Amitriptyline is approved for the treatment of depression but is used off-label for a number of conditions, including insomnia, pain, and irritable bowel syndrome (IBS). However, it also causes many side effects that turn people away, such as sleepiness, weight gain, and impaired immune and sexual function. Learn about the potential uses of this drug and the side effects.
What Is Amitriptyline?
Amitriptyline is a tricyclic antidepressant. It is otherwise known as Elavil or Endep [1, 2].
The tricyclic simply means that it contains three rings in its chemical structure [1].
This drug was at one point the most widely used antidepressant. In England, it was prescribed over 11 million times in 2013 [3, 1].
While amitriptyline is only FDA-approved for the treatment of depression, it is sometimes used off-label for several other conditions, such as migraines, fibromyalgia, and irritable bowel syndrome [4].
Amitriptyline is converted to nortriptyline in the body, which is its active form. This drug works via many mechanisms hence the many benefits and side effects [5, 6].
Mechanism of Action
- It blocks the reuptake of both serotonin and noradrenaline. Therefore, both serotonin and noradrenaline stay in your system longer, which prolongs their effects [1].
- It blocks the action of histamine in the brain, which results in drowsiness [7].
- It blocks NMDA receptors and activates adenosine A1 and opioid receptors. All of these may lead to pain relief [8, 9].
Uses of Amitriptyline
FDA-Approved Uses
1) Depression
Amitriptyline is only FDA-approved for the treatment of depression.
According to a number of clinical trials, amitriptyline may be more effective at improving depression symptoms compared to many other antidepressants. However, the frequency of side effects often limits its use [10].
Two large meta-analyses of 186 and 194 studies compared amitriptyline against other tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs). Both found that amitriptyline helped more people. However, it also produced more side effects than the other drugs [11, 12].
More people who were taking amitriptyline dropped out of the studies due to side effects compared to people taking other drugs [12].
With this drug, the antidepressant effects take a long time to take effect. Often, patients see improvements in other areas such as in insomnia or pain before noticing any antidepressant effects [13].
Off-Label Uses
Amitriptyline is used for several off-label conditions, which we’ll discuss in the following sections. If you are prescribed amitriptyline, always take the medication as directed by your doctor.
2) Migraines
A meta-analysis (12 studies, 1,006 participants) found that amitriptyline helped with migraines much better than placebo. The effects were better for those that took the drug for longer periods of time [4].
However, it causes more side effects than other drugs used to treat migraines, such as selective serotonin reuptake inhibitors (SSRIs), selective norepinephrine reuptake inhibitors (SNRIs), or nortriptyline [4, 14].
Also, research suggests that amitriptyline may not help children with migraines [15, 16].
3) Neuropathic Pain
Amitriptyline is sometimes used for neuropathic pain, which is caused by damage to nerve tissue.
According to a meta-analysis (17 studies, 1,342 participants), amitriptyline may improve chronic neuropathic pain, but it was only effective in about 25% of people. It may help people with pain due to diabetes, shingles, spinal cord injury, or stroke [1].
However, many studies concluded that this drug was not any better for pain than other pain relievers/antidepressants such as nortriptyline, maprotiline, desipramine, pregabalin, or fluoxetine [17, 18, 19, 20].
4) Irritable Bowel Syndrome (IBS)
There are three types of IBS: IBS with diarrhea (IBS-D), IBS with constipation, and mixed-stool pattern IBS. Tricyclic antidepressants work best against IBS-D [21].
Tricyclic antidepressants like amitriptyline increase the time that food stays in the gut, which allows for more solid defecations [21].
In 101 IBS patients given this drug, IBS improved in 66% of cases. The treatment decreased stomach pain, stomach discomfort, and stool frequency and improved the quality of life. However, side effects were frequent [21].
In a study (double-blind randomized controlled trial) of 54 patients, amitriptyline increased rates of full recovery (no more symptoms) [22].
A different study (double-blind randomized controlled trial) of 32 adolescents (12-18 years) showed similar results [23].
A meta-analysis and other studies all showed that this drug improved IBS [22, 24, 25].
5) Fibromyalgia
Fibromyalgia is a continuous pain in “tender points” lasting over three months. It can lead to sleep loss, fatigue, and depression [26].
A meta-analysis (9 studies, 649 patients) showed that amitriptyline was effective for fibromyalgia in 36% of patients [26].
In two studies (double-blind randomized controlled trial) with 22 and 62 fibromyalgia patients, this drug improved sleep and decreased fatigue [27, 28].
However, one study (double-blind randomized controlled trial) found that it actually worsened fibromyalgia in 4 of the 19 patients [29].
5) Sleep Issues and Insomnia
In a study (double-blind randomized controlled trial) of 27 opiate withdrawal patients suffering from insomnia, amitriptyline induced sleep equally well as another hypnotic drug, lorazepam. However, amitriptyline caused less drowsiness after waking. This may allow patients to go about their mornings without feeling sluggish [30].
Amitriptyline increased total sleep by 15 minutes in a study (double-blind randomized controlled trial) of 14 patients. They also fell asleep faster. The study noted increases in slow-wave sleep, or deep sleep, which is when muscles recover and you re-energize. A week after going off of the drug, patients reported it was harder to fall asleep [3].
This drug may also reduce rapid eye movement (REM) sleep, according to a double-blind randomized controlled trial of 30 patients. REM sleep can be abnormally long in patients with depression [31, 32, 33].
6) Anxiety
Amitriptyline decreased anxiety in a study (double-blind randomized controlled trial) of 55 patients awaiting surgery [34].
In a pilot study of 32 patients with anxiety and depression, this drug was effective in reducing anxiety [35].
Similarly, in two other studies, both with 30 patients, it reduced anxiety in insomnia patients [36, 37].
Anxiety is also common in people with migraines. Reducing the frequency of migraines with amitriptyline may help reduce anxiety as well [38, 39].
Although useful for anxiety, it has a high dropout rate (30 to 50%) due to side effects. Patients tend to prefer selective serotonin reuptake inhibitors (SSRIs) and only move to tricyclic antidepressants when SSRIs fail [40].
Research On Amitriptyline
Clinical Research
Clinical research is also exploring the use of amitriptyline for several other conditions, which are described below. However, this research is preliminary and investigational only. The safety and effectiveness of amitriptyline for these conditions is unclear until more studies are performed.
Functional Dyspepsia
Functional dyspepsia, more commonly known as indigestion, is a disorder that causes pain in the upper stomach, discomfort, and fullness after meals. Fifty-one of the 96 patients with functional dyspepsia improved when given amitriptyline in a double-blind randomized controlled trial [41].
In another double-blind randomized controlled trial of 28 volunteers, amitriptyline increased gut transit time, which may be important for gut function and better digestion. Amitriptyline may also make it easier to drink large volumes of water without problems, which may be important for people suffering from diarrhea [42].
Cystic Fibrosis Symptoms
According to a double-blind randomized controlled trial of 19 patients, amitriptyline may improve cystic fibrosis symptoms. It may also decrease levels of ceramides that tend to accumulate in the lungs of cystic fibrosis patients [43].
Another double-blind randomized controlled trial of 19 patients showed similar results [44].
Autism
According to a study of 50 children with autism, amitriptyline may improve symptoms of [45]:
- Excessive activity
- Impulsivity
- Aggression
- Self-injury
Chronic Cough
A randomized controlled study of 28 people found that amitriptyline may be more effective in suppressing chronic cough than the cough-suppressant drug codeine/guaifenesin. In total, 14 of the 15 patients on amitriptyline saw some improvement. In fact, 11 of the 15 patients improved by 75 to 100% [46].
Vocal Cord Dysfunction
In a study of 62 patients with vocal cord dysfunction, amitriptyline improved symptoms in 90% of cases. People that have had the condition for less than 12 months showed greater and quicker results [47].
Cyclic Vomiting Syndrome
Cyclic vomiting syndrome is a disorder leading to constant nausea and vomiting. In a double-blind randomized controlled trial of 64 children, 66% of patients given amitriptyline saw temporary recovery [48].
Animal And Cell Research
No clinical evidence supports the use of amitriptyline for any of the conditions listed in this section. Below is a summary of the existing animal and cell-based research, which should guide further investigational efforts. However, the studies listed below should not be interpreted as supportive of any health benefit.
Parkinson’s Disease
In rat models of Parkinson’s disease, amitriptyline decreased the loss of dopamine-sensitive neurons. It also protected neurons with tyrosine hydroxylase activity, which are decreased in patients with Parkinson’s disease [49, 50].
The drug also increased dopamine levels and improved movement in rats with Parkinson’s-like disease [51].
Inflammation
In cell studies, amitriptyline decreased the release of inflammatory agents from mast cells by up to 98% [52, 53].
In rats, this drug also decreased levels of nitric oxide, IL1-beta, and TNF-alpha, which all increase inflammation [54, 55].
Amitriptyline decreased gut and kidney inflammation in rats [56, 57].
Brain Health and Repair
In rat studies, amitriptyline increased BDNF in rats with Alzheimer’s disease, which increased both their short and long-term memory [58].
Similarly, amitriptyline increased GDNF levels in brain cells. Increasing GDNF may improve neuron survival and protect neurons against stress [59, 60].
In cell studies, amitriptyline increased the production of brain-derived neurotrophic factor (BDNF) in brain cells (astrocytes and microglia). BDNF protects neurons and stimulates their growth. Increased BDNF is a potential mechanism by which amitriptyline produces antidepressant effects [61].
Cognitive Function
Amitriptyline improved cognitive function and decreased stress (HPA axis activity) in aged rats [62].
It slightly improved cognitive function in depressed rats [63].
The drug also improved cognitive function in rats with Alzheimer’s disease and in stressed baby rats [58, 64].
Stress
In rats, amitriptyline decreased the functioning of the hypothalamic-pituitary-adrenal (HPA) axis, which reacts to stress by releasing adrenocorticotropic (ACTH) hormone. Amitriptyline decreased stress-induced ACTH levels by 38% [65].
The HPA system also increases levels of corticosterone in response to stress. Rats stressed by separating them from their mothers saw no such increase when given amitriptyline [66].
Stomach Ulcers
In rats, amitriptyline reduced stomach ulcers caused by [67]:
- Alcohol
- Aspirin
- Indomethacin (an anti-inflammatory drug)
- Stress
The drug reduced the acidity of the stomach [67].
Another rat study found that this drug also decreased gut bleeding [68].
Histamine Regulation
Amitriptyline enhanced histamine-N-methyltransferase (HNMT) and diamine oxidase (DAO) activity in guinea pigs. Both of these enzymes degrade histamine [69].
This drug also caused mast cells to release less histamine, a potent allergy-inducing molecule [70].
Polycystic Ovary Syndrome (PCOS)
According to animal studies, amitriptyline improved the function of ovaries, increased the production of sex hormones (estradiol, testosterone, and progesterone), and restored the reproductive cycle of rats with polycystic ovaries [71].
Safety of Amitriptyline
Side Effects
Side effects can be common when taking amitriptyline. If any side effects persist or worsen, let your doctor know. This is also not a complete list of possible side effects. Tell your doctor if you experience any serious side effects or notice any effects not listed here.
Some common side effects are [72]:
- Dry mouth
- Drowsiness
- Weight gain
- Dizziness
- Constipation
- Difficulty urinating
- Blurred vision
Some rare, but serious side effects include [72]:
- Increased agitation
- Severe stomach pain
- Decreased sexual desire
- Muscle spasms
- Rashes
- Nightmares
- Confusion
- Delirium
- Seizures
- Irregular heartbeats
- Bruising and bleeding
Precautions
1) Increased Risk of Suicide
Antidepressants are associated with a higher risk of suicidal thinking and behavior, especially in children and young adults. Those taking amitriptyline should be monitored and any changes in behavior should be reported to a doctor [72].
2) Withdrawal Symptoms
There is a high risk of experiencing adverse events or withdrawal symptoms after abruptly discontinuing amitriptyline therapy, in as little as 12 hours. Consult with your doctor before stopping this medication [72].
Withdrawing from amitriptyline may cause [73]:
- Gut distress
- Pain
- Fatigue
- Sleep disturbances
- Mood changes
- Movement disorders
3) Drowsiness
Taking amitriptyline may cause drowsiness, dizziness, and blurred vision. Do not operate a vehicle or heavy machinery until you know how this medication may affect you [72].
4) Caution in Pregnancy and Breastfeeding
Some research suggests that amitriptyline may be associated with birth defects, although strong clinical evidence is lacking. Amitriptyline should only be used during pregnancy if a doctor determines that the benefits outweigh risks [72].
Small amounts of amitriptyline are excreted in breast milk. Again, a doctor will decide if amitriptyline can be used during breastfeeding [74].
If you are taking amitriptyline and are pregnant or planning to become pregnant, let your doctor know.
5) Risk of Bleeding
Amitriptyline may increase the risk of bleeding. Tell your doctor that you are taking amitriptyline before having any kind of surgery.
Contraindications
Hypersensitivity
People who are sensitive or allergic to amitriptyline or any other excipients (substances that are present in the medication along with the drug) should avoid using amitriptyline.
Concomitant Use with Monoamine Oxidase Inhibitors (MAOIs)
The concomitant use of amitriptyline with monoamine oxidase inhibitors (another type of antidepressant) is contraindicated. The combination of both medications may result in dangerously high blood pressure, convulsions, and even death [72].
MAOI treatment should not be started until after at least 7 days after discontinuing amitriptyline.
Amitriptyline treatment should not be started within 14 days of discontinuing treatment with MAOIs.
Drug Interactions
Amitriptyline inhibits cytochrome P450 enzymes (CYP1A2, CYP2D6, and CYP2C9) at higher rates than other TCAs such as desipramine and nortriptyline. This causes more side effects and worse drug interactions [14].
Below are some reported drug interactions with amitriptyline. This is not a comprehensive list, always let your doctor know about all the medications and supplements you are taking [72].
- MAO inhibitors, such as isocarboxazid, linezolid, phenelzine, selegiline
- Antipsychotics, such as quetiapine (Seroquel) and chlorpromazine (Largactil, Thorazine) [75, 76]
- Antifungals such as terbinafine (Lamisil) and fluconazole (Diflucan) [77, 78, 79]
- Valproic acid (Depakote) [80]
- Rifampicin (Rifadin, Rimactane), an antibiotic [81]
- Phenprocoumon (Marcoumar), a drug that keeps blood from clumping [82]
- NSAIDs, such as ibuprofen
- Warfarin
- Cimetidine
- Amiodarone
- Quinidine
- Sotalol
Amitriptyline Dosing
Patients will respond to antidepressants differently and it may take time to find the right dose for you. Antidepressants like amitriptyline may take time to work and patients may not feel benefits for 1-3 weeks or more. Always take amitriptyline as directed by a doctor and do not discontinue the medication abruptly.
Amitriptyline is available in various forms and dosages. Amitriptyline is most commonly taken as an oral tablet.
When starting this medication, dosages are typically started low and gradually increased.
For depression in adults, the initial dose of amitriptyline is usually 75 mg per day which may be taken in divided doses [72].
The maintenance dose usually ranges from 40 to 100 mg per day. The maximum dose is 150 mg per day.
Amitriptyline is not approved for patients under 12 years old.
Amitriptyline Compared to Other Medications
Nortriptyline
Research suggests that both are equally effective in relieving pain, headaches, and migraines. However, amitriptyline may have more side effects [5, 1, 14].
Benzodiazepines
Studies suggest that amitriptyline may have better antidepressive effects than adinazolam (Deracyn), a benzodiazepine. However, it also caused more side effects [83].
Amitriptyline may also be more effective than diazepam (Valium) [83].
Both amitriptyline and Xanax (alprazolam) drugs were effective against depression in 80 patients in a double-blind randomized controlled trial. Amitriptyline worked faster, but also caused more people to drop out of the study, even though the overall side effects were similar between the two drugs [84].
Another study (double-blind randomized controlled trial) of 130 patients found that Xanax was the quicker of the two and may be better for anxiety [85].
Selective Serotonin Reuptake Inhibitors (SSRIs)
In a study (double-blind randomized controlled trial) with 148 patients, paroxetine (Paxil, Pexeva) was better in relieving pain, improving quality of life, sleep, and emotional well-being [86].
Both drugs were effective in treating depression in a study (double-blind randomized controlled trial) of 40 patients. However, paroxetine produced a quicker response. Side effects were similar [87].
Opioids
A study (double-blind randomized controlled trial) of 45 patients found that tramadol (Ultram) and meperidine (Pethidine), stopped shivering quicker than amitriptyline. The response rate for amitriptyline was only 13% compared to 87% for tramadol and 93% for meperidine [88].
When used as an anesthetic, amitriptyline was more sedative than meperidine and produced fewer side effects [89].
Genetics
CYP2D6
CYP2D6 ultrarapid metabolizers may need to avoid the use of tricyclic antidepressants due to the potential lack of effectiveness (the drug gets degraded too quickly) [90].
For CYP2D6 intermediate metabolizers, a 25% reduction of the starting dose is recommended [90].
CYP2D6 poor metabolizers have higher than expected blood concentrations of tricyclic antidepressants when given usual doses. If the use of amitriptyline is warranted, it is recommended to take 50% of the starting dose to avoid side effects [90].
In a pilot study of 31 patients, patients with normal or ultrarapid metabolism of amitriptyline (CYP2D6) displayed fewer side effects [91].
However, a study of 100 patients with major depressive order found that those with CYP2D6 ultrarapid metabolism were more likely to drop out from the study when drug doses were low. This was most likely due to a lack of effect [92].
CYP2C19
CYP2C19 ultrarapid metabolizers may need to avoid the use of this drug due to reduced effectiveness [90].
CYP2C19 poor metabolizers, should avoid the drug or consider a 50% reduction of the starting dose while monitoring drug blood levels to avoid side effects [90].
