Nortriptyline

Nortriptyline is a second-generation tricyclic antidepressant (TCA) marketed as the hydrochloride salt under the trade names Sensoval, Aventyl, Pamelor, Norpress, Allegron, Noritren and Nortrilen. It is used in the treatment of major depression and childhood nocturnal enuresis (bedwetting). In addition, it is sometimes used for chronic illnesses such as chronic fatigue syndrome, chronic pain and migraine, and labile affect in some neurological conditions.

Clinical pharmacology
Nortriptyline is the active metabolite of amitriptyline that is demethylated in the liver. It inhibits the reuptake of norepinephrine (noradrenaline) and, to a lesser extent, serotonin with negligible effects on dopamine reuptake. Nortriptyline also has antagonistic effects at a variety of receptors:


 * Strong: H1
 * Moderate: 5-HT2, α1-adrenergic, mACh
 * Weak: 5-HT1

These effects account for some therapeutic actions as well as for most side effects (sedation, hypotension, anticholinergic effects, etc.). Nortriptyline may also have a sleep-improving effect due to its affinity for 5HT2A and histaminergic receptors. In the short run however, nortriptyline may disturb sleep due to its activating effect.

Like other tricyclic antidepressants, nortriptyline also blocks sodium channels, possibly accounting in part for its analgesic action.

Indications
Nortriptyline is FDA-approved for the treatment of major depression. In the United Kingdom, it may also be used for treating nocturnal enuresis, with courses of treatment lasting no more than three months. It is also used off-label for the treatment of panic disorder, irritable bowel syndrome, migraine prophylaxis and chronic pain or neuralgia modification (particularly TMJ disorder). It can also aid in quitting smoking, with one study showing a six-month abstinence rate of 14% for subjects receiving nortriptyline compared to 3% for subjects not undergoing pharmacological treatment. Research has been done suggesting it can reduce symptoms of ADHD.

Neuropathic pain
Although not approved by the FDA for neuropathic pain, a large number of randomized controlled trials have proven the efficacy of tricyclic antidepressants for the treatment of this condition in both depressed and non-depressed individuals. Recently, an evidence-based guideline sponsored by the International Association for the Study of Pain recommends nortriptyline as a first-line medication for neuropathic pain.

Metabolism
Nortriptyline is metabolised in the liver by hepatic enzyme CYP2D6. Approximately 7 to 10 percent of caucasians are poor metabolisers and might experience more adverse effects, so a lower dosage is often necessary in these individuals. Blood levels of nortriptyline should be obtained during long term treatment to avoid toxicity and optimise response.

Dosage
For depression: Low starting doses are used, increasing as necessary to 75–100 mg (0–50 mg for adolescents and the elderly). Maximum daily dosage is 150 mg.

For the management of nocturnal enuresis: lower dosages are used with the maximum period of treatment, including gradual withdrawal, being three months and a full examination including electrocardiogram (ECG or EKG) required before further courses.

For its off-label use for migraine and headache prophylaxis and treating chronic pain: Treatment is started at very low 10 mg once at night to minimise side-effects. The dose is then increased every two weeks if required to a maximum of 150 mg.

Dosage availability is 10mg, 25mg, 50mg, and 75mg capsules (Sandoz/Mallinckrodt Pharm).

Side effects
The most common side effects include dry mouth, sedation, constipation, and increased appetite. An occasional side effect is a rapid or irregular heartbeat. Alcohol may exacerbate some of its side effects and should be avoided.

However, the incidence of side effects with nortriptyline is lower than with the first-generation tricyclics (e.g., imipramine (Tofranil), amitriptyline (Elavil)).

A study with men has found that treatment with nortriptyline is associated with higher risk of suicidal ideation compared to escitalopram.

Warnings
Closer monitoring is required for those with a history of cardiovascular disease, stroke, glaucoma, and/or seizures, as well as those that have hyperthyroidism or are receiving thyroid medication.

Excessive consumption of alcohol in combination with nortriptyline therapy may have a potentiating effect, which may lead to the danger of increased suicidal attempts or overdosage, especially in patients with histories of emotional disturbances or suicidal ideation.

Contraindications
In the acute recovery phase after myocardial infarction (e.g., heart attack). As for all tricyclic antidepressants, concurrent use, or failure to allow a two week gap, with monoamine oxidase inhibitors (MAO inhibitors, e.g., phenelzine, tranylcypromine, etc.) may precipitate hyperpyretic crisis and/or severe convulsions; fatalities have occurred.

Overdose
The symptoms and the treatment of an overdose are largely the same as for the other tricyclic antidepressants.