Imipramine is a tricyclic antidepressant, the first to be synthesized and to undergo clinical testing. It was widely marketed as “Tofranil.” Imipramine is available in tablets of the following dosages: 75, 100, 125, or 150 mg.

Imipramine carries the same black box warning as amitriptyline and nortriptyline [Imipramine]. It requires special monitoring for clinical worsening, suicidality, and behavior changes that are unusual. The proposed mechanism of action against depression is through the blockage of norepinephrine reuptake. The FDA has approved imipramine for the treatment of the symptoms of depression. It is noted that treatment effects may not be apparent for 1–3 weeks.

The absolute contraindications, as for the other tricyclics, include acute myocardial ischemia and recovery from such, current or recent use of MAO inhibitors, and hypersensitivity to the medication.

The package insert for imipramine notes the necessity for EKG screening prior to administering larger than usual doses of the medication. Although it has been recommended that a screening EKG be obtained prior to TCA treatment for all patients over age 40 [5], a recent study suggests that patients without known cardiovascular history in fact have a lower risk for MI during treatment with tricyclic antidepressants [6]. Clinical judgment is clearly appropriate. Abrupt cessation of the medication should be avoided as headache, nausea, and malaise may ensue.

Imipramine is less potent than the other tricyclic antidepressants, and the recommended starting dose is 75 mg daily, with lower starting doses recommended for older adults and those younger. The medication is not recommended for use in children [Imipramine].

Imipramine was among the earliest antidepressants to demonstrate efficacy against neuropathic pain [7]. It has been shown in repeated clinical studies to have good efficacy against the symptoms of diabetic neuropathy; however, side effects may interfere with successful management [8, 9]. A recent Cochrane Database Review indicates that imipramine is efficacious against neuropathic pain with a NNT of 2.2 [10]. Among the earliest references to imipramine in the treatment of pain is the efficacy of amitriptyline and imipramine in the treatment of tension headache [11]. Amitriptyline was superior to all other therapies attempted in this early study.

Desipramine is a tricyclic antidepressant and a metabolite of imipramine. It is available in tablets of 10, 25, 50, 75, 100, or 150 mg dosage. Widely marketed as “Norpramin,” it should not be confused with nortriptyline.

Relative to amitriptyline, desipramine is a more potent as a relative inhibitor of norepinephrine reuptake, compared with inhibition of serotonin reuptake. Relative to imipramine, it is noted that the onset of treatment effects with desipramine is more rapid and benefits may be observed as soon as 2–5 days following the initiation of treatment [Desipramine]. An additional potential benefit of desipramine is that it is relatively nonsedating and is well tolerated when taken twice daily. Thus, in those patients for whom pain is a more constant feature of their daily routine, desipramine may be an excellent choice. There are those patients who are very busy with work demands and for whom the residual sedating effects of amitriptyline, which may persist even with nighttime administration, preclude successful dose titration for pain relief. In these patients also, desipramine may represent a useful alternative. It was shown in one high-quality study to have efficacy against PHN, and it is observed to work well with gabapentin in clinical practice.

Desipramine is metabolized in the liver but largely excreted in the urine. There is a wide range in serum levels among individuals receiving the same dose. Serum levels are generally higher with fixed doses in the elderly, consistent with decreased renal function. Cimetidine impedes metabolism and raises serum levels, whereas tobacco, barbiturates, and alcohol resulted in induced metabolic losses. It is recommended that caution be exercised in considering coadministration of SSRIs with desipramine as metabolic interactions will result in increased concentrations of desipramine.

TCAs have idiosyncratic metabolism, and serum levels can vary widely potentially accounting for variations in clinical responses. Metabolism is markedly decreased in a small but significant percentage of patients. Partially due to a polymorphism in CYP2D6 metabolizing protein transcripts, variants result in higher than anticipated serum drug levels [12].

The contraindications for desipramine are similar to those for other tricyclics that are discussed here and include MAO inhibitor administration, recent myocardial ischemia, and allergy to the medication.

The black box warning for the tricyclic antidepressants pertains also to desipramine. Patients should be monitored during therapy, and caregivers should receive appropriate instructions regarding behavioral changes and the need to contact health providers with concerns.

“Extreme caution” is urged in considering use of this medication in those with cardiovascular disease, a family history of sudden death, difficulty with urination, glaucoma, thyroid disease, or seizure disorder. It is established that desipramine can lower the seizure threshold.

The usual adult dosage is noted as 100–200 mg daily with recommendations not to exceed 300 mg daily. The starting dose should be lower than the usual dosage. Dosage adjustment for adolescents and geriatric patients includes recommendations for doses of 25–100 mg daily.

Although desipramine does not carry FDA approval for the treatment of any pain condition, it has been investigated for such in clinical trials and may be used at the discretion of the prescribing physician. In 1990, desipramine was described as effective against pain in patients with postherpetic neuralgia. In this randomized, double-blind crossover trial, the average desipramine dose was 167 mg daily. Compared with placebo, desipramine provided significant pain relief beginning at week 3 of the active treatment [13]. A study of desipramine for the treatment of painful diabetic neuropathy found that somewhat higher doses were prescribed following titration (201 mg daily) and that significant pain relief was demonstrable following week 5 of the treatment period [14]. Comparison with amitriptyline and fluoxetine demonstrated that amitriptyline and desipramine were both efficacious in relieving the pain of diabetic neuropathy while fluoxetine was not significantly different from placebo. The mean titrated dose of desipramine was 111 mg daily which compared to 105 for amitriptyline [15]. Recent Cochrane Database Review indicates that desipramine is efficacious against neuropathic pain with a NNT of 2.6 [10]. The use of TCAs for acute pain management is not common practice; however, in a trial of preemptive analgesia for pain following dental surgery, desipramine was effective in reducing opioid requirements [1]. Other applications for acute or subacute pain have not been extensively studied.

Amitriptyline was approved by the FDA for the relief of symptoms of depression in 1961 and widely prescribed as “Elavil.” It is metabolized to nortriptyline, another “pain-active” antidepressant described below. Although amitriptyline is not FDA approved for indications other than depression, it is used for a variety of conditions including diabetic neuropathy, fibromyalgia, migraine prophylaxis, neuropathic pain, postherpetic neuralgia, and tension headache [11].

Amitriptyline has multiple mechanisms of action that may be important for notable activity against neuropathic pain. These include both central (noradrenergic) and peripheral (sodium channel blocking) mechanisms.

Nortriptyline is a tricyclic antidepressant, widely prescribed as “Pamelor.” It is a metabolite of amitriptyline but is relatively less sedating. Nortriptyline is FDA approved for the relief of symptoms of depression [Nortriptyline]. It has multiple potential mechanisms of action but clearly “interferes with the transport, release, and storage of catecholamines” [Nortriptyline]. According to the package insert, preclinical trials of nortriptyline indicated that it has both “stimulant and depressant properties.”

Nortriptyline carries the same black box warning as amitriptyline and imipramine. It requires special monitoring for clinical worsening, suicidality, and behavior changes that are unusual. The absolute contraindications, as for the other tricyclics, include acute myocardial ischemia and recovery from such, current or recent use of MAO inhibitors, and hypersensitivity to the medication. It has been written that nortriptyline carries significant cardiovascular dangers [5], but the study that supports this compared nortriptyline to a SSRI that was not pain-active, in patients who were post-MI and who were depressed. Relative to the SSRI used for the treatment of depression, nortriptyline did produce an increase in average heart rate (eight beats per minute) and did result in more patients discontinuing therapy for cardiac-related side effects (sinus tachycardia and ventricular ectopy) [16]. In follow-up studies of this effect, it was shown that these effects of nortriptyline relate to the vagolytic activity of nortriptyline relative to paroxetine [17], an aspect of this medication that may have a significant relationship to its mechanism of action against pain. There is little evidence to support the notion that nortriptyline is more pronounced in this effect than other pain-active antidepressants. One point of interest is that in recent preclinical studies screening a large compound library for efficacy against hypoxic injury, nortriptyline has in fact shown a neuroprotective effect in models of cerebral ischemia [18].

Caveats aside, nortriptyline is an important medication option in the management of persistent pain. For many pain specialists, it is the tricyclic of choice. In a clinical trial of postherpetic neuralgia, nortriptyline and desipramine showed similar efficacy to morphine [19]. In diabetic and postherpetic neuralgia, nortriptyline has been shown to be at least as effective as gabapentin in the treatment of these disorders [20]. It is accompanied by dry mouth in the majority of patients, but nortriptyline in combination with gabapentin provided additional incremental pain relief [20].

Amitriptyline and other tricyclic antidepressants (nortriptyline, desipramine) are contraindicated for concomitant prescription with MAO inhibitors. MAO inhibitors block the metabolism of catecholamines, and in concert with agents which block the reuptake of amines from the synaptic cleft can produce a life-threatening syndrome of elevated temperature and seizures. It is recommended that tricyclics should not be started sooner than 14 days after discontinuation of MAO inhibitors [Amitriptyline]. Amitriptyline and the tricyclic antidepressants are also contraindicated during the acute recovery phase following myocardial ischemia. One of the important side effects of tricyclic antidepressants and a serious problem in the setting of medication overdose is the prolongation of the Q-T interval. TCAs should be avoided in patients with conduction defects such as AV block [5]. Patients with hypersensitivity to amitriptyline or other tricyclic antidepressants should not receive this drug [Amitriptyline].