Amitriptyline, once marketed under the trade name Elavil, but now only available as a generic drug, is an tricyclic antidepressant medication widely used to treat clinical depression and certain types of neuropathic pain.1
Tricyclics were first introduced in the 1950s and 1960s as one of the earlier classes of antidepressant medications.1 More recently, other classes of medications, such as selective serotonin reuptake inhibitors (e.g., Prozac, Zoloft, etc.) and atypical depressants (e.g., Effexor, Cymbalta, Wellbutrin, etc.) have, to some extent, supplanted the use of tricyclics and other earlier-generation agents for the treatment of depression. The preference by many prescribing physicians today is to use SSRIs or atypical antidepressants as first-line treatments, as these drugs have fewer side effects than tricyclics like amitriptyline.2 However, the tricyclic antidepressants remain similarly effective as some newer drugs in their overall ability to reduce the symptoms of MDD, and they continue to be used for a number of off-label purposes such as migraine prophylaxis and management of chronic pain states.1
Mechanism of Action of Amitriptyline
Amitriptyline’s therapeutic properties stem from its ability to inhibit the reuptake of several different neurotransmitters in the brain, particularly norepinephrine and serotonin.3
When the drug blocks the reuptake of the neurotransmitter, it doesn’t allow neurons in the brain to reabsorb the neurotransmitter once it has been released. This means that more of these neurotransmitters are available in the brain and spinal cord. Early theories of depression developed the idea that the cause of clinical depression was a lack of certain neurotransmitters in the brain, and it is believed that drugs like amitriptyline relieve the symptoms of MDD by allowing the brain to have more of these neurotransmitters available. However, despite this hypothesis, the specific mechanism of action for most of these drugs has not been definitively confirmed.4
Although it is Food and Drug Administration (FDA) approved for the treatment of clinical depression, the drug is also used by physicians for several other medical reasons, including:1
- The treatment of chronic pain.
- To assist in the treatment of fibromyalgia.
- As a treatment for migraine headache.
- As a treatment for nocturnal bedwetting in children.
Though tricyclic antidepressants aren’t as frequently utilized as primary approaches to the treatment of MDD, they still may be used for this purpose. Certain individuals may have better success with drugs like amitriptyline than they do with newer antidepressants.
Withdrawal from Amitriptyline
The abuse liability of amitriptyline and many other antidepressants is extremely low. Some people mistakenly believe that since these drugs are used to treat severe depression, they might elicit euphoria in high doses or in individuals who are not depressed. This is not the case.
Antidepressants do not work by producing the opposite effects of depression (e.g., mania, extreme happiness, etc.). Instead, they are believed to be instrumental in restoring a neurochemical balance to the brain that helps people to better manage MDD. Taking large amounts of amitriptyline will not make you extremely happy, euphoric, giddy, etc. In fact, taking large doses of amitriptyline may be more likely to result in certain pathological cardiac changes and other signs of toxicity and overdose.3
Even when used therapeutically for prolonged periods of time, abrupt discontinuation of amitriptyline may be associated with certain withdrawal symptoms.3 The withdrawal syndrome associated with amitriptyline and other antidepressant medications is not always referred to as antidepressant withdrawal, as one may expect; instead, it is more commonly referred to as antidepressant discontinuation syndrome (ADS).5
The risk of developing ADS as a result of using amitriptyline may be increased for individuals who:
- Have used amitriptyline on a continual basis for six weeks or longer, with the risk increasing the longer the drug is taken.
- Are prescribed relatively high doses of the drug.
- Suddenly stop using amitriptyline without the aid of a tapering schedule.5
Other factors, such as individual differences in metabolism, emotional makeup, etc., can influence whether or not a person develops ADS.5 The withdrawal symptoms associated with discontinuing antidepressant medications are relatively rare compared to other types of prescription medications for which pronounced physiological dependence may develop (e.g., benzodiazepines like Valium or opioid drugs like OxyContin).
Overall, it appears that approximately 20 percent of people who have been using antidepressant medications for more than eight weeks and suddenly stop using the medication develop some symptoms of withdrawal, and most of these symptoms are very mild. Reliable figures for withdrawal associated specifically with the use of amitriptyline are not available.6 The symptom profile associated with ADS can be quite variable. Some people will display very mild symptoms; others may display numerous symptoms or just one or two serious symptoms.6
Symptoms that have been reported in individuals who are believed to be undergoing withdrawal associated with discontinuing amitriptyline include:6
- Dizziness and headaches.
- Other physical symptoms, such as nausea, vomiting, appetite loss, diarrhea, muscle aches, aching joints, fever, chills, and sweating.
- Psychological symptoms, such as appetite loss, an increase in anxiety, irritability, fatigue, insomnia, problems with concentration, restlessness, issues with memory, hypersensitivity to environmental stimulation such as lights or sound, and crying spells (mood swings).
- More serious psychological symptoms, including feelings of depersonalization (feeling as if one is not real), severe depression, panic attacks, and even suicidality (very rare).
- Feeling as if one has the flu during withdrawal (e.g., headaches, fatigue, nausea, etc.).
In some cases, individuals who experience hallucinations during withdrawal, which is very rare, may be experiencing a more severe manifestation of some other mental health condition, such as bipolar disorder or psychotic disorder.6
It is known that antidepressant medications that affect the neurotransmitter serotonin, such as amitriptyline, are more likely to be associated with ADS if a person is abruptly taken off the drug after using it for more than 6-8 weeks. The general pattern of withdrawal from amitriptyline could be expected to progress according to the timeline below, though there may be quite a bit of individual variability involved.6
Withdrawal symptoms will typically last 1-3 weeks overall:6
- Symptoms will most often peak within three days to one week and then begin to decline, although this can be quite variable.
- The majority of cases appear to be very mild, are associated with very little discomfort, and most often resolve rather quickly.
- The majority of individuals undergoing withdrawal from amitriptyline describe it as feeling as if they have a cold or the flu.
- If a person begins to develop severe psychological symptoms, such as anxiety and depression, it may be a sign that the individual’s MDD is returning and further treatment is needed.
- The symptoms of withdrawal will most resolve very quickly (most often within 24 hours) if the person begins taking amitriptyline again.
How Is the Withdrawal Syndrome Managed?
Withdrawal from amitriptyline is not considered to be significantly dangerous unless the person begins to feel suicidal or has hallucinations as a result of some other disorder. Anyone who is undergoing any withdrawal syndrome may have issues with concentration, judgment, and memory that may lead to functional issues that could potentially be dangerous. In addition, individuals who experience vomiting and diarrhea may be at risk for dehydration, which can lead to significant health issues. Anyone who has been taking amitriptyline and wishes to discontinue the drug should only do so under the guidance of a physician.6
The standard procedure to address any potential withdrawal symptoms associated with discontinuing amitriptyline is for the physician to place the patient on a tapering schedule over the course of several weeks. This tapering schedule is performed under the supervision and monitoring of the physician.6
The physician begins with the dose of the drug that results in the patient not experiencing any withdrawal symptoms. Then, at specified intervals, the physician attempts to slowly reduce the dosage. The patient’s responses are monitored, and the physician ensures that the patient does not experience any significant withdrawal symptoms at this lower dosage. This process continues until the person can be weaned off of amitriptyline.
In some cases, physicians may use other medications to treat specific symptoms, such as headaches, nausea, etc.; however, there is no specific medication designed to address withdrawal from amitriptyline currently. Since the withdrawal process is mild for most individuals, use of a tapering approach appears to be sufficient in nearly every case.6
- Amitriptyline | Drugbank. https://www.drugbank.ca/drugs/DB00321. Accessed June 22, 2019.
- Ferguson JM. SSRI Antidepressant Medications: Adverse Effects and Tolerability. Prim Care Companion J Clin Psychiatry. 2001;3(1):22-27.
- Elavil (Amitriptyline): Side Effects, Interactions, Warning, Dosage, Uses. https://www.rxlist.com/elavil-drug.htm#medguide. Accessed June 18, 2019.
- U.S. National Library of Medicine. Amitriptyline Compound Summary.
- Haddad PM, Anderson IM. Recognising and managing antidepressant discontinuation symptoms. Adv Psychiatr Treat. 2007;13(6):447-457.
- Warner CH, Bobo W, Warner CM, Reid S, Rachal J. Antidepressant Discontinuation Syndrome. Vol 74. American Academy of Family Physicians; 2006. https://www.aafp.org/afp/2006/0801/p449.html. Accessed June 24, 2019.