The Many Dangers of Tricyclic Antidepressants

Tricyclic antidepressants are recommended by the CDC for chronic pain but my research shows they have a vast number of and types of side effects affecting most bodily systems.

I’m outraged that these dangerous and “dirty” (having effects on many other biological systems) drugs are being pushed on us by our government.

Straight from the CDC guideline: 

Several nonpharmacologic and nonopioid pharmacologic treatments have been shown to be effective in managing chronic pain in studies ranging in duration from 2 weeks to 6 months. For example…  

Nonopioid pharmacologic approaches used for pain include

• analgesics such as acetaminophen, NSAIDs, and cyclooxygenase 2 (COX-2) inhibitors;
• selected anticonvulsants; and
• selected antidepressants (particularly tricyclics and serotonin and norepinephrine reuptake inhibitors [SNRIs]).

Several guidelines agree that first- and second-line drugs for neuropathic pain include anticonvulsants (gabapentin or pregabalin), tricyclic antidepressants, and SNRIs

In patients with or without depression, tricyclic antidepressants and SNRIs provide effective analgesia for neuropathic pain conditions including diabetic neuropathy and post-herpetic neuralgia

It’s clear the CDC feels that these nonopioid drugs are far preferable to opioids, despite their numerous, wide ranging, and dangerous side effects.

Tricyclic antidepressant – Wikipedia

Indications

The TCAs are used primarily in the clinical treatment of mood disorders such as 

• major depressive disorder (MDD),
• dysthymia, and
• treatment-resistant variants.

They are also used in the treatment of a number of other medical disorders, including 

• anxiety disorders such as
• generalized anxiety disorder (GAD),
• social phobia (SP) also known as social anxiety disorder(SAD),
• obsessive-compulsive disorder (OCD), and
• panic disorder (PD),
• post-traumatic stress disorder (PTSD),
• body dysmorphic disorder (BDD),
• eating disorders like anorexia nervosa and bulimia nervosa,
• certain personality disorders such as borderline personality disorder (BPD),

Neurological disorders such as 

• attention-deficit hyperactivity disorder (ADHD),^[5]
• Parkinson’s disease^[6] as well as
• chronic pain,
• neuralgia or neuropathic pain, and
• fibromyalgia,
• headache, or migraine,
• smoking cessation,
• tourette syndrome,
• trichotillomania,
• irritable bowel syndrome(IBS),
• interstitial cystitis (IC),
• nocturnal enuresis (NE),^[7]
• narcolepsy,
• insomnia,
• pathological crying and/or laughing,
• chronic hiccups,
• ciguatera poisoning, and
• as an adjunct in schizophrenia.

Clinical depression

For many years the TCAs were the first choice for pharmacological treatment of clinical depression.

Although they are still considered to be highly effective, they have been increasingly replaced by antidepressants with an improved safety and side effect profile, such as the SSRIs and other newer antidepressants such as the novel reversible MAOI moclobemide.

However, tricyclic antidepressants are possibly more effective in treating melancholic depression than other antidepressant drug classes.^[8]

Newer antidepressants are thought to have fewer and less severe side effects and are also thought to be less likely to result in injury or death if used in a suicide attempt, as the doses required for clinical treatment and potentially lethaloverdose (see therapeutic index) are far wider in comparison.

Nonetheless, the TCAs are still occasionally used for treatment-resistant depression that has failed to respond to therapy with newer antidepressants.^[9] They are not considered addictive

Chronic pain

The TCAs show efficacy in the clinical treatment of a number of different types of chronic pain, notably neuralgia or neuropathic pain and fibromyalgia.^[15][16]

The precise mechanism of actionin explanation of their analgesic efficacy is unclear, but it is thought that they indirectly modulate the opioid system in the brain downstream via serotonergic and noradrenergicneuromodulation, among other properties.^[17][18][19]

They are also effective in migraine prophylaxis, though not in the instant relief of an acute migraine attack.

They may also be effective to prevent chronic tension headaches.

Pharmacology

The majority of the TCAs act primarily as serotonin-norepinephrine reuptake inhibitors (SNRIs) by blocking the serotonin transporter (SERT) and the norepinephrine transporter (NET), respectively, which results in an elevation of the synaptic concentrations of these neurotransmitters, and therefore an enhancement of neurotransmission.^[20][21]

Notably, with the sole exception of amineptine, the TCAs have negligible affinity for the dopamine transporter (DAT), and therefore have no efficacy as dopamine reuptake inhibitors (DRIs).^[20]

Both serotonin and norepinephrine have been highly implicated in depression and anxiety, and it has been shown that facilitation of their activity has beneficial effects on these mental disorders.^[22]

...they also act as potent antihistamines and anticholinergics. These properties are often beneficial in antidepressants, especially with comorbid anxiety, as it provides a sedative effect.^[33]

Most, if not all, of the TCAs also potently inhibit sodium channels and L-type calcium channels, and therefore act as sodium channel blockers and calcium channel blockers, respectively.[34][35]

The former property is responsible for the high mortality rate upon overdose seen with the TCAs via cardiotoxicity.[36] It may also be involved in their efficacy as analgesics, however.

Side effects

Many side effects may be related to the antimuscarinic properties of the TCAs.

Such side effects are relatively common and may include

• dry mouth,
• dry nose,
• blurry vision,
• lowered gastrointestinal motility or constipation,
• urinary retention,
• cognitive and/or memory impairment, and
• increased body temperature.

Other side effects may include

• drowsiness,
• anxiety,
• emotional blunting (apathy/anhedonia),
• confusion,
• restlessness,
• dizziness,
• akathisia,
• hypersensitivity,
• changes in appetite and weight,
• sweating,
• sexual dysfunction,
• muscle twitches,
• weakness,
• nausea and vomiting,
•  hypotension,
• tachycardia, and
• rarely, irregular heart rhythms.

Tolerance to these adverse effects of these drugs often develops if treatment is continued.

Side effects may also be less troublesome if treatment is initiated with low doses and then gradually increased, although this may also delay the beneficial effects.

TCAs can behave like class 1A antiarrhythmics, as such, they can theoretically terminate ventricular fibrillation, decrease cardiac contractility and increase collateral blood circulation to ischemic heart muscle.

Naturally, in overdose, they can be cardiotoxic, prolonging heart rhythms and increasing myocardial irritability.

New research has also revealed compelling evidence of a link between long-term use of anticholinergic medications likeTCAs and dementia.

Although many studies have investigated this link, this was the first study to use a long-term approach (over seven years) to find that dementias associated with anticholinergics may not be reversible even years after drug use stops.

Anticholinergic drugs block the action of acetylcholine, which transmits messages in the nervous system.

In the brain, acetylcholine is involved in learning and memory.

Discontinuation

Antidepressants in general may produce a withdrawal. 

Discontinuation symptoms can be managed by a gradual reduction in dosage over a period of weeks or months to minimise symptoms. In tricyclics, discontinuation syndrome symptoms include anxiety, insomnia, headache, nausea, malaise, or motor disturbance.

Interactions

The TCAs are highly metabolised by the cytochrome P450 hepatic enzymes.

Drugs that inhibit cytochrome P450 (for example cimetidine, methylphenidate, fluoxetine, antipsychotics, and calcium channel blockers) may produce decreases in the TCAs’ metabolism, leading to increases in their blood concentrations and accompanying toxicity.^[49]

Overdose

TCA overdose is a significant cause of fatal drug poisoning.

The severe morbidity and mortality associated with these drugs is well documented due to their cardiovascular and neurological toxicity.

Additionally, it is a serious problem in the pediatric population due to their inherent toxicity[ and the availability of these in the home when prescribed for bed-wetting and depression.

An overdose on TCA is especially fatal as it is rapidly absorbed from the GI tract in the alkaline conditions of the small intestines. As a result, toxicity often becomes apparent in the first hour after an overdose.

However, symptoms may take several hours to appear if a mixed overdose has caused delayed gastric emptying.

Many of the initial signs are those associated to the anticholinergic effects of TCAs such as dry mouth, blurred vision, urinary retention, constipation, dizziness, and emesis (or vomiting).

Due to the location of norepinephrine receptors all over the body, many physical signs are also associated with a TCA overdose:

• Anticholinergic effects: altered mental status (e.g., agitation, confusion, lethargy, etc.), resting sinus tachycardia, dry mouth, mydriasis (pupil dilation), fever
• Cardiac effects: hypertension (early and transient, should not be treated), tachycardia, orthostasis and hypotension, arrhythmias (including ventricular tachycardia and ventricular fibrillation, most serious consequence) / ECG changes (prolonged QRS, QT, and PR intervals)
• CNS effects: syncope, seizure, coma, myoclonus, hyperreflexia
• Pulmonary effects: hypoventilation resulting from CNS depression
• Gastrointestinal effects: decreased or absent bowel sounds

List of TCA’s

Those that preferentially inhibit the reuptake of serotonin (by at least 10-fold over norepinephrine) include:

• Clomipramine (Anafranil) (~200-fold selective for serotonin over norepinephrine reuptake)
• Imipramine (Tofranil, Janimine, Praminil)
• Trimipramine (Surmontil) (relatively weak serotonin reuptake inhibitor)

Those that preferentially inhibit the reuptake of norepinephrine (by at least 10-fold over serotonin) include:

• Desipramine (Norpramin, Pertofrane)
• Dibenzepin‡ (Noveril, Victoril)
• Lofepramine§ (Lomont, Gamanil)
• Nortriptyline (Pamelor, Aventyl, Norpress)
• Protriptyline (Vivactil)

Whereas fairly balanced serotonin-norepinephrine reuptake inhibitors include:

• Amitriptyline (Elavil, Endep)
• etcetera…

Here are the anticholinergic effects of these antidepressants that make the side effects so unpleasant and dangerous:

Anticholinergic – Wikipedia

Side effects

Long-term use may increase the risk of both mental and physical decline.^{[6][7][8][9][10][11]} It is unclear if they affect the risk of death generally.^[6]

However, in older adults they do appear to increase the risk of death.^[12]

Possible effects of anticholinergics include:

• Poor coordination
• Dementia^[13]
• Decreased mucus production in the nose and throat; consequent dry, sore throat
• Dry-mouth with possible acceleration of dental caries
• Stopping of sweating; consequent decreased epidermal thermal dissipation leading to warm, blotchy, or red skin
• Increased body temperature
• Pupil dilation; consequent sensitivity to bright light (photophobia)
• Loss of accommodation (loss of focusing ability, blurred vision – cycloplegia)
• Double-vision
• Increased heart rate
• Tendency to be easily startled
• Urinary retention
• Diminished bowel movement, sometimes ileus (decreases motility via the vagus nerve)
• Increased intraocular pressure; dangerous for people with narrow-angle glaucoma.

Possible effects in the central nervous system resemble those associated with delirium, and may include:

• Confusion
• Disorientation
• Agitation
• Euphoria or dysphoria
• Respiratory depression
• Memory problems^[14]
• Inability to concentrate
• Wandering thoughts; inability to sustain a train of thought
• Incoherent speech
• Irritability
• Mental confusion (brain fog)
• Wakeful myoclonic jerking
• Unusual sensitivity to sudden sounds
• Illogical thinking
• Photophobia
• Visual disturbances
  • Periodic flashes of light
  • Periodic changes in visual field
  • Visual snow
  • Restricted or “tunnel vision”
• Visual, auditory, or other sensory hallucinations
  • Warping or waving of surfaces and edges
  • Textured surfaces
  • “Dancing” lines; “spiders”, insects; form constants
  • Lifelike objects indistinguishable from reality
  • Phantom smoking
  • Hallucinated presence of people not actually there
• Rarely: seizures, coma, and death
• Orthostatic hypotension (severe drop in systolic blood pressure when standing up suddenly) and significantly increased risk of falls in the elderly population.^[15]

Older patients are at a higher risk of experiencing CNS sideffects due to lower acetylcholine production.

A common mnemonic for the main features of anticholinergic syndrome is the following:^[16]

• Blind as a bat (dilated pupils)
• Red as a beet (vasodilation/flushing)
• Hot as a hare (hyperthermia)
• Dry as a bone (dry skin)
• Mad as a hatter (hallucinations/agitation)
• Bloated as a toad (ileus, urinary retention)
• And the heart runs alone (tachycardia)

So, these are drugs that the CDC recommends instead of opioids, whose main side effects are fairly harmless, like constipation and sleepiness, plus a 2%-5% chance of triggering an addiction (that can be managed with medical care).