Amitriptyline, sold under the brand name Elavil among others, is a

tricyclic antidepressant Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and wer ...

primarily used to treat

cyclic vomiting syndrome Cyclic vomiting syndrome (CVS) is a chronic functional condition of unknown pathogenesis. CVS is characterized as recurring episodes lasting a single day to multiple weeks. Each episode is divided into four phases: inter-episodic, prodrome, vo ...

(CVS),

major depressive disorder Major depressive disorder (MDD), also known as clinical depression, is a mental disorder characterized by at least two weeks of pervasive low mood, low self-esteem, and loss of interest or pleasure in normally enjoyable activities. Intro ...

and a variety of pain syndromes from neuropathic pain to

fibromyalgia Fibromyalgia (FM) is a medical condition defined by the presence of chronic widespread pain, fatigue, waking unrefreshed, cognitive symptoms, lower abdominal pain or cramps, and depression. Other symptoms include insomnia and a general hyp ...

migraine Migraine (, ) is a common neurological disorder characterized by recurrent headaches. Typically, the associated headache affects one side of the head, is pulsating in nature, may be moderate to severe in intensity, and could last from a few hou ...

and tension headaches. Due to the frequency and prominence of side effects, amitriptyline is generally considered a second-line therapy for these indications. The most common side effects are dry mouth, drowsiness, dizziness, constipation, and weight gain. Of note is sexual dysfunction, observed primarily in males.

Glaucoma Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for aqueous humor, fluid withi ...

, liver toxicity and abnormal heart rhythms are rare but serious side effects. Blood levels of amitriptyline vary significantly from one person to another, and amitriptyline interacts with many other medications potentially aggravating its side effects. Amitriptyline was discovered in the late 1950s by scientists at Merck and approved by the US

Food and Drug Administration The United States Food and Drug Administration (FDA or US FDA) is a federal agency of the Department of Health and Human Services. The FDA is responsible for protecting and promoting public health through the control and supervision of food ...

(FDA) in 1961. It is on the

World Health Organization's List of Essential Medicines The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health s ...

. It is available as a

generic medication A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ...

. In 2020, it was the 81st most commonly prescribed medication in the United States, with more than 9million prescriptions.

Medical uses

Amitriptyline is indicated for the treatment of

and neuropathic pain and for the prevention of

and chronic

tension headache Tension headache, also known as stress headache, or tension-type headache (TTH), is the most common type of primary headache. The pain can radiate from the lower back of the head, the neck, eyes or other muscle groups in the body typically affect ...

. It can be used for the treatment of nocturnal enuresis in children older than 6 after other treatments have failed.

Depression

Amitriptyline is effective for depression, but it is rarely used as a first-line antidepressant due to its higher toxicity in overdose and generally poorer tolerability. It can be tried for depression as a second-line therapy, after the failure of other treatments. For treatment-resistant adolescent depression or for cancer-related depression amitriptyline is no better than placebo. It is sometimes used for the treatment of depression in

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a long-term degenerative disorder of the central nervous system that mainly affects the motor system. The symptoms usually emerge slowly, and as the disease worsens, non-motor symptoms beco ...

, but supporting evidence for that is lacking.

Pain

Amitriptyline alleviates painful

diabetic neuropathy Diabetic neuropathy is various types of nerve damage associated with diabetes mellitus. Symptoms depend on the site of nerve damage and can include motor changes such as weakness; sensory symptoms such as numbness, tingling, or pain; or autonomic c ...

. It is recommended by a variety of guidelines as a first or second line treatment. It is as effective for this indication as

gabapentin Gabapentin, sold under the brand name Neurontin among others, is an anticonvulsant medication primarily used to treat partial seizures and neuropathic pain. It is a first-line medication for the treatment of neuropathic pain caused by diabeti ...

pregabalin Pregabalin, sold under the brand name Lyrica among others, is an anticonvulsant, analgesic and anxiolytic medication used to treat epilepsy, neuropathic pain, fibromyalgia, restless leg syndrome, opioid withdrawal and generalized anxiety diso ...

but less well tolerated. Low doses of amitriptyline moderately improve sleep disturbances and reduce pain and fatigue associated with

. It is recommended for fibromyalgia accompanied by depression by

Association of the Scientific Medical Societies in Germany Association may refer to: *Club (organization), an association of two or more people united by a common interest or goal * Trade association, an organization founded and funded by businesses that operate in a specific industry * Voluntary associat ...

and as a second-line option for fibromyalgia, with exercise being the first line option, by

European League Against Rheumatism The European Alliance of Associations for Rheumatology (EULAR) formerly the European League Against Rheumatism is a European non-governmental organization which represents the people with arthritis/rheumatism, health professional and scientific so ...

. Combinations of amitriptyline and

fluoxetine Fluoxetine, sold under the brand names Prozac and Sarafem, among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used for the treatment of major depressive disorder, obsessive–compulsive diso ...

melatonin Melatonin is a natural product found in plants and animals. It is primarily known in animals as a hormone released by the pineal gland in the brain at night, and has long been associated with control of the sleep–wake cycle. In vertebrat ...

may reduce fibromyalgia pain better than either medication alone. There is some (low-quality) evidence that amitriptyline may reduce pain in cancer patients. It is recommended only as a second line therapy for non-chemotherapy-induced neuropathic or mixed neuropathic pain, if

opioid Opioids are substances that act on opioid receptors to produce morphine-like effects. Medically they are primarily used for pain relief, including anesthesia. Other medical uses include suppression of diarrhea, replacement therapy for opioid use ...

s did not provide the desired effect. Moderate evidence exists in favor of amitriptyline use for

atypical facial pain Atypical facial pain (AFP) is a type of chronic facial pain which does not fulfill any other diagnosis. There is no consensus as to a globally accepted definition, and there is even controversy as to whether the term should be continued to be use ...

. Amitriptyline is ineffective for HIV-associated neuropathy.

Headache

Amitriptyline is probably effective for the prevention of periodic

in adults. Amitriptyline is similar in efficacy to

venlafaxine Venlafaxine, sold under the brand name Effexor among others, is an antidepressant medication of the serotonin-norepinephrine reuptake inhibitor (SNRI) class. It is used to treat major depressive disorder, generalized anxiety disorder, panic ...

and

topiramate Topiramate, sold under the brand name Topamax among others, is a carbonic anhydrase inhibitor medication used to treat epilepsy and prevent migraines. It has also been used in alcohol dependence. For epilepsy this includes treatment for genera ...

but carries a higher burden of adverse effects than topiramate. For many patients, even very small doses of amitriptyline are helpful, which may allow for minimization of side effects. Amitriptyline is not significantly different from placebo when used for the prevention of migraine in children. Amitriptyline may reduce the frequency and duration of chronic

, but it is associated with worse adverse effects than

mirtazapine Mirtazapine, sold under the brand name Remeron amongst others, is an atypical antidepressant, and as such is used primarily to treat depression. Its effects may take up to four weeks, but can also manifest as early as one to two weeks. It is o ...

. Overall, amitriptyline is recommended for tension headache

prophylaxis Preventive healthcare, or prophylaxis, consists of measures taken for the purposes of disease prevention.Hugh R. Leavell and E. Gurney Clark as "the science and art of preventing disease, prolonging life, and promoting physical and mental hea ...

, along with lifestyle advice, which should include avoidance of analgesia and caffeine.

Other indications

Amitriptyline is effective for the treatment of

irritable bowel syndrome Irritable bowel syndrome (IBS) is a "disorder of gut-brain interaction" characterized by a group of symptoms that commonly include abdominal pain and or abdominal bloating and changes in the consistency of bowel movements. These symptoms may ...

; however, because of its side effects, it should be reserved for select patients for whom other agents do not work. There is insufficient evidence to support its use for abdominal pain in children with functional gastrointestinal disorders.

Tricyclic antidepressants Tricyclic antidepressants (TCAs) are a class of medications that are used primarily as antidepressants, which is important for the management of depression. They are second-line drugs next to SSRIs. TCAs were discovered in the early 1950s and wer ...

decrease the frequency, severity, and duration of

episodes. Amitriptyline, as the most commonly used of them, is recommended as a first-line agent for its therapy. Amitriptyline may improve pain and urgency intensity associated with bladder pain syndrome and can be used in the management of this syndrome. Amitriptyline can be used in the treatment of nocturnal enuresis in children. However, its effect is not sustained after the treatment ends. Alarm therapy gives better short- and long-term results. In the US, amitriptyline is commonly used in children with

ADHD Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by excessive amounts of inattention, hyperactivity, and impulsivity that are pervasive, impairing in multiple contexts, and otherwise age-inap ...

as an adjunct to stimulant medications without any evidence or guideline supporting this practice. Many physicians in the UK (and the US also) commonly prescribe amitriptyline for

insomnia Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...

; however,

Cochrane Cochrane may refer to: Places Australia *Cochrane railway station, Sydney, a railway station on the closed Ropes Creek railway line Canada * Cochrane, Alberta * Cochrane Lake, Alberta * Cochrane District, Ontario ** Cochrane, Ontario, a town wit ...

reviewers were not able to find any randomized controlled studies that would support or refute this practice.

Contraindications and precautions

The known contraindications of amitriptyline are: * History of

myocardial infarction A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which ma ...

* History of arrhythmias, particularly any degree of

heart block Heart block (HB) is a disorder in the heart's rhythm due to a fault in the natural pacemaker. This is caused by an obstruction – a block – in the electrical conduction system of the heart. Sometimes a disorder can be inherited. Despite the se ...

Coronary artery disease Coronary artery disease (CAD), also called coronary heart disease (CHD), ischemic heart disease (IHD), myocardial ischemia, or simply heart disease, involves the reduction of blood flow to the heart muscle due to build-up of atherosclerotic pl ...

Porphyria Porphyria is a group of liver disorders in which substances called porphyrins build up in the body, negatively affecting the skin or nervous system. The types that affect the nervous system are also known as acute porphyria, as symptoms are ...

* Severe liver disease (such as

cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, and end-stage liver disease, is the impaired liver function caused by the formation of scar tissue known as fibrosis due to damage caused by liver disease. Damage causes tissue rep ...

) * Being under six years of age * Patients who are taking

monoamine oxidase inhibitors Monoamine oxidase inhibitors (MAOIs) are a class of drugs that inhibit the activity of one or both monoamine oxidase enzymes: monoamine oxidase A (MAO-A) and monoamine oxidase B (MAO-B). They are best known as effective antidepressants, espec ...

(MAOIs) or have taken them within the last 14 days Amitriptyline should be used with caution in patients with

epilepsy Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrica ...

, impaired liver function,

pheochromocytoma Pheochromocytoma (PHEO or PCC) is a rare tumor of the adrenal medulla composed of chromaffin cells, also known as pheochromocytes. When a tumor composed of the same cells as a pheochromocytoma develops outside the adrenal gland, it is referred t ...

urinary retention Urinary retention is an inability to completely empty the bladder. Onset can be sudden or gradual. When of sudden onset, symptoms include an inability to urinate and lower abdominal pain. When of gradual onset, symptoms may include loss of bladd ...

, prostate enlargement,

hyperthyroidism Hyperthyroidism is the condition that occurs due to excessive production of thyroid hormones by the thyroid gland. Thyrotoxicosis is the condition that occurs due to excessive thyroid hormone of any cause and therefore includes hyperthyroidis ...

, and

pyloric stenosis Pyloric stenosis is a narrowing of the opening from the stomach to the first part of the small intestine (the pylorus). Symptoms include projectile vomiting without the presence of bile. This most often occurs after the baby is fed. The typical a ...

. In patients with the rare condition of shallow

anterior chamber of eyeball The anterior chamber ( AC) is the aqueous humor-filled space inside the eye between the iris and the cornea's innermost surface, the endothelium. Hyphema, anterior uveitis and glaucoma are three main pathologies in this area. In hyphema, blood f ...

and narrow

anterior chamber angle The anterior chamber angle is a part of the eye located between the cornea and iris which contains the trabecular meshwork. The size of this angle is an important determinant of the rate aqueous humour flows out of the eye, and thus, the intraocul ...

, amitriptyline may provoke attacks of acute

glaucoma Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for aqueous humor, fluid withi ...

due to dilation of the pupil. It may aggravate

psychosis Psychosis is a condition of the mind that results in difficulties determining what is real and what is not real. Symptoms may include delusions and hallucinations, among other features. Additional symptoms are incoherent speech and behavi ...

, if used for depression with

schizophrenia Schizophrenia is a mental disorder characterized by continuous or relapsing episodes of psychosis. Major symptoms include hallucinations (typically hearing voices), delusions, and disorganized thinking. Other symptoms include social w ...

, or precipitate the switch to

mania Mania, also known as manic syndrome, is a mental and behavioral disorder defined as a state of abnormally elevated arousal, affect, and energy level, or "a state of heightened overall activation with enhanced affective expression together wi ...

in those with

bipolar disorder Bipolar disorder, previously known as manic depression, is a mental disorder characterized by periods of Depression (mood), depression and periods of abnormally elevated Mood (psychology), mood that last from days to weeks each. If the elevat ...

. CYP2D6 poor metabolizers should avoid amitriptyline due to increased side effects. If it is necessary to use it, half dose is recommended. Amitriptyline can be used during pregnancy and lactation, in the cases when SSRI do not work.

Side effects

The most frequent side effects, occurring in 20% or more of users, are dry mouth, drowsiness, dizziness, constipation, and weight gain (on average 1.8 kg). Other common side effects (in 10% or more) are vision problems ( amblyopia, blurred vision),

tachycardia Tachycardia, also called tachyarrhythmia, is a heart rate that exceeds the normal resting rate. In general, a resting heart rate over 100 beats per minute is accepted as tachycardia in adults. Heart rates above the resting rate may be normal ( ...

, increased appetite, tremor, fatigue/

asthenia Weakness is a symptom of a number of different conditions. The causes are many and can be divided into conditions that have true or perceived muscle weakness. True muscle weakness is a primary symptom of a variety of skeletal muscle diseases, i ...

/feeling slowed down, and

dyspepsia Indigestion, also known as dyspepsia or upset stomach, is a condition of impaired digestion. Symptoms may include upper abdominal fullness, heartburn, nausea, belching, or upper abdominal pain. People may also experience feeling full earlier ...

. A literature review about abnormal movements and amitriptyline found that this drug is associated with various movement disorders, particularly dyskinesia, dystonia, and myoclonus. Stuttering and restless legs syndrome are some of the less common associations. A less common side effect of amitriptyline is urination problems (8.7%). Amitriptyline-associated

sexual dysfunction Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction a ...

(occurring at a frequency of 6.9%) seems to be mostly confined to males with depression and is expressed predominantly as erectile dysfunction and low

libido Libido (; colloquial: sex drive) is a person's overall sexual drive or desire for sexual activity. Libido is influenced by biological, psychological, and social factors. Biologically, the sex hormones and associated neurotransmitters that act u ...

disorder, with lesser frequency of ejaculatory and orgasmic problems. The rate of sexual dysfunction in males treated for indications other than depression and in females is not significantly different from placebo. Liver tests abnormalities occur in 10-12% of patients on amitriptyline, but are usually mild, asymptomatic and transient, with consistently elevated

alanine transaminase Alanine transaminase (ALT) is a transaminase enzyme (). It is also called alanine aminotransferase (ALT or ALAT) and was formerly called serum glutamate-pyruvate transaminase or serum glutamic-pyruvic transaminase (SGPT) and was first characte ...

in 3% of all patients. The increases of the enzymes above the 3-fold threshold of liver toxicity are uncommon, and cases of clinically apparent liver toxicity are rare; nevertheless, amitriptyline is placed in the group of antidepressants with greater risks of hepatic toxicity. Amitriptyline prolongs the QT interval. This prolongation is relatively small at therapeutic doses but becomes severe in overdose.

Overdose

The symptoms and the treatment of an overdose are largely the same as for the other TCAs, including the presentation of

serotonin syndrome Serotonin syndrome (SS) is a group of symptoms that may occur with the use of certain serotonergic medications or drugs. The degree of symptoms can range from mild to severe, including a potentiality of death. Symptoms in mild cases include high ...

and adverse cardiac effects. The

British National Formulary The ''British National Formulary'' (BNF) is a United Kingdom (UK) pharmaceutical reference book that contains a wide spectrum of information and advice on prescribing and pharmacology, along with specific facts and details about many medicine ...

notes that amitriptyline can be particularly dangerous in overdose, thus it and other TCAs are no longer recommended as first-line therapy for depression. The treatment of overdose is mostly supportive as no specific antidote for amitriptyline overdose is available. Activated charcoal may reduce absorption if given within 1–2 hours of ingestion. If the affected person is unconscious or has an impaired gag reflex, a nasogastric tube may be used to deliver the activated charcoal into the stomach. ECG monitoring for cardiac conduction abnormalities is essential and if one is found close monitoring of cardiac function is advised. Body temperature should be regulated with measures such as heating blankets if necessary. Cardiac monitoring is advised for at least five days after the overdose. Benzodiazepines are recommended to control seizures. Dialysis is of no use due to the high degree of protein binding with amitriptyline.

Interactions

Since amitriptyline and its active metabolite nortriptyline are primarily metabolized by cytochromes

CYP2D6 Cytochrome P450 2D6 (CYP2D6) is an enzyme that in humans is encoded by the ''CYP2D6'' gene. ''CYP2D6'' is primarily expressed in the liver. It is also highly expressed in areas of the central nervous system, including the substantia nigra. CYP2D ...

and

CYP2C19 Cytochrome P450 2C19 (abbreviated CYP2C19) is an enzyme protein. It is a member of the CYP2C subfamily of the cytochrome P450 mixed-function oxidase system. This subfamily includes enzymes that catalyze metabolism of xenobiotics, including some p ...

(see Amitriptyline#Pharmacology), the inhibitors of these enzymes are expected to exhibit pharmacokinetic interactions with amitriptyline. According to the prescribing information, the interaction with

inhibitors may increase the plasma level of amitriptyline. However, the results in the other literature are inconsistent: the co-administration of amitriptyline with a potent CYP2D6 inhibitor

paroxetine Paroxetine, sold under the brand names Paxil and Seroxat among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is used to treat major depressive disorder, obsessive-compulsive disorder, panic disorder ...

does increase the plasma levels of amitriptyline two-fold and of the main active metabolite nortriptyline 1.5-fold, but combination with less potent CYP2D6 inhibitors

thioridazine Thioridazine (Mellaril or Melleril) is a first generation antipsychotic drug belonging to the phenothiazine drug group and was previously widely used in the treatment of schizophrenia and psychosis. The branded product was withdrawn worldwid ...

levomepromazine Levomepromazine, also known as methotrimeprazine, is a phenothiazine neuroleptic drug. Brand names include Nozinan, Levoprome, Detenler, Hirnamin, Levotomin and Neurocil. It is a low-potency antipsychotic (approximately half as potent as chlorpr ...

does not affect the levels of amitriptyline and increases nortriptyline by about 1.5-fold; a moderate CYP2D6 inhibitor fluoxetine does not seem to have a significant effect on the levels of amitriptyline or nortriptyline. A case of clinically significant interaction with potent CYP2D6 inhibitor

terbinafine Terbinafine, sold under the brand name Lamisil among others, is an antifungal medication used to treat pityriasis versicolor, fungal nail infections, and ringworm including jock itch and athlete's foot. It is either taken by mouth or applied to ...

has been reported. A potent inhibitor of

and other cytochromes

fluvoxamine Fluvoxamine, sold under the brand name Luvox and Faverin among others, is an antidepressant of the selective serotonin reuptake inhibitor (SSRI) class. It is primarily used to treat major depressive disorder and obsessive–compulsive disorder ...

increases the level of amitriptyline two-fold while slightly decreasing the level of nortriptyline. Similar changes occur with a moderate inhibitor of CYP2C19 and other cytochromes cimetidine: amitriptyline level increases by about 70%, while nortriptyline decreases by 50%. CYP3A4 inhibitor ketoconazole elevates amitriptyline level by about a quarter. On the other hand,

cytochrome P450 Cytochromes P450 (CYPs) are a superfamily of enzymes containing heme as a cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are important for the clearance of various co ...

inducers such as

carbamazepine Carbamazepine (CBZ), sold under the trade name Tegretol among others, is an anticonvulsant medication used primarily in the treatment of epilepsy and neuropathic pain. It is used as an adjunctive treatment in schizophrenia along with other m ...

and

St. John's Wort ''Hypericum perforatum'', known as St. John's wort, is a flowering plant in the family Hypericaceae and the type species of the genus ''Hypericum''. Possibly a hybrid between ''Hypericum maculatum, H. maculatum'' and ''Hypericum attenuatum, H. ...

decrease the levels of both amitriptyline and nortriptyline Oral contraceptives may increase the blood level of amitriptyline by as high as 90%. Valproate moderately increases the levels of amitriptyline and nortriptyline through an unclear mechanism. The prescribing information warns that the combination of amitriptyline with monoamine oxidase inhibitors may cause potentially lethal

; however, this has been disputed. The prescribing information cautions that some patients may experience a large increase in amitriptyline concentration in the presence of topiramate. However, other literature states that there is little or no interaction: in a pharmacokinetic study topiramate only increased the level of amitriptyline by 20% and nortriptyline by 33%. Amitriptiline counteracts the antihypertensive action of guanethidine. When given with amitriptyline, other

anticholinergic Anticholinergics (anticholinergic agents) are substances that block the action of the neurotransmitter called acetylcholine (ACh) at synapses in the central and peripheral nervous system. These agents inhibit the parasympathetic nervous sys ...

agents may result in

hyperpyrexia Fever, also referred to as pyrexia, is defined as having a temperature above the normal range due to an increase in the body's temperature set point. There is not a single agreed-upon upper limit for normal temperature with sources using val ...

paralytic ileus Ileus is a disruption of the normal propulsive ability of the intestine. It can be caused by lack of peristalsis or by mechanical obstruction. The word 'ileus' is from Ancient Greek ''eileós'' (, "intestinal obstruction"). The term 'subileus' r ...

. Co-administration of amitriptyline and

disulfiram Disulfiram is a medication used to support the treatment of chronic alcoholism by producing an acute sensitivity to ethanol (drinking alcohol). Disulfiram works by inhibiting the enzyme acetaldehyde dehydrogenase, causing many of the effects of ...

is not recommended due to the potential for the development of toxic delirium. Amitriptyline causes an unusual type of interaction with the anticoagulant phenprocoumon during which great fluctuations of the

prothrombin time The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the ''extrinsic'' pathway and common pathway of coagulation. This blood test is als ...

have been observed.

Pharmacology

Pharmacodynamics

Amitriptyline inhibits

serotonin transporter The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein tha ...

(SERT) and

norepinephrine transporter The norepinephrine transporter (NET), also known as noradrenaline transporter (NAT), is a protein that in humans is encoded by the solute carrier family 6 member 2 (SLC6A2) gene. NET is a monoamine transporter and is responsible for the sodium- ...

(NET). It is metabolized to

nortriptyline Nortriptyline, sold under the brand name Pamelor, among others, is a medication used to treat depression. This medicine is used for: neuropathic pain, attention deficit hyperactivity disorder (ADHD), smoking cessation and anxiety. As with many a ...

, a stronger

norepinephrine reuptake inhibitor A norepinephrine reuptake inhibitor (NRI, NERI) or noradrenaline reuptake inhibitor or adrenergic reuptake inhibitor (ARI), is a type of drug that acts as a reuptake inhibitor for the neurotransmitters norepinephrine (noradrenaline) and epin ...

, further augmenting amitriptyline's effects on norepinephrine reuptake (see the Table on the right). Amitriptyline additionally acts as a potent inhibitor of the serotonin 5-HT_2A, 5-HT_2C, the α_1A-adrenergic, the

histamine Histamine is an organic nitrogenous compound involved in local immune responses, as well as regulating physiological functions in the gut and acting as a neurotransmitter for the brain, spinal cord, and uterus. Since histamine was discovered ...

H₁ and the M₁-M₅

muscarinic acetylcholine receptor Muscarinic acetylcholine receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled receptor complexes in the cell membranes of certain neurons and other cells. They play several roles, including acting as the main end-rec ...

s (see the Table on the right). Amitriptyline is a non-selective blocker of multiple ion channels, in particular,

voltage-gated sodium channel Sodium channels are integral membrane proteins that form ion channels, conducting sodium ions (Na+) through a cell's membrane. They belong to the superfamily of cation channels and can be classified according to the trigger that opens the channel ...

s Na_v1.3, Na_v1.5, Na_v1.6, Na_v1.7, and Na_v1.8, voltage-gated potassium channels K_v7.2/ K_v7.3, K_v7.1, K_v7.1/

KCNE1 Potassium voltage-gated channel subfamily E member 1 is a protein that in humans is encoded by the ''KCNE1'' gene. Voltage-gated potassium channels (Kv) represent the most complex class of voltage-gated ion channels from both functional and struc ...

, and

hERG hERG (the human '' Ether-à-go-go''-Related Gene) is a gene () that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel (sometimes simply denoted as 'hERG') is best known for its contribution to th ...

Mechanism of action

Inhibition of serotonin and norepinephrine transporters by amitriptyline results in interference with neuronal reuptake of serotonin and

norepinephrine Norepinephrine (NE), also called noradrenaline (NA) or noradrenalin, is an organic chemical in the catecholamine family that functions in the brain and body as both a hormone and neurotransmitter. The name "noradrenaline" (from Latin '' ad' ...

. Since the reuptake process is important physiologically in terminating transmitting activity, this action may potentiate or prolong activity of serotonergic and adrenergic neurons and is believed to underlie the antidepressant activity of amitriptyline. Inhibition of norepinephrine reuptake leading to increased concentration of norepinephrine in the posterior grey column of the spinal cord appears to be mostly responsible for the analgesic action of amitriptyline. Increased level of norepinephrine increases the basal activity of

alpha-2 adrenergic receptor The alpha-2 (α2) adrenergic receptor (or adrenoceptor) is a G protein-coupled receptor (GPCR) associated with the Gi heterotrimeric G-protein. It consists of three highly homologous subtypes, including α2A-, α2B-, and α2C-adrenergic. Some ...

s, which mediate an analgesic effect by increasing gamma-aminobutyric acid transmission among

spinal interneuron A spinal interneuron, found in the spinal cord, relays signals between (afferent) sensory neurons, and (efferent) motor neurons. Different classes of spinal interneurons are involved in the process of sensory-motor integration. Most interneuron ...

s. The blocking effect of amitriptyline on sodium channels may also contribute to its efficacy in pain conditions.

Pharmacokinetics

Amitriptyline is readily absorbed from the gastrointestinal tract (90–95%). Absorption is gradual with the peak concentration in blood plasma reached after about 4 hours. Extensive metabolism on the first pass through the liver leads to average

bioavailability In pharmacology, bioavailability is a subcategory of absorption and is the fraction (%) of an administered drug that reaches the systemic circulation. By definition, when a medication is administered intravenously, its bioavailability is 100%. Ho ...

of about 50% (45%-53%). Amitriptyline is metabolized mostly by

into

and by

leading to a variety of hydroxylated metabolites, with the principal one among them being (''E'')-10-hydroxynortriptyline (see metabolism scheme), and to a lesser degree, by CYP3A4. Amitriptyline metabolism

Nortriptyline Nortriptyline, sold under the brand name Pamelor, among others, is a medication used to treat depression. This medicine is used for: neuropathic pain, attention deficit hyperactivity disorder (ADHD), smoking cessation and anxiety. As with many a ...

, the main active metabolite of amitriptyline, is an antidepressant on its own right. Nortriptyline reaches 10% higher level in the

blood plasma Blood plasma is a light amber-colored liquid component of blood in which blood cells are absent, but contains proteins and other constituents of whole blood in suspension. It makes up about 55% of the body's total blood volume. It is the intr ...

than the parent drug amitriptyline and 40% greater

area under the curve In mathematics, an integral assigns numbers to functions in a way that describes displacement, area, volume, and other concepts that arise by combining infinitesimal data. The process of finding integrals is called integration. Along with ...

, and its action is an important part of the overall action of amitriptyline. Another active metabolite is (''E'')-10-hydroxynortriptyline, which is a norepinephrine uptake inhibitor four times weaker than nortriptyline. (''E'')-10-hydroxynortiptyline blood level is comparable to that of nortriptyline, but its

cerebrospinal fluid Cerebrospinal fluid (CSF) is a clear, colorless body fluid found within the tissue that surrounds the brain and spinal cord of all vertebrates. CSF is produced by specialised ependymal cells in the choroid plexus of the ventricles of the ...

level, which is a close proxy of the brain concentration of a drug, is twice higher than nortriptyline's. Based on this, (''E'')-10-hydroxynortriptyline was suggested to significantly contribute to antidepressant effects of amitriptyline. Blood levels of amitriptyline and nortriptyline and pharmacokinetics of amitriptyline in general, with clearance difference of up to 10-fold, vary widely between individuals. Variability of the area under the curve in steady state is also high, which makes a slow upward

titration Titration (also known as titrimetry and volumetric analysis) is a common laboratory method of quantitative chemical analysis to determine the concentration of an identified analyte (a substance to be analyzed). A reagent, termed the ''titrant'' ...

of the dose necessary. In the blood, amitriptyline is 96% bound to plasma proteins; nortriptyline is 93–95% bound, and (''E'')-10-hydroxynortiptyline is about 60% bound. Amitriptyline has an elimination half life of 21 hours, nortriptyline - 23–31 hours, and (''E'')-10-hydroxynortiptyline - 8–10 hours. Within 48 hours, 12-80% of amitriptyline is eliminated in the urine, mostly as metabolites. 2% of the unchanged drug is excreted in the urine. Elimination in the feces, apparently, have not been studied. Therapeutic levels of amitriptyline range from 75 to 175 ng/mL (270–631 nM), or 80–250 ng/mL of both amitriptyline and its metabolite nortriptyline.

Pharmacogenetics

Since amitriptyline is primarily metabolized by CYP2D6 and CYP2C19, genetic variations within the genes coding for these enzymes can affect its metabolism, leading to changes in the concentrations of the drug in the body. Increased concentrations of amitriptyline may increase the risk for side effects, including anticholinergic and nervous system adverse effects, while decreased concentrations may reduce the drug's efficacy. Individuals can be categorized into different types of CYP2D6 or CYP2C19 metabolizers depending on which genetic variations they carry. These metabolizer types include poor, intermediate, extensive, and ultrarapid metabolizers. Most individuals (about 77–92%) are extensive metabolizers, and have "normal" metabolism of amitriptyline. Poor and intermediate metabolizers have reduced metabolism of the drug as compared to extensive metabolizers; patients with these metabolizer types may have an increased probability of experiencing side effects. Ultrarapid metabolizers use amitriptyline much faster than extensive metabolizers; patients with this metabolizer type may have a greater chance of experiencing pharmacological failure. The Clinical Pharmacogenetics Implementation Consortium recommends avoiding amitriptyline in patients who are CYP2D6 ultrarapid or poor metabolizers, due to the risk for a lack of efficacy and side effects, respectively. The consortium also recommends considering an alternative drug not metabolized by CYP2C19 in patients who are CYP2C19 ultrarapid metabolizers. A reduction in starting dose is recommended for patients who are CYP2D6 intermediate metabolizers and CYP2C19 poor metabolizers. If use of amitriptyline is warranted, therapeutic drug monitoring is recommended to guide dose adjustments. The Dutch Pharmacogenetics Working Group also recommends selecting an alternative drug or monitoring plasma concentrations of amitriptyline in patients who are

poor or ultrarapid metabolizers, and selecting an alternative drug or reducing initial dose in patients who are

intermediate metabolizers.

Chemistry

Amitriptyline is a highly lipophilic molecule having an

octanol-water partition coefficient The ''n''-octanol-water partition coefficient, ''K''ow is a partition coefficient for the two-phase system consisting of ''n''-octanol and water. ''K''ow is also frequently referred to by the symbol P, especially in the English literature. It is a ...

(pH 7.4) of 3.0, while the log P of the free base was reported as 4.92. Solubility of the free base amitriptyline in water is 14 mg/L. Amitriptyline is prepared by reacting dibenzosuberone with 3-(dimethylamino)propylmagnesium chloride and then heating the resulting intermediate product with

hydrochloric acid Hydrochloric acid, also known as muriatic acid, is an aqueous solution of hydrogen chloride. It is a colorless solution with a distinctive pungent smell. It is classified as a strong acid Acid strength is the tendency of an acid, symbol ...

to eliminate water.

History

Amitriptyline was first developed by the American pharmaceutical company Merck in the late 1950s. In 1958, Merck approached a number of clinical investigators proposing to conduct clinical trials of amitriptyline for schizophrenia. One of these researchers, Frank Ayd, instead, suggested using amitriptyline for depression. Ayd treated 130 patients and, in 1960, reported that amitriptyline had antidepressant properties similar to another, and the only known at the time, tricyclic antidepressant imipramine. Following this, the US

approved amitriptyline for depression in 1961. In Europe, due to a quirk of the patent law at the time allowing patents only on the chemical synthesis but not on the drug itself,

Roche F. Hoffmann-La Roche AG, commonly known as Roche, is a Swiss multinational healthcare company that operates worldwide under two divisions: Pharmaceuticals and Diagnostics. Its holding company, Roche Holding AG, has shares listed on the SIX ...

and

Lundbeck H. Lundbeck A/S (commonly known simply as Lundbeck) is a Danish international pharmaceutical company engaged in the research, development, manufacturing, marketing and sale of pharmaceuticals across the world. The company’s products are targe ...

were able to independently develop and market amitriptyline in the early 1960s. According to research by the historian of psychopharmacology David Healy, amitriptyline became a much bigger selling drug than its precursor imipramine because of two factors. First, amitriptyline has much stronger anxiolytic effect. Second, Merck conducted a marketing campaign raising clinicians' awareness of depression as a clinical entity.

Society and culture

English folk singer Nick Drake died from an overdose of Tryptizol in 1974. Senteni Masango, wife of Swaziland King Mswati, died on 6 April 2018 after committing suicide by overdosing on amytriptyline capsules. In the 2021 film ''

The Many Saints of Newark ''The Many Saints of Newark'' (marketed with the subtitle ''A Sopranos Story'') is a 2021 American crime drama film directed by Alan Taylor and written by David Chase and Lawrence Konner. A prequel to Chase's HBO crime drama series ''The So ...

'', amitriptyline (referred to by the brand name Elavil) is part of the plot line of the movie.

Generic names

''Amitriptyline'' is the English and French generic name of the drug and its , , and , while ''amitriptyline hydrochloride'' is its , , , and . Its generic name in Spanish and Italian and its are , in German is , and in

Latin Latin (, or , ) is a classical language belonging to the Italic branch of the Indo-European languages. Latin was originally a dialect spoken in the lower Tiber area (then known as Latium) around present-day Rome, but through the power of the ...

is . The embonate salt is known as ''amitriptyline embonate'', which is its BANM, or as ''amitriptyline pamoate'' unofficially.

Prescription trends

Between 1998 and 2017, along with imipramine, amitriptyline was the most commonly prescribed first antidepressant for children aged 5-11 years in England. It was also the most prescribed antidepressant (along with

) for 12 to 17 year olds.

Research

The few randomized controlled trials investigating amitriptyline efficacy in eating disorder have been discouraging.

References

External links

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