Amitriptyline for LPR: Will An Antidepressant Really Help?

A subset of LPR patients may exhibit underlying abnormalities in autonomic nervous system (ANS) function and/or brain activation – which causes and/or sustains the LPR condition.

Another subset of “LPR patients” may actually have a functional esophageal disorder or a somatic symptom disorder wherein either: connections in the brain are erroneous (functional) or anxiety is fueling symptoms (somatic).

In both of the above scenarios, the administration of a neuromodulatory agent such as amitriptyline, a tricyclic antidepressant, may provide therapeutic benefit for some and might even cure LPR for others.

How amitriptyline may help LPR (My hypotheses)

There are a variety of ways in which amitriptyline may prove useful for a subset of individuals with: (1) medically-verified LPR or (2) LPR-like symptoms (i.e. persistent laryngeal manifestations).

1. Rewiring the CNS & brain

Chronic stress and/or depression can impair neuroplasticity in the brain.

It can also create and reinforce atypical neural pathways (i.e. connections) between brain regions such as to perpetuate the pathophysiology of these conditions.

Among individuals with functional esophageal disorders and/or LPR occurring secondary to erroneous connectivity in the brain and CNS – the condition will not improve without neuromodulation.

Administration of a neuromodulator or antidepressant such as amitriptyline has potential to counteract decreased neuroplasticity and “rewire” connectivity in the brain/CNS to a healthier pattern. (R)

In some cases, this rewiring effect may normalize esophageal sphincter function (e.g. LES & UES) and esophageal motility – such as to improve or cure suspected “LPR.”

2. Improving sleep quality

Many individuals with LPR exhibit sleep disorders (e.g. sleep apnea, UARS, insomnia, sleep deprivation, etc.) – possibly in part due to the effect of LPR or shared pathophysiological underpinnings with LPR (e.g. obesity). (R)

Chronic untreated sleep disorders may cause changes in hormones and/or neurotransmitters that influence: (1) LPR frequency/severity (e.g. worse reflux when sleep deprived) and/or (2) perception of LPR symptoms.

In other words, individuals with sleep problems could end up with objectively worse LPR symptoms because of poor sleep and/or subjectively worse LPR symptoms due to perceptual changes resulting from poor sleep.

Amitriptyline is a medication that significantly interacts with H1 receptors; serotonin transporters (SERTs); serotonin receptors (5-HT2C & 5-HT2A); alpha-1A adrenergic receptors; and muscarinic acetylcholine receptors – to induce a sedative/hypnotic effect and enhance sleep.

Assuming amitriptyline significantly improves sleep quality and/or quantity relative to pre-treatment, this has potential to improve both objective and subjective LPR symptoms.

3. Anxiety and/or depression

Huang et al. (2022) report that anxiety and depressive symptoms influence the occurrence, development, and treatment of refractory laryngopharyngeal reflux disease. (R)

This report was based upon the fact that a small study showed significantly improvement on both RSI & RFS with the use of a neuromodulator (flupentixol-melitracen) – a combination of antipsychotic + tricyclic antidepressant – in patients with refractory LPR.

In this study, it is unknown as to whether drug-induced changes in sleep, anxiety, depression, brain/CNS connectivity, neurotransmitter levels, etc. – generated improvement in LPR symptoms.

Nonetheless, it’s possible that anxiety and/or depression trigger and sustain the pathophysiology of LPR and that by treating both anxiety and/or depression with a clinically effective antidepressant/anxiolytic like amitriptyline, symptoms decrease or end up cured.

4. Gut-brain axis activation

About 95% of serotonin (5-HT) is produced in the gut mainly within enterochromaffin cells whereas about 5% is found in the brain. (R)

Concentrations of peripheral (i.e. gut) serotonin is thought to influence: hormonal, autocrine, paracrine, endocrine actions – and intestinal motility, gut inflammation, and gut physiology. (R)

It’s possible that dysregulation of the gut-brain axis (GBA) – the 2-way bidirectional signaling that takes place between the GI tract and brain/CNS – causes and/or sustains certain reflux conditions like LPR and GERD.

An overview suggests that any substantial abnormalities in the gut-brain axis could affect: inflammation, immunity, sleep quality, diet, genetics, etc. – along with peripheral (e.g. vagal nerve) & central nervous system function. (R)

It’s possible that amitriptyline’s effect within the brain alters activation within the gut via the gut-brain axis (GBA) and/or that amitriptyline directly exerts a peripheral effect that affects function of the GI tract to improve symptoms of LPR.

Other ways amitriptyline may improve LPR…

Allergy treatment

LPR can sometimes be caused by environmental and/or food allergies.

Because amitriptyline functions as a H1 histamine receptor antagonist – it effectively blocks the binding of histamine (stemming from an IgE-mediated immune response) to H1 receptors.

If symptoms improve on amitriptyline – it’s possible that you had an untreated allergy such that allergy testing may be warranted.

Note: Amitriptyline will not block non-IgE-mediated food allergies – such that it’s still technically possible to have an allergy and not derive benefit from amitriptyline. Non-IgE-mediated allergies are usually discovered and treated with elimination diets.

Neurotransmitter shifts

Amitriptyline interacts with a variety of neurotransmitter systems – primarily: histamine, serotonin, norepinephrine, acetylcholine.

Simultaneous modulation of numerous neurotransmitter systems in the brain/CNS could yield multifactorial changes across numerous biological systems: brain, gut, nerves, ANS (SNS/PNS balance), muscles, etc. – to improve LPR.

Research suggests that antidepressants like amitriptyline act centrally and peripherally to enhance the availability of physiologically-released serotonin and might alter both sensory and motor underpinnings associated with certain cases of LPR.

Reducing pain signals (?)

Amitriptyline is capable of lowering pain signals sent to the brain and increasing one’s pain threshold as a result of this effect – this is why it’s commonly used to treat neuropathy (i.e. nerve pain).

Because LPR can cause burning sensations and pain in the throat/esophagus, many will report significantly less LPR-related pain while using amitriptyline – and thus improved LPR-related symptoms.

Although some will perceive the LPR-related pain reduction as a huge benefit (particularly if pain levels were high before treatment), blocking pain can sometimes be a bad thing.

Why? Blocking pain may give individuals a false sense of LPR recovery – such that they’re convinced the actual LPR is improving or gone and they revert back to reflux-inducing habits/lifestyles.

The problem with this is that LPR may not have actually improved or gone away – such that damage is still occurring and reversion back to reflux-inducing habits/lifestyle could inflict significant esophageal damage (without even knowing it because the pain signaling is reduced).

Note: A reduction in pain signaling is why amitriptyline works well for glossopharyngeal, laryngeal, and vagal neuropathies.

Amitriptyline for LPR (Research)

There are zero studies that’ve directly examined the efficacy of amitriptyline for the treatment of LPR (laryngopharyngeal reflux).

This is probably due to: (1) lack of funding and/or (2) the fact that many cases of LPR present with mechanical abnormalities (e.g. hiatal hernia) such that trying amitriptyline wouldn’t make logical sense.

Included below are studies in which amitriptyline was evaluated for the treatment of certain symptoms that are commonly associated with LPR.

Understand that improvement in symptoms associated with LPR or LPR-like symptoms does NOT mean that amitriptyline is effective for medically-confirmed LPR.

2017: GERD Associated with Anxiety: Efficacy & Safety of Amitriptyline + Pantoprazole

Faruqui (R)

Aim: Evaluate the efficacy and tolerability of fixed-dose amitriptyline + pantoprazole in GERD associated with anxiety.

Methods: A total of 96 patients received fixed-dose amitriptyline (10 mg/night) + pantoprazole (40 mg/day) for 4 weeks.

Measures: GERD questionnaire. Anxiety & depression scale. Health survey.

What were the results?

GERD symptoms and anxiety score decreased significantly at week 4 compared to baseline.

Health survey scores also exhibited significant improvement after 4 weeks vs. baseline.

Conclusion: Amitriptyline and pantoprazole combination was effective in the management of GERD patients with comorbid anxiety.

Critical thinking…

This study was not randomized or controlled – such that it’s unknown as to whether the improvement observed is a legitimate reflection of amitriptyline + pantoprazole’s effect in this population.

This study did NOT demonstrate that amitriptyline improved symptoms of GERD – as it was combined with a proven GERD therapy (pantoprazole which likely accounted for most or all of the GERD improvement).

Amitriptyline probably helped with anxiety symptoms (as it is often used to treat anxiety disorders) and the anxiety reduction might’ve led to GERD improvement.

These findings suggest that perhaps amitriptyline may be useful in some cases of LPR when combined with a PPI such that the PPI reduces stomach acid and the amitriptyline alleviates anxiety symptoms that may be exacerbating LPR.

2017: Amitriptyline vs. placebo in chronic laryngopharyngeal neuropathy

Jang et al.: “There was a trend toward greater subjective improvement in overall symptoms with amitriptyline.” (R)

Aim: Compare the efficacy of amitriptyline to a placebo for the treatment of chronic laryngopharyngeal neuropathy in a randomized controlled trial (RCT).

Methods: Patients assigned to receive either: (1) amitriptyline (12.5-50 mg/night) (N=9) vs. (2) placebo (N=9) – for an 8-week period.

Results: Average difference in mRSI & VHI scores after treatment were not significantly different between study arms. More amitriptyline users felt subjective improvement in symptoms (6/9 or 67%) relative to placebo users.

Critical thinking…

This was an extremely small study such that it’s difficult to know whether the observed effect (or lack thereof) accurately reflects amitriptyline in the management of laryngopharyngeal neuropathy.

There was significantly greater subjective improvement in symptoms among amitriptyline users than placebo users – suggestive of a therapeutic effect.

Based on the finding that amitriptyline improved subjective symptoms of persons with laryngopharyngeal neuropathy – it’s possible amitriptyline could improve LPR or LPR-like symptoms (particularly in patients with neurological disorders).

2013: Effect of low-dose amitriptyline on globus pharyngeus and its side effects

You et al.: “Low-dose amitriptyline is well-tolerated and can significantly improve patient symptoms, sleep and quality of life. Thus, low-dose amitriptyline may be an effective treatment for globus pharyngeus.” (R)

Aim: Evaluate the efficacy and side effects of low-dose amitriptyline vs. PPI (pantoprazole) in patients with globus pharyngeus.

Methods: 30 patients with Rome III criteria for functional esophageal disorders assigned to receive either amitriptyline (25 mg/night) (N=16) vs. pantoprazole (once daily) (N=14) – for a 4-week period.

Measures: Glasgow Edinburgh Throat Scale (GETS). Medical Outcomes Study 36-item health survey (social functioning). Pittsburgh Sleep Quality Index. Treatment response = >50% reduction in GETS.

What were the results?

Amitriptyline users exhibited a significantly greater response than pantoprazole users at the 4-week endpoint (75% AMI vs. 35.7% PAN).

After just 3 days, amitriptyline users exhibited significantly more improvement than the pantoprazole users in GETS score (3.69 vs. 5.64).

After 4 weeks, amitriptyline users exhibited significantly greater improvements in GETS score and sleep quality than the pantoprazole users (GETS 1.25 vs. 3.79 & PSQI 4.19 vs. 8.5).

The amitriptyline users were more likely to experience improvement in: general health, vitality, social functioning, and mental health – based on the SF-36 health survey.

Critical thinking…

This study included just 16 patients on amitriptyline (vs. 14 on pantoprazole) – such that the reported improvement from amitriptyline may have been more due to random chance or placebo response than a legitimate ability to reverse globus.

A subset of the patients in this study were diagnosed with moderate or severe anxiety or depression – and thus this may have completely explained the presenting globus (e.g. anxiety-induced) and subsequent response to amitriptyline.

This study did NOT recruit patients with LPR – all patients in this study were diagnosed with “globus pharyngeus” (a functional esophageal disorder).

Functional esophageal disorders are thought to be caused by erroneous brain/CNS & ANS activation/connectivity – such that they cause specific symptoms like globus to emerge.

Amitriptyline may have subjectively improved “globus” for these patients via perceptual changes (brain/CNS & ANS modulation) and/or actions on laryngopharyngeal nerves (numbing them).

In other words, amitriptyline may not have actually fixed the functional globus – but instead may have made the globus less perceptible due to a unique combination of mental status changes and nerve numbing.

2013: Low-dose amitriptyline combined with PPI for functional chest pain

Park et al. (R)

Aim: Investigate the efficacy of amitriptyline with PPI for the treatment of functional chest pain (FCP) refractory to PPI therapy.

Methods: Randomized, open-label trial comparing: (A) amitriptyline (10 mg/night) + rabeprazole (20 mg/day) vs. (B) rabeprazole (20 mg, b.i.d.).

Outcomes: Global symptom score assessment. Total number of individuals with >50% improvement in symptom score.

What were the results?

70.6% of patients in the amitriptyline + rabeprazole group had symptoms improve by over 50% vs. 26.3% of patients in the standalone rabeprazole group.

Patients using amitriptyline + rabeprazole combo had greater improvement in body pain and general health perception.

Conclusion: Adding amitriptyline to a PPI was more effective than double-dose PPI in patients with refractory FCP.

Critical thinking…

This was a small trial with 40 participants – such that results may have been due more to random chance than an actual effect of amitriptyline.

There were no objective measures in functional chest pain severity – such that it’s difficult to gauge the true magnitude of symptom improvement.

This study involved patients with functional chest pain – which is not the same as LPR although some individuals diagnosed with LPR may have a functional esophageal disorder and laryngeal symptoms.

2006: Effectiveness of amitriptyline versus cough suppressants in the treatment of chronic cough from postviral vagal neuropathy

Jeyakumar et al. (R)

Aim: Evaluate the efficacy of amitriptyline vs. cough suppressants (codeine/guaifenesin) for the treatment of chronic cough resulting from postviral vagal neuropathy.

Methods: 28 patients with chronic cough occurring from postviral vagal neuropathy were selected to participate in this study. Patients were assigned at random to receive either: amitriptyline (10 mg/night) vs. codeine/guaifenesin (10-100 mg/5-10 mg, 10 mL every 6 hours) – for a 10-day period.

Measures: Cough frequency/severity ratings. Cough QoL questionnaire.

Results: Most patients using amitriptyline achieved complete response on the initial dose of 10 mg – and none of the codeine/guaifenesin users achieved a complete response. Amitriptyline was found to be a highly significant predictor of a greater than 50% response vs. the codeine/guaifenesin combo.

Conclusion: Chronic cough can have a significant negative psychosocial impact on patients – and there are few effective treatments but amitriptyline appears promising.

Critical thinking…

This study included a small sample size of just 28 patients – such that findings could be more attributable to random chance, spontaneous improvement, or a placebo response than an actual effect of either intervention.

This study also employed zero objective analyses – and instead relied upon subjective patient reports which may not reliably reflect the true frequency/severity of cough.

It’s possible that amitriptyline simply altered perception of the cough (such as to make it seem less bothersome) rather than its true frequency/severity.

We must consider that a subset of individuals with postviral vagal neuropathy could also have LPR (secondary to this condition) or LPR-like symptoms – and others with LPR may actually have an undiagnosed neuropathy contributing to the condition.

If amitriptyline significantly improves symptoms of postviral vagal neuropathy – and LPR occurs secondary to this neuropathy, then it’s possible that amitriptyline will contribute to improvement of LPR-like symptoms.

2006: Sensory neuropathic cough: a common and treatable cause of chronic cough

Bastian et al. (R)

Aim: Examine the effect of amitriptyline in patients with chronic sensory neuropathic cough.

Methods: 12 patients were treated with amitriptyline and asked to report the effect on cough at fixed intervals via telephone interviews.

Results: All patients exhibited at least 40% reduction of self-reported symptoms with most reporting 75% to 100% short-term relief.

Conclusion: Amitriptyline (10 mg/day) or another anti-neuralgia medication may be helpful in the treatment of sensory neuropathic cough.

Critical thinking…

This was a small study (just 12 patients) such that findings of symptom improvement may have been due to random chance.

The trial was not randomized, double-blinded, nor controlled – and thus the improvements could’ve been due to some sort of placebo effect, spontaneous symptom remission, or influenced by researchers rather than amitriptyline.

Still, it’s possible that amitriptyline does improve symptoms of chronic sensory neuropathic cough.

If amitriptyline is effective for the management of sensory neuropathic cough symptoms – then it might improve LPR-like symptoms or LPR occurring secondary to a neuropathic condition.

Related research: neuromodulators for esophageal disorders & neuropathies

Other studies have examined the effects of neuromodulators (e.g. tricyclic antidepressants; SSRIs; gabapentinoids; antipsychotics) on persistent laryngeal symptoms – some of which may overlap and/or contribute to LPR.

Keep in mind that just because a neuromodulator is effective for symptom reduction doesn’t necessarily mean that amitriptyline is equally effective (as the specific neuromodulatory mechanism of action might matter to some degree).

Huang et al.: Adding Deanxit (flupentixol-melitracen) – antipsychotic/tricyclic combo – to PPI therapy significantly improved symptoms of LPR (RFS & RSI) within ~1 month of treatment. (R)

Ding et al.: “Globus pharyngeus without LPR may occur due to high UES pressure. Stress, smoking, alcoholic drinking, high salt, and anxiety may be its risk factors.” (R)

(Some of these patients may mistakenly assume they have LPR based on self-diagnosis or misdiagnosis – and thus treatment with a neuromodulator to reduce stress may improve UES pressure and alleviate symptoms).

Weijenborg et al.: “There is limited evidence that antidepressants benefit a subgroup of patients with GERD.” (R)

(It’s possible antidepressants also benefit a subgroup of patients with LPR.)

Mokhtare et al.: “We found that the combination of duloxetine and lansoprazole is a safe and tolerable regimen and it can significantly improve anxiety, heartburn, coffee consumption, the quality of sleep, and life in patients who suffer from the symptoms of GERD.” (R)

(It’s possible that a similar effect will occur in patients with LPR such that combining a PPI with a neuromodulator improves quality of life to a greater degree than just the PPI.)

Ryan et al.: “The treatment of refractory chronic cough with gabapentin is both effective and well tolerated.” (R)

(Chronic cough may be present with LPR or LPR-like symptoms – and a neuromodulator might help).

Vertigan et al.: “Combined SPT (speech pathology treatment) and pregabalin reduces symptoms and improves quality of life (QoL) compared with SPT alone in patients with CRC (chronic refractory cough).” (R)

(Chronic cough may cause and/or present with LPR-type sypmtoms such that a neuromodulator may help.)

Cohen & Misono: “Benefit from neuromodulator treatment with amitriptyline, gabapentin, pregabalin, and baclofen in chronic idiopathic cough patients was demonstrated.” (R)

Z. Bastian & R. Bastian: “Amitriptyline, desipramine, and gabapentin appear to vary in their effectiveness for individual cases of sensory neuropathic cough; across a whole cohort, symptom relief was similar in frequency and degree on any of the 3 medications.” (R)

Seccia et al.: Amitriptyline was successfully used to treat symptoms of oral burning with dysphagia and weight loss in an 80-year-old Caucasian woman. (R)

Gilberto et al.: “Current literature includes three level 1 evidence studies (RCTs) and several level 2 & 3 studies supporting the use of neuromodulating medications in chronic neurogenic cough.” (R)

(Individuals with chronic cough associated with LPR or LPR-like symptoms may benefit from amitriptyline).

Halum et al.: “Pregabalin therapy appears to be an effective treatment option for laryngeal sensory neuropathy.” (R)

(Some individuals with laryngeal sensory neuropathy may have LPR or exhibit LPR-like symptoms. A neuromodulator may improve these symptoms.)

Boston Medical Center: Tried to do a study examining the effect of amitriptyline on chronic laryngitis (cough, hoarseness, throat clearing, globus sensation, throat pain, phlegm, difficulty swallowing) but it was terminated due to lack of funding. (R)

(This suggests that researchers think amitriptyline has potential to improve chronic laryngeal symptoms.)

What does the research suggest re: Amitriptyline & neuromodulators for laryngeal symptoms?

Individuals with LPR or LPR-like symptoms may benefit from a trial of amitriptyline.

Particularly if the LPR or LPR-like symptoms occur with or secondary to:

• Chronic cough
• Neuropathies (laryngeal, pharyngeal, vagal, etc.)
• Neuropsychiatric disorders (e.g. anxiety, depression, insomnia, somatic symptom disorders)
• Functional esophageal disorders

Amitriptyline may be most effective in managing pain perception (particularly in neuropathic pain) and treating psychiatric conditions like anxiety, depression, insomnia, etc. – but these conditions have potential to exacerbate LPR if left untreated.

Therefore, even if amitriptyline doesn’t directly help with LPR – it might make LPR more tolerable (via pain reduction) and/or objectively less severe due to fewer LPR exacerbations secondary to psychiatric symptoms (e.g. panic attacks).

Still, it is important to underscore the fact that ZERO trials have directly examined amitriptyline for the treatment of LPR.

Therefore, amitriptyline might have no effect in LPR or might make symptoms worse.

Downsides to trying amitriptyline for LPR

Trialing amitriptyline for LPR should not be done without first carefully considering the potential downsides.

Only after a patient and his/her medical doctor believe that the potential benefits outweigh the potential downsides – should amitriptyline be trialed for LPR.

Worsening of LPR & reflux

Some claim that amitriptyline significantly worsens the severity and/or frequency of reflux events – and it makes logical sense that this could occur in a subset of users.

Just like amitriptyline may improve symptoms of anxiety, depression, and sleep disorders (e.g. insomnia) for some – it may actually have the opposite effect for others.

If amitriptyline causes new-onset psychiatric symptoms (e.g. anxiety, depression, insomnia, etc.) or worsens preexisting symptoms – this may cause LPR symptoms to both objectively and subjectively worsen.

However, even if amitriptyline doesn’t worsen reflux via induction of unwanted psychiatric symptoms – it could adversely alter: esophageal motility and/or function of the LES/UES to worsen reflux.

Additionally, common side effects associated with amitriptyline include: weight gain, constipation, and dry mouth (i.e. xerostomia) – all of which could significantly worsen LPR.

One case report suggests that antidepressant therapy could cause GERD – such that GERD symptoms emerge in lockstep with initiation of antidepressant treatment. (R)

Blocking pain perception & signaling

Amitriptyline may help desensitize nerves in the laryngopharyngeal region to pain resulting from refluxate-induced laryngeal irritation, inflammation, and damage in LPR.

Although nerve desensitization can beneficial in the context of hypersensitive esophageal disorder – it may otherwise be problematic for those with LPR.

Numbing the nerves and/or turning down the intensity of pain signals sent to the brain means that a person with LPR may be unable to detect the severity of laryngeal damage or irritation that’s occurring from LPR.

This may lead to the erroneous conclusion that LPR is healing when the reality is that pain signaling is merely blocked or “turned down” to some extent.

If the individual with LPR reverts back to bad habits such as: consuming acidic foods/drinks, binge eating, overeating calories, etc. – the damage might become more severe (and the person might not be aware of this due to the pain blocking effect of amitriptyline).

Masking allergies (?)

Amitriptyline functions as a potent antihistamine (H1 receptor antagonist) such that it may reduce allergic reactions associated with histamine release.

If you have allergies are causing or exacerbating LPR – it’s possible that the antihistamine effect of amitriptyline counteracts these allergic reactions.

This could cause partial or complete symptom remission – but some individuals may mistakenly assume that the amitriptyline is treating the LPR (when actually treating allergies).

If amitriptyline is solely treating allergies – then cessation of amitriptyline will likely cause allergies to worsen and/or flare up (along with LPR symptoms) until the offending allergens are eliminated.

For this reason, it’s probably smart to: (1) get allergy testing or trial an OTC allergy medication and/or (2) try an elimination diet – for 2-4 weeks to rule out allergy as a contributor to LPR.

Brain chemistry changes

Medications like amitriptyline can cause significant changes in neural pathways (i.e. brain connections) and the concentrations of various neurotransmitters in specific regions of the brain.

Amitriptyline significantly modulates activity within a variety of neurotransmitter systems including: histamine, serotonin, norepinephrine, and acetylcholine.

These neurotransmitter changes (i.e. “brain chemistry” adjustments) could cause changes in: perception; mood; arousal; anxiety; behavior; motivation; and cognitive function.

Some people may begin treatment with a normal mood, no anxiety, healthy cognition, and high motivation – and notice that mood becomes more depressed, anxiety level increases, cognitive function takes a hit, and motivation plummets.

These changes may affect one’s ability to navigate relationships and stay productive in academic and/or occupational settings.

Side effects

Amitriptyline can cause a variety of side effects and adverse reactions during treatment. (R)

The alpha-adrenergic blockade of amitriptyline can cause orthostatic hypotension; dizziness; sedation; heart rate variability; slow intracardiac conduction; arrhythmias; and QT prolongation.

Anticholinergic side effects such as: blurred vision; dry mouth; urinary retention; tachycardia; acute angle glaucoma; confusion; and delirium may occur.

Antihistamine side effects such as: sedation; increased appetite; weight gain; confusion; and delirium can occur.

Amitriptyline decreases seizure threshold in a dose-dependent manner – such that individuals with a seizure disorder may want to avoid this medication or use with extra caution.

Some individuals may experience changes in liver function during treatment with amitriptyline – despite the fact that actual liver injury from amitriptyline is uncommon.

Amitriptyline increases risk of bone fracture and bone marrow suppression.

Amitriptyline may increase risk of suicidal ideation and behavior – and can sometimes induce mania or hypomania.

Withdrawal

Discontinuation of amitriptyline, particularly among those who’ve used it for a long-term and/or at a high-dose can be challenging.

Why? One’s brain/CNS adapts to the neuromodulatory effects exerted by amitriptyline over time and thus becomes “tolerant” (at least partially) to its regular actions.

When amitriptyline treatment is discontinued, there’s a period of neurochemical “chaos” wherein the brain/CNS is expecting amitriptyline but the amitriptyline is never administered.

As a result, there are likely significant abnormalities or “rebound” reactions within histamine, serotonin, norepinephrine, and acetylcholine systems (production, signaling, receptor densities, etc.) – and these abnormalities can cause a variety of uncomfortable physical and mental symptoms.

These symptoms essentially last as long as it takes for one’s physiology to readjust to pre-amitriptyline “homeostasis” (i.e. neurobiological activation before amitriptyline was used) – and sometimes this adjustment period can take weeks or months.

Alternatives to amitriptyline for LPR?

Included below are some potential alternatives to LPR for the treatment of LPR or LPR-like symptoms.

Keep in mind that the efficacies of “alternatives” may differ slightly or significantly from amitriptyline based on disparities in mechanism of action.

That said, for sensory neuropathic cough – amitriptyline, desipramine, and gabapentin exhibited roughly equal effectiveness.

Other tricyclic antidepressants

Some individuals may find amitriptyline difficult to tolerate for whatever reason(s) despite finding it beneficial for LPR – and thus may want to test some alternative albeit similar medications within the tricyclic antidepressant class.

• Nortriptyline
• Desipramine
• Doxepin

Most tricyclic antidepressants exhibit relatively similar mechanisms of action, although may have slight disparities in pharmacological targets (e.g. nortriptyline can enhance noradrenergic tone more than amitriptyline).

Serotonergic antidepressants (SSRIs & SNRIs)

SSRIs & SNRIs are generally considered safer and/or more tolerable than older generations of antidepressants (e.g. tricyclics).

These medications function by inhibiting the reuptake of serotonin (SSRIs) and/or norepinephrine (SNRIs) within the brain – which significantly alters neurochemistry and brain activation.

Some individuals have found certain SSRIs/SNRIs to be effective for the treatment of LPR or LPR-like symptoms.

Although SSRIs & SNRIs haven’t been as extensively evaluated for the treatment of laryngeal conditions as tricyclic antidepressants – they might have similar efficacies and could be worth trying.

Gabapentin

Gabapentin is a medication of the “gabapentinoid” class that effectively treats neuropathic pain conditions via modulation of voltage-gated calcium channels.

Evidence suggests that gabapentin also increases serotonin and GABA – despite having no direct action on these neurotransmitter systems.

Gabapentin can turn down nerve pain signaling (if laryngeal, pharyngeal, vagal nerves are damaged) and thus could improve chronic cough secondary to neurological damage.

It’s possible that treatment of laryngopharyngeal neuropathy with gabapentin could improve LPR or LPR-like symptoms in some individuals.

It’s also possible that gabapentin could modify brain/CNS activational patterns in ways that treat LPR stemming from a functional esophageal disorder.

Low-dose antipsychotics (?)

Antipsychotics are medications that are commonly used to treat conditions like schizophrenia, psychosis, schizoaffective disorder, bipolar disorder, and refractory depression.

At high doses these medications substantially modify the neurotransmission of dopamine – and can cause serious side effects and hormonal changes (such that monitoring is necessary).

However, at low doses, certain antipsychotics like quetiapine function primarily as H1 histamine receptor blockers and alpha-1A/1B adrenergic receptor blockers – which can significantly improve sleep and reduce anxiety.

An antipsychotic called “flupentixol” combined with melitracen (a tricyclic antidepressant) seemed to significantly improve symptoms of LPR over a 1-month period – and thus there may be some rationale for trialing antipsychotics either with or without tricyclic antidepressants.

Various supplements

Talk to a medical doctor and/or pharmacist to verify that supplements are safe before using.

Below are some supplements that I believe could help treat some cases of LPR.

Note: If you have LPR occurring secondary to reflux – many drugs and/or supplements have potential to make it worse as a result of: (1) acidity; (2) effect on motility; (3) effect on esophageal sphincter function; etc. – so don’t just take random supplements.

Note: These contain affiliate links – the cost is the same regardless. Buying through the links help me support the upkeep and maintenance of this site.

Melatonin: Probably one of the safest interventions to trial for both reflux conditions (due to the fact that melatonin may improve LES function and prevent nocturnal reflux). (I’ve found that melatonin only helps my reflux if I dose at least 20 mg per night – but your mileage may vary).

Methylfolate: This is vitamin B9 and may improve methylation status in persons with specific MTHFR variants – and thus help treat neuropsychiatric disorders like depression and anxiety.

B vitamins: May improve neurological function in those with B-vitamin deficiencies. I’d probably just try a B-vitamin complex for a few weeks and determine whether any improvement is noticed. Thankfully these are not usually acidic.

Chamomile extract: Could also try chamomile tea – but extracts make it easier to confirm precise dosing. Some claim chamomile tea helps LPR. (Personally I’ve found the opposite and I think it opens the LES – but it could be worth trying).

Lavender oil: This would be mostly for individuals with high levels of anxiety. Lavender burps have potential to exacerbate LPR – but lavender oil is an effective intervention for anxiety.

Psychoplastogens: If medical doctors cannot find actual evidence of reflux (no objective signs) or another laryngeal condition (e.g. cancer, neuropathy, etc.) – odds are good that we’re dealing with a functional esophageal/laryngeal disorder.

This is not somatic – it’s a CNS/brain connectivity/activational disorder and strategic use of psychoplastogens may prove therapeutic or curative.

Will amitriptyline “cure” or improve LPR?

Depends on the specific case.

If a person has a medical condition that’s contributing to LPR such as: hiatal hernia; neurological damage; immune dysfunction; food allergy; etc. – then amitriptyline won’t “cure” LPR.

However, if all medical conditions that might cause or explain LPR symptoms have been ruled out – amitriptyline has a chance of facilitating a therapeutic effect (possibly even a curative effect).

If LPR is caused by a combination of ANS dysfunction, atypical brain connectivity, gut-brain axis dysfunction, and/or neurotransmission abnormalities – then amitriptyline is probably worth trying.

Will amitriptyline help everyone with LPR?

No. In fact, amitriptyline should be probably avoided in a subset of individuals with LPR – particularly those with a clear mechanical issue that’s contributing to LPR (e.g. large hiatal hernia).

In some cases, there’s no logical reason or strong rationale to use amitriptyline for LPR.

There are also potential downsides including side effects, worsening reflux, and exacerbation of LPR-related laryngeal damage (due to feeling improved from numb nerves and reverting back to consuming acidic foods/drinks).

Amitriptyline for LPR (Anecdotes)

Included below are anecdotes from individuals that have trialed amitriptyline or a related drug (e.g. nortriptyline) for the treatment of LPR (laryngopharyngeal reflux).

Keep in mind that – in the anecdotes below – it’s unclear as to whether: (1) LPR was formally diagnosed and/or (2) LPR diagnosis was accurate (assuming a diagnosis was made).

It’s possible that a significant percentage of individuals who respond to amitriptyline for persistent laryngeal symptoms have: nerve damage or neurological disorders; functional esophageal disorders; and/or somatic symptom disorders.

Lastly, we must consider that some of these individuals may have recovered from LPR with the passage of time – regardless of whether they used amitriptyline or did nothing.

My thoughts: This sounds like the individual was misdiagnosed with LPR but may have had LPR-like symptoms. More likely diagnosis is either a functional esophageal disorder or neuropathy.

My thoughts: This sounds like the individual was misdiagnosed with LPR and probably has a functional esophageal disorder or neuropathy (more likely the former). Hopefully the amitriptyline continues to help.

My thoughts: Individual likely had sensory neuropathic cough or psychogenic cough a.k.a. somatic cough syndrome (i.e. “habit cough).

My thoughts: Could be a neurological condition but could certainly be a functional esophageal/laryngeal disorder as well.

My thoughts: Sounds like hypersensitive esophagus (a functional esophageal disorder) but could also be laryngopharyngeal neuropathy.

My thoughts: Probably a functional esophageal disorder or a neurological complication.

My thoughts: Amitriptyline usually works relatively quickly for both neurological disorders and functional esophageal disorders – such that using it for 10 months was unnecessary.

What is the best dosage of amitriptyline for LPR?

Unknown. Most evidence suggests trialing a low dose like 10 mg – and seeing how well it’s tolerated for 2-4 weeks before making adjustments.

Evidence supports the idea that a very low dose of just 10 mg may significantly alleviate symptoms of laryngeal neuropathy.

However, some individuals may prefer to titrate the dosage upwards until within the 100-150 mg range.

Why? Because higher doses may exert stronger neuromodulatory effects and thus generate greater symptom improvement.

If dramatic symptom improvement is reported, it’s probably smart to stay on the amitriptyline for a period of several months (e.g. 3-6 months) and then gradually taper off to determine whether symptoms return.

In some cases, symptoms of LPR might not return even after amitriptyline cessation if certain brain/CNS or gut-brain axis activational patterns remain modified post-treatment.

How long does it take for amitriptyline to help LPR?

Varies among users. Some individuals report experiencing improvement in LPR or LPR-like symptoms within the first few days of treatment – even while using a low dose (e.g. 10 mg).

Others may need to take amitriptyline for several weeks before certain symptoms (e.g. globus sensation, postnasal drip, difficulty swallowing, hoarseness, etc.) improve to a noticeable extent.

Assuming amitriptyline is effective for a specific case of LPR or persistent laryngeal symptoms – most people should notice at least some degree of improvement within the first 4-8 weeks.

If no improvement is noticed within 4-8 weeks, then chances are amitriptyline and other neuromodulators aren’t going to effectively help with LPR – such that discontinuation is probably a smart move unless amitriptyline is treating another condition (e.g. depression).

My thoughts on amitriptyline for LPR: Ideal Use Cases

LPR-like symptoms without objective evidence

Amitriptyline is probably an ideal drug to try in individuals who are convinced they have LPR (i.e. LPR-like symptoms) but no objective evidence supports the diagnosis from 24-hour pH monitoring; endoscopic examination; and/or laryngoscopic examination.

Medically unexplainable LPR

Amitriptyline may be worth trying for individuals with no medically-explainable “causes” for LPR – even if they clearly have objective signs/symptoms of LPR (as it’s possible abnormal activity in the brain/CNS & ANS may be causing the condition).

No response to PPIs

Among individuals who’ve followed strict diet & lifestyle changes and tested acid-reducing agents (e.g. PPIs, H2 blockers, etc.) without any significant benefit – amitriptyline is worth a trial (as legitimate reflux conditions should at least benefit partially from reducing stomach acid).

Infection beforfe onset

Those who had an upper respiratory tract infection just prior to the onset of their LPR or LPR-like symptoms may want to try amitriptyline on the basis that they could be dealing with post-infectious vagal, laryngeal, and/or pharyngeal neuropathy.

Underlying reflux-inducing problems (avoid)

Individuals with clear underlying conditions that contribute to reflux (e.g. large hiatal hernia, obese/overweight BMI, binge eating disorder) and/or reflux-inducing habits (e.g. late-night eating) – are unlikely to benefit from amitriptyline for LPR.

Will I try amitriptyline for LPR?

I may try a neuromodulator like amitriptyline for LPR – as I have access to nortriptyline, gabapentin & pregabalin, other tricyclic antidepressants, and various serotonergic antidepressants.

That said, I’ve never had good experiences with antidepressants in the past – all either made me feel subjectively worse or zombified and caused new “symptoms” that lingered long after discontinuation.

Still, LPR is really uncomfortable and I still have no clue what may have caused it or set it into motion – and neither does my ENT (yet he insists that I have LPR) – so perhaps feeling miserable on antidepressants is worth it if it helps me recalibrate my brain/CNS in a way that “cures” LPR?

I did do a relatively short-term trial of low-dose alprazolam (once per night) and failed to notice any significant improvement in reflux symptoms despite my sleep improving.

However, alprazolam would probably be most useful in persons with somatic symptom disorders – and not necessarily in people with functional esophageal disorders.

I trialed chamomile for my LPR and found that chamomile made my reflux significantly worse (despite lowering my anxiety) – and I suspect this is due to the effect chamomile has on LES function (probably induces transient relaxations).

At night, I’ve found that administration of high-dose melatonin (20-40 mg/night) provides benefit in terms of enhancing total sleep duration and quality and nighttime reflux reduction – but it causes excessive next-day grogginess & brain fog after ~5-7 days of consistent use.

Lower dose melatonin (e.g. less than 20 mg) provided zero significant benefit in terms of reflux reduction – and this is probably because the bioavailability of melatonin is low and thus low-dose melatonin probably doesn’t alter LES function in any significant way (even if it improves sleep and/or anxiety for some).

Other supplements I’ve experimented with include (but are not limited to): 5-HTP; valerian root; glycine; magnesium threonate; magnesium glycinate; taurine; vitamin B12; vitamin B9 (methylfolate); vitamin B6; lavender oil (Silexan); lithium orotate; ashwagandha; etc.

None of these supplements had any appreciable impact on my reflux symptoms and some made my reflux worse – I assume due to transient lower esophageal sphincter (LES) relaxations, altered GI motility, and/or the acidity of the supplements themselves (pH value).

Furthermore, my ENT has told me that I definitely have LPR – and I benefitted significantly from PPIs (suggesting that stomach acid was causing or at least contributing to my symptoms).

Have you tried amitriptyline for LPR?

If you’ve trialed amitriptyline, nortriptyline, or any “neuromodulator” (including antidepressants or antipsychotics) for LPR – feel free to share a comment about your experience.

• Did it help your LPR symptoms? Or did it worsen LPR symptoms?
• If it helped LPR – how significant was the improvement? (Explain)
• How long did you use amitriptyline for LPR?
• What dosage of LPR did you use for LPR?
• Did you employ diet & lifestyle changes for LPR along with amitriptyline?
• Did you use PPIs, H2 blockers, antacids, alginates, etc. with amitriptyline?
• If you experienced benefit from amitriptyline, then stopped amitriptyline – did LPR symptoms return upon discontinuation? (If they returned were they better, worse, or the same as before amitriptyline?)