’s relatively difficult to discontinue this drug without experiencing debilitating Nortriptyline withdrawal symptoms.  These discontinuation effects may last for weeks and/or months after cessation.
  • Worsening of migraines: The fact that Nortriptyline is a potent norepinephrine transporter (NET) inhibitor suggests that it could worsen migraine attacks in some individuals. Individuals with migraines tend to exhibit dysfunction within the sympathetic branch of the nervous system.  Dysfunction within this branch can lead to abnormalities in peripheral and central norepinephrine, which could [theoretically] be exacerbated by norepinephrine transporter (NET) inhibition provided by Nortriptyline.

Nortriptyline for Migraines (Review of Evidence)

Although anecdotal reports from migraine sufferers and clinicians suggest that Nortriptyline may be efficacious as a migraine prophylactic, there is a paucity of evidence to support these claims.  Furthermore, many speculate that Nortriptyline is of similar efficacy to its parent compound Amitriptyline for preventing migraines.  Included below is a summary of the available studies that have sought to elucidate the antimigraine efficacy of Nortriptyline.

2012: Topiramate plus nortriptyline in the preventive treatment of migraine: a controlled study for nonresponders.

A study conducted by Krymchantowski et al. (2012) assessed the efficacy of Topamax plus Nortriptyline as a combined dual-pharmacological therapy among migraine sufferers.  Their impetus for the study stemmed from the fact that migraine prophylaxis monotherapy often fails to sufficiently prevent migraine attacks among a subset of sufferers.  For this reason, researchers organized a randomized controlled trial (RCT) to determine whether the combination of Topamax plus Nortriptyline would improve therapeutic outcomes among monotherapy non-responders.

Researchers noted that all patients included in the trial had been diagnosed with episodic migraines and previously underwent initial monotherapy treatment with either Topamax (100 mg/day) or Nortriptyline (30 mg/day) for 8 weeks – and derived inadequate symptomatic relief.  Inadequate symptomatic improvement was defined as “less than 50% reduction in headache frequency” after the 8-week span of treatment.  Thereafter, 68 participants were randomized to one of the following groups: “continued monotherapy (plus placebo)” OR “Topamax plus Nortriptyline.”

To gauge efficacy of the combination treatment, researchers recorded the number of headache days at baseline and compared it to number of headache days after 6 weeks treatment.  A secondary measure assessed whether patients experienced at least 50% reduction in headache frequency after 6 weeks (as compared to baseline).  Results indicated that headache frequency was significantly reduced (by 4.6) among the 38 participants receiving the Topamax plus Nortriptyline compared to the 30 participants receiving the “continued monotherapy plus placebo.”

Moreover, of those receiving the Topamax plus Nortriptyline (combination treatment), headache reduction of at least 50% was noted in 78.3% of patients.  Contrastingly, only 37% of those in the group continuing monotherapy (and receiving a placebo) experienced a 50% reduction in headaches.  This suggests that Nortriptyline’s pharmacodynamics are useful for migraine prevention when combined with Topamax – especially among non-responders to monotherapy.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/22008899

2012: Evaluation of the efficacy of caffeine cessation, nortriptyline, and topiramate therapy in vestibular migraine and complex dizziness of unknown etiology.

Researchers Mikulec et al. (2012) sought to determine the efficacy of various interventions for vestibular migraine and complex dizziness of unknown etiology.  Vestibular migraine, sometimes referred to as “migraine associated vertigo,” is characterized by attacks of spontaneous or positional vertigo of short duration (minutes) to longer duration (days).  The vertigo presents as loss of balance and/or sensation of whirling, and is thought to be triggered by the vestibular nerve.

They conducted a retrospective chart review and determined whether symptoms could be improved with caffeine cessation, as well as discontinuation of other migraine-triggering substances. Thereafter, pharmaceutical agents Nortriptyline or Topamax were provided if dietary modification failed to improve symptoms.  A total of 34 patients in this review had been formally diagnosed with vestibular migraine, whereas just 10 were diagnosed with complex dizziness of unknown etiology.

To assess efficacy of these interventions, researchers noted improvements in self-reported dizziness.  Results indicated that 14% of patients experienced symptomatic improvement following caffeine withdrawal, whereas Nortriptyline therapy significantly benefitted 46% of patients.  Comparatively, Topamax therapy reduced symptoms in just 25% of patients.

This suggests that Nortriptyline may be a highly-effective agent for minimizing dizziness associated with vestibular migraines.  More patients responded to Nortriptyline than both caffeine cessation and Topamax.  Further research is warranted to investigate the therapeutic potential of Nortriptyline for the attenuation of vestibular migraine symptoms.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/21704423/

2009: A double-blind randomized controlled trial of low doses of propranolol, nortriptyline, and the combination of propranolol and nortriptyline for the preventive treatment of migraine.

A double-blinded, randomized controlled trial conducted by Domingues et al. (2009) analyzed the efficacy of low-dose Propranolol, low-dose Nortriptyline, and combined Propranolol plus Nortriptyline for migraine prophylaxis.  Study authors noted that few published trials had evaluated the efficacy of 2+ agents as migraine prophylactics, and for this reason, they were determined to do so.  A total of 76 patients with a clinical diagnosis of migraines in accordance with International Headache Society criteria were recruited as participants.

All participants were at least 18 years of age, experienced 4 or more migraines per month, had no additional medical conditions, and were not utilizing any prophylaxis medication.  Participants were randomized to 3 groups and matched in terms of age, sex, and migraine frequency.  The three groups were as follows: Group A – Propranolol, Group B – Nortriptyline, and Group C – Propranolol plus Nortriptyline.

Dosages were adjusted for each of the 3 groups throughout the duration of the experiment.  Group A received 20 mg (b.i.d.) Propranolol for 2 weeks followed by 40 mg (b.i.d.) for 6 weeks.  Group B received Nortriptyline 10 mg (b.i.d.) for 2 weeks followed by 20 mg (b.i.d.) for 6 weeks.  Group C received Propranolol plus Nortriptyline at the same dosages mentioned in the groups receiving standalone treatment.

Headache diaries were recorded by patients and included information regarding presence of headaches and severity (on a scale from 0 to 3).  To collect baseline data, patients were monitored for a month without any prophylactic intervention.  After the first month, patients were instructed to use medications for 2 consecutive months.

Researchers compared headache diary data from the initial baseline month (Day 1 to Day 30) to the second month (from Day 30 to Day 60) and third month (Day 60 to Day 90).  The primary outcome measure was number of patients per group that attained at least 50% reduction in number of days with migraine headache.  The secondary outcome measures included: number of headache days per month, side effects, and number of patients discontinuing the study.

Of the 44 participants that completed the study, 15 were in Group A, 14 in Group B, and 16 in Group C).  Results indicated that 48.2% of Group A, 28.6% of Group B, and 37.5% of Group C experienced at least 50% reduction in number of migraine days – the differences in these percentages were not statistically significant.  Within each group, the number of days with headache compared to pre-treatment baseline was significant for those in Group A and Group C; no significant benefit was seen in Group B.

Additionally, frequency of headaches during treatment was reduced among those within Group A and Group C compared to baseline measures, but no difference was seen among those within Group B.  Based on these findings we can conclude that Propranolol significantly alleviated migraine symptoms regardless of whether used as a standalone intervention (Group A) or combination therapy (Group C).  Furthermore, Nortriptyline appears ineffective as an antimigraine agent when administered as a standalone agent for 2 months.

This study provides evidence indicating that Nortriptyline may lack therapeutic efficacy when administered as part of migraine prophylactic monotherapy.  Though the combination of Propranolol plus Nortriptyline was effective as an antimigraine intervention, we cannot automatically assume that Nortriptyline contributed to the therapeutic value of this combination (based on the fact that it was ineffective as a standalone option).  That said, researchers mention that Nortriptyline may require a higher dose and/or longer duration of administration (compared to what was used in this study) for therapeutic antimigraine efficacy.

It should also be mentioned that this study was relatively small-scale in that 15 (or fewer) participants per group were able to complete the full 3 months of therapy.  While there is evidence from this study to support the usage of Propranolol for migraine prophylaxis, there’s none to support usage of Nortriptyline – especially as a monotherapy.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/20069203

2005: Pediatric migraine: recognition and treatment.

Researchers Hershey and Winner (2005) conferred interventions for migraine among pediatrics.  Their report discussed the fact that migraine headaches among children slightly differ from those occurring in adults.  Particularly, children tend to experience migraines of shorter duration than adults and the attack is often bilateral among children (compared to unilateral in adults).

They went on to discuss that treatment options commonly implemented among adults are usually successful and well-tolerated among children.  Various treatments they discussed included NSAIDs, triptans (e.g. Sumatriptan), antihistamines, anticonvulsants, as well as antidepressants such as Amitriptyline and Nortriptyline.  Though this wasn’t a study testing the efficacy of Nortriptyline in children, authors imply that it is an effective intervention for pediatric migraine.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/15928347

2003: Antidepressants in the treatment of migraine headache.

A report by Punay and Couch (2003) confers the administration of antidepressants for the prevention of migraines.  Authors note that tricyclic antidepressants (TCAs) are are regarded as effective options in migraine prophylactic therapy.  In particular, they mention Amitriptyline, Nortriptyline, and Doxepin as the predominant tricyclic agents utilized in prophylactic therapy.

Though tricyclic antidepressants are associated with unwanted side effects, they are more effective than SSRIs in terms of migraine prevention.  Authors state that among individuals diagnosed with severe depression and concurrent severe migraines, tricyclic antidepressants may be the among the most logical interventions.  While the therapeutic efficacy of Nortriptyline wasn’t fully assessed, this report suggests that it has some value in prophylaxis of migraines.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/12525271/

2001: Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial.

A study conducted by Holroyd et al. (2001) compared the efficacy of tricyclic antidepressants Amitriptyline or Nortriptyline with stress management therapy, as well as a combination of the two for the treatment of chronic tension type headache (CTTH).  Chronic tension-type headaches are incessant headaches that are tough to treat and compromise functionality and/or quality of life for patients.  For the study, researchers recruited 203 adults that had been formally diagnosed with CTTH.

A randomized, placebo-controlled trial was conducted from 1995 to 1998 at various outpatient clinics in Ohio.  Participants were assigned at random to receive tricyclic medication (Amitriptyline or Nortriptyline), stress management therapy, medication plus stress management therapy, or stress management therapy plus placebo.  Efficacy of these interventions were determined based on change in monthly headache index scores.

Results indicated that tricyclic antidepressants Amitriptyline (up to 100 mg/day) or Nortriptyline (up to 75 mg/day) and stress management significantly reduced headaches.  That said, taking either of the antidepressants was associated with more rapid improvement compared to stress management.  Combination therapy of antidepressant medication PLUS stress management yielded greatest symptomatic improvement in CTTH.

With this information, it is apparent that Nortriptyline (up to 75 mg/day) improves symptoms of those who cannot tolerate Amitriptyline (up to 100 mg/day) with chronic tension-type headaches.  While this study didn’t assess Nortriptyline’s efficacy for migraine prophylaxis, the fact that it is therapeutic for CTTH may be beneficial for migraine sufferers with comorbid tension headaches.  Since medication plus stress management was the most effective for tension-type headache management, it may be worth considering that Nortriptyline plus stress management therapy may be equally therapeutic among migraine suffers.

  • Source: http://www.ncbi.nlm.nih.gov/pubmed/11325322

Limitations associated with research of Nortriptyline for migraines

There are some notable limitations associated with the research of Nortriptyline as a migraine prophylactic.  Most obvious is the fact that Nortriptyline hasn’t been extensively analyzed as a standalone option for migraine prophylaxis, as well as the fact that it has only been tested in a handful of studies.  The lack of overall studies makes it difficult to confirm or dismiss its efficacy in a clinical setting.

  • Designs: Of the few available studies that have tested Nortriptyline as a migraine prophylactic, only 2 implemented randomized, controlled designs. While the designs in these 2 studies is strong, the same cannot be said for other research.  Assuming further trials are conducted to analyze the efficacy of Nortriptyline for migraine prophylaxis, designs should be placebo-controlled, randomized, and double-blinded.
  • Dosage: It is unclear as to what the optimal dosage of Nortriptyline is for migraine prophylaxis. It could be that in order to prevent headaches, Nortriptyline needs to be administered within a highly-specific dosage range.  Nonetheless, in some studies, researchers suggested that Nortriptyline may have appeared ineffective due to the fact that it was administered at too low of a dose.
  • Duration: The duration of studies assessing Nortriptyline in migraine prophylaxis ranged from 2 months to 14 weeks; the latter (14-week study) was among migraine sufferers who were unresponsive to monotherapy. Researchers suggested that the 2-month study may have been too short to observe a therapeutic effect from Nortriptyline.  It is known that tricyclics can take up to 3 months to yield maximal migraine prophylaxis.
  • Lack of studies: The main limitation associated with research of Nortriptyline for migraines is that there aren’t enough studies. There are really only 2 studies that were conducted with robust randomized controlled designs, yet authors admitted that 1 of these 2 may have been flawed in dosing and total time of administration.  This means there is really only a single study from which we may be able to extract useful information.  Before we know whether Nortriptyline is actually capable of preventing migraines, more research is necessary.
  • Migraine subtypes: It is known that not everyone suffering from migraine exhibits the same set of causative factors. Additionally, some individuals experience migraines with a “long warning” and/or triggered by a specific stimulus.  Others may experience migraines with “short warning” and non-specific triggers.  Though we know that Amitriptyline tends to be most effective for short-warning migraines with non-specific triggers – it is unclear as to whether Nortriptyline may be more beneficial for this specific subtype as well.
  • Participants: The number of participants in several studies that have analyzed the antimigraine efficacy of Nortriptyline include: 44 participants, 34 participants, and 68 participants. However, not all of these participants received Nortriptyline.  In fact, in one of the studies, less than 15 received standalone Nortriptyline as an intervention.  Additional studies with larger sample sizes are necessary to legitimize preliminary findings.
  • Questionable efficacy: With the available literature, it’s difficult to know whether Nortriptyline is an effective intervention. Some reports suggest it may effectively prevent migraines, while other studies note that it is no more effective than a placebo.  Some reports suggest that it may be effective only when combined with Topamax.  Since its efficacy remains unclear, further testing is warranted.

Verdict: Nortriptyline is a non-evidence-based migraine prophylactic

The usage of Nortriptyline as a standalone monotherapy for migraine prophylaxis is not supported by scientific research nor the FDA.  The United States Headache Consortium has rated Nortriptyline as a “Grade C” monotherapy for prophylaxis of migraines.  This letter-grade rating is solely based upon reports from clinicians documenting the degree to which patients seem to derive migraine prevention benefit from Nortriptyline.

Interestingly, clinical evidence is suggestive of the fact that Nortriptyline is “very effective” among patients and results in significant improvement (when compared to other interventions).  Furthermore, numerous anecdotal accounts suggest that Nortriptyline reduces migraine attack frequency.  Due to the lack of well-designed trials, it may be worth considering that Nortriptyline has had significant success in clinical settings as a migraine prophylactic.

Whether this success should be attributed to a placebo response isn’t known and cannot be known until more randomized controlled trials are conducted.  While it seems unlikely that a placebo effect would account for symptomatic improvement in clinical cases, it cannot be dismissed as a possibility.  That said, there is some evidence to suggest that Nortriptyline may be highly useful when combined with Topamax for the treatment of refractory migraines.

The main goal of migraine prophylaxis is to reduce frequency, severity, and disability associated with migraine attacks.  Nortriptyline may reduce frequency (via preventative mechanisms) and severity or disability by reducing pain, increasing energy levels, and enhancing mood.  Though some individuals may experience unwanted side effects, these are less common at the low-dosages typically employed for migraine prophylaxis (starting at just 10 mg).

In conclusion, it appears as though clinical usage of Nortriptyline for migraines isn’t justified by scientific data.  However, the fact that: its parent-drug Amitriptyline appears to work well for migraine prophylaxis, few studies have analyzed the efficacy of Nortriptyline for migraines, and numerous anecdotal/clinical reports suggest it is highly-effective – it may be worth using for unresponsive, atypical cases of chronic migraine.  Nonetheless, Nortriptyline should only be recommended as a treatment after all other options have been tried and/or deemed unsuitable (such as Amitriptyline from a CYP2C19 polymorphism).

Have you tried Nortriptyline for migraines?

If you’ve used Nortriptyline for migraine prophylaxis, feel free to share your experience in the comments section below.  How would you rate the perceived efficacy of Nortriptyline in reducing migraine occurrence on a scale of 1 to 10 (with 10 being most effective)?  If you had to estimate, how long would you say it took for Nortriptyline to fully “kick in” and prevent migraines after you began treatment?

To help others get a better understanding of your situation, include some details in your comment such as: the dosage you take, type of migraines you have, whether you use other drugs or supplements, comorbid health conditions, and how long you’ve been taking it.  For those that have tested other interventions prior to Nortriptyline, would you say that it is more or less effective for migraine prophylaxis?  It may be helpful to know whether you tested Amitriptyline (its parent-drug) before trying Nortriptyline, and if Amitriptyline failed to work, whether it was because you have a CYP2C19 polymorphism.

Though Nortriptyline may be an effective antimigraine intervention for some, it clearly does not work for everyone.  Additionally, it may cause unwanted side effects such as dry mouth, and may lead to a debilitating set of discontinuation symptoms upon cessation.  Overall, Nortriptyline is a useful, atypical migraine prophylactic when conventional pharmacological treatments fail.

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