Tricyclic Antidepressants for Anxiety and Chronic Pain

A pharmacist explains their benefits and risks.

Medically reviewed by Erika Prouty, PharmD

Depression is a common but serious mental health condition that can significantly decrease quality of life and productivity.

Scientists still don't know exactly what causes depression. Some factors that contribute to it include:

• Having family members with depression

• Trauma or stress, including childhood abuse

• Medical conditions like chronic pain, stroke, or cancer

• Alcohol, drugs, and some prescription medications

Tricyclic antidepressants (TCAs) were introduced in the late 1950s. They remain an option for people with depression because they are very effective. However, they are typically not a first-line treatment (initial treatment choice).

The following article covers the uses of TCAs and safety considerations to keep in mind if you take them.

What to Do If You're Feeling Depressed or Anxious

If you or a loved one is struggling with depression, contact the Substance Abuse and Mental Health Services Administration (SAMHSA) National Helpline at 800-662-4357 for information on support and treatment facilities in your area.

If you are having suicidal thoughts, dial 988 to contact the 988 Suicide & Crisis Lifeline and connect with a trained counselor. If you or a loved one are in immediate danger, call 911.

For more mental health resources, see our National Helpline Database.

What Are Tricyclic Antidepressants?

As their name implies, TCAs are medications that contain three rings and a side chain.

They work by increasing levels of serotonin and norepinephrine, chemical messengers in the body that help regulate mood. Low levels of these neurotransmitters are associated with depression.

Beyond anxiety and depression, TCAs are used off-label--meaning they've been proven to help but have not been approved by the Food and Drug Administration (FDA)-- to treat the following conditions:

• Neuropathic pain

• Migraine

• Gastrointestinal syndromes

• Fibromyalgia

• Pelvic pain

• Abdominal pain

• Insomnia

• Obsessive-compulsive disorder (OCD)

• Panic disorder

• Posttraumatic stress disorder (PTSD)

• Bulimia nervosa

TCAs available on the market include the following medications and recommended dosages for depression:

• Elavil (amitriptyline): 25 to 200 milligrams (mg) daily

• Pamelor (nortriptyline): 25 to 150 mg daily

• Tofranil (imipramine): 50 to 200 mg daily

• Norpramin (desipramine): 100 to 300 mg daily

• Anafranil (clomipramine): 25 to 250 mg daily for Obsessive-Compulsive Disorder (OCD)

Keep in mind that TCAs are often dosed lower for other conditions than they are for severe depression. These lower dosages are effective and carry a lower risk of side effects.

How Do Tricyclic Antidepressants Work?

TCAs inhibit serotonin and norepinephrine reuptake in the brain. This means that TCAs increase the levels of these chemical messengers in the brain to counteract depression symptoms.

In addition, TCAs have analgesic effects. They reduce nerve pain by increasing norepinephrine levels in the spinal cord.

It takes about two to four weeks for symptoms of depression to improve after starting a TCA, but beneficial effects on chronic pain may be seen within just a few days.

TCAs combat depression and pain in a similar way to a newer class of antidepressants known as serotonin-norepinephrine reuptake inhibitors (SNRIs). Prescription SNRIs include Effexor (venlafaxine) and Cymbalta (duloxetine). Like TCAs, SNRIs increase the levels of both serotonin and norepinephrine. TCAs and SNRIs are helpful for chronic pain, as well as symptoms of depression such as:

• Low energy

• Anhedonia (lack of pleasure)

• Cognitive decline

The other major class of antidepressants prescribed is selective serotonin reuptake inhibitors (SSRIs), which increase levels of serotonin only. SSRIs do not treat chronic pain. They are most effective for symptoms of depression like:

• Agitation

• Anxiety

• Insomnia

• Decreased appetite

TCAs work about as well for depression as newer antidepressants like SSRIs and SNRIs. But while each of these classes have some serious side effects to be aware of, TCAs are considered more dangerous in an overdose.

When Do You Use Tricyclic Antidepressants?

The use of TCAs has decreased since the discovery of other classes of antidepressants beginning in the 1980's. TCAs are still used to treat major depressive disorder (MDD), though typically only if other classes like SSRIs and SNRIs haven't worked.

TCAs are generally not used for mild depression, but they may be helpful for severe cases. Symptoms of severe depression can include:

• Hopelessness

• Psychosis

• Catatonia (not communicating or moving)

• Suicidal ideation, though keep in mind that TCAs should be used with caution as overdoses are dangerous and may cause death

Two TCAs, Tofranil (imipramine) and Anafranil (clomipramine), are also used off-label for anxiety disorders like generalized anxiety disorder (GAD). Although they're effective, side effects limit their use. For this reason, TCAs are generally only used if other medications like SSRIs or SNRIs haven't worked.

TCAs are very effective against neuropathic (nerve) pain, which is a component of many conditions including:

• Diabetic neuropathy

• Multiple sclerosis

• Spinal cord injury

• Shingles

Many of the studies of TCAs for nerve pain have used Elavil (amitriptyline) 25 to 150 mg per day.

The TCA Anafranil (clomipromene) was the first medicine approved by the FDA for OCD in the 1980's. Today, it is considered second-line after trying an SSRI.

Research shows that TCAs are also effective for symptoms of fibromyalgia including fatigue, quality of sleep, and muscle stiffness. Again, they are typically not prescribed first-line but may be recommended if other medicines haven't helped.

Lastly, low-dose TCAs are used for other chronic pain conditions including:

• Irritable bowel syndrome

• Pelvic pain

• Lower back pain

About 3 of every 4 antidepressants prescribed for chronic pain are TCAs. But interestingly, a recent review of the research found only low-quality evidence to support using TCAs for chronic pain conditions.

Side Effects and Risks

As a whole, antidepressant medications are known to cause side effects that range from mild to serious.

Some clinical trials have shown that SSRIs and SNRIs are safer than TCAs from a side effect standpoint. But other research suggests that all of these classes have a similar safety profile, meaning the risk of significant side effects is about the same.

Potential side effects associated with the use of TCAs include:

• Anticholinergic effects like dry mouth, constipation, and blurred vision. These occur because TCAs block histamine and acetylcholine receptors in the body.

• Cardiovascular effects, including orthostatic hypotension (dizziness when standing up) and tachycardia (fast heart rate).

• Sedation and cognitive impairment.

• Seizures, especially at high doses.

• Weight gain.

• Sexual dysfunction, which is common when using any antidepressant.

Various strategies can be used to manage and mitigate these side effects. If you are experiencing side effects from a TCA, consult your healthcare provider or pharmacist. Consider the following tips as well:

• For drowsiness, try taking your medicine at night instead of the morning, gradually increasing exercise, or practicing sleep hygiene.

• For constipation, add fiber to your diet or increase fluids. Over-the-counter (OTC) laxatives like MiraLAX or stool softeners like Colace (docusate) may also be helpful.

• For sexual dysfunction, ask your healthcare provider if it's safe for you to use a lower dose or take a short drug holiday (a few days without the medication). Prescription medicines like Viagra (sildenafil) can help with erectile dysfunction if this is a concern.

Precautions

There are some important considerations to keep in mind when prescribing or taking tricyclic antidepressants.

TCAs are contraindicated for the following groups (meaning they shouldn't be taken):

• Older people. Side effects of TCAs may worsen dementia, urinary retention, or glaucoma in this population.

• Pregnant women. Though it's rare, babies can be born with TCA withdrawal symptoms like irritability, seizures, or heart problems.

• People with some cardiovascular diseases, such as heart conduction abnormalities or arrhythmias (abnormal heart rhythm).

• People with epilepsy. TCAs can lower the seizure threshold and make it more likely that seizures will occur.

• People at risk of suicide. Overdosing on TCAs is very dangerous and can be fatal.

TCAs have potential drug interactions with other medications, including:

• Monoamine oxidase inhibitors (MAOIs), another class of antidepressants. Taking these medications together can cause serotonin syndrome and hypertensive crisis, a sudden high blood pressure that can lead to organ damage. This combination could also cause seizures or death.

• Other anticholinergic medicines, like antihistamines, antipsychotics, and some medicines for Parkinson's disease. Taking these with TCAs increases the likelihood of anticholinergic side effects.

• SSRIs, SNRIs, pain medications like tramadol and opioids, and dietary supplement St. John's wort. These medicines all increase serotonin levels and can cause serotonin syndrome, especially if two or more of them are taken together. Symptoms of serotonin syndrome or toxicity include high heart rate, sweating, and agitation.

• Other sedating medications, including alcohol. The effects of alcohol can be increased if taken with TCAs.

If you are prescribed a TCA, your healthcare provider may recommend therapeutic drug monitoring to make sure the levels of medicine in your body are appropriate, especially when you are starting treatment or if you're changing doses.

If you take high doses of TCAs (above the recommended amounts) discuss with your healthcare provider whether you need electrocardiogram monitoring (EKG) to monitor for heart abnormalities.

Be sure to discuss treatment safety and effectiveness at follow-up appointments, or with your pharmacist.

Summary

TCAs have been used to treat depression since the 1950s. They remain a treatment option but are not usually prescribed first-line due to potentially dangerous side effects and the risk of death that's associated with an overdose.

If you are prescribed TCAs for depression, anxiety, or another condition, keep in mind that these medications can cause side effects. Common ones are constipation, weight gain, and sedation. More serious ones include seizures and heart problems.

In general, older people and those with heart disease or epilepsy should not take TCAs. These drugs may also be dangerous during pregnancy.

Because there are many options for the treatment of depression and chronic pain, be sure to discuss your symptoms and goals with your healthcare provider to optimize your therapy. If TCAs aren't for you, there are many other medications that may help.

Read the original article on Verywell Health.