tofranil
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Synonyms | |||
Imipramine hydrochloride, marketed under the brand name Tofranil, represents one of the foundational tricyclic antidepressants (TCAs) that fundamentally reshaped psychiatric practice beginning in the late 1950s. Before the era of SSRIs, this medication was among the few pharmacological options for managing major depressive episodes. Its mechanism, primarily through potent inhibition of norepinephrine and serotonin reuptake, provided the first real biochemical model for understanding mood disorders. While contemporary practice often favors newer agents due to side effect profiles, Tofranil maintains specific niches in treatment-resistant depression, childhood enuresis, and certain neuropathic pain conditions. Its extensive documentation in clinical literature spanning six decades offers a robust evidence base that newer medications are still accumulating.
1. Introduction: What is Tofranil? Its Role in Modern Medicine
Tofranil (imipramine hydrochloride) is a tricyclic antidepressant belonging to the dibenzazepine class. Originally developed in the 1950s, it was the first TCA to demonstrate significant antidepressant efficacy in controlled trials. While its use has declined with the advent of selective serotonin reuptake inhibitors (SSRIs) and other newer antidepressants, Tofranil remains a valuable therapeutic option in specific clinical scenarios. The medication is approved for the treatment of major depressive disorder in adults and nocturnal enuresis (bedwetting) in children aged 6 years and older. Off-label applications include panic disorder, neuropathic pain syndromes, and attention-deficit/hyperactivity disorder (ADHD). Understanding what Tofranil is used for requires appreciating its unique receptor binding profile, which differs substantially from modern antidepressants and explains both its enduring utility and its challenging side effect spectrum.
2. Key Components and Pharmaceutical Properties
The active pharmaceutical ingredient in Tofranil is imipramine hydrochloride. Chemically designated as 5-(3-Dimethylaminopropyl)-10,11-dihydro-5H-dibenz[b,f]azepine monohydrochloride, this compound has a molecular weight of 316.88. The hydrochloride salt form enhances the stability and aqueous solubility of the base compound. Tofranil is available in several formulations including 10mg, 25mg, and 50mg tablets, with the 25mg tablet being the most commonly prescribed strength for initial titration. The bioavailability of Tofranil after oral administration is approximately 40-60% due to significant first-pass metabolism in the liver. The medication is highly lipophilic, facilitating rapid distribution across the blood-brain barrier. The pharmacokinetic profile shows peak plasma concentrations within 1-2 hours post-administration, with an elimination half-life ranging from 11-25 hours, supporting once-daily dosing in maintenance therapy.
3. Mechanism of Action: Scientific Substantiation
The mechanism of action of Tofranil centers on its potent inhibition of presynaptic norepinephrine and serotonin transporters. Unlike SSRIs that selectively target serotonin, Tofranil exerts balanced reuptake inhibition of both monoamines, with approximately 3-fold greater potency for norepinephrine transporters compared to serotonin transporters. This dual mechanism increases synaptic concentrations of these neurotransmitters, enhancing neurotransmission in brain regions regulating mood, arousal, and motivation. Additionally, Tofranil demonstrates significant antagonism at muscarinic M1, histamine H1, and alpha-1 adrenergic receptors, which directly explains its anticholinergic, sedative, and orthostatic hypotensive effects respectively. The therapeutic antidepressant effects are believed to develop through downstream adaptations including beta-adrenergic receptor downregulation and enhanced serotonergic neurotransmission, which typically require 2-4 weeks of consistent dosing to manifest clinically.
4. Indications for Use: What is Tofranil Effective For?
Tofranil for Major Depressive Disorder
Tofranil demonstrates well-established efficacy in treating major depressive episodes, with numerous controlled trials showing superiority over placebo. Response rates typically range from 60-70% in moderate to severe depression. The medication appears particularly effective for depression with melancholic features, characterized by profound anhedonia, psychomotor disturbances, and vegetative symptoms.
Tofranil for Nocturnal Enuresis
In pediatric populations, Tofranil at lower doses (25-75mg nightly) produces complete cessation of bedwetting in approximately 30-50% of children and significant improvement in another 20-30%. The antienuretic effect is thought to involve both anticholinergic-mediated reduction in bladder contractility and alteration of sleep architecture, though the exact mechanism remains incompletely understood.
Tofranil for Neuropathic Pain
Multiple randomized controlled trials support Tofranil’s efficacy in various neuropathic pain conditions, including diabetic neuropathy, postherpetic neuralgia, and central pain states. Doses for pain management (typically 50-150mg daily) are generally lower than those required for antidepressant effects, with analgesia often apparent within one week of treatment.
Tofranil for Panic Disorder
Despite not being FDA-approved for this indication, Tofranil was among the first medications systematically studied for panic disorder and demonstrates efficacy comparable to modern antidepressants in blocking spontaneous panic attacks and reducing phobic avoidance.
5. Instructions for Use: Dosage and Administration
Dosing of Tofranil must be individualized based on indication, patient age, and tolerability. The following table provides general guidance:
| Indication | Initial Dose | Therapeutic Range | Administration | Duration |
|---|---|---|---|---|
| Adult Depression | 25mg TID or 75mg HS | 75-200mg daily | With food to minimize GI upset | 6-12 months after symptom remission |
| Geriatric Depression | 10mg HS | 30-100mg daily | Bedtime dosing preferred | Individualized based on response |
| Childhood Enuresis (≥6 years) | 25mg HS | 25-75mg daily | 1 hour before bedtime | 3-6 month trials with drug-free periods |
| Neuropathic Pain | 10-25mg HS | 50-150mg daily | Evening administration | Chronic management as needed |
Dose titration should proceed gradually, with increases of 25-50mg every 3-7 days as tolerated. Abrupt discontinuation should be avoided; tapering over 2-4 weeks is recommended to prevent withdrawal symptoms.
6. Contraindications and Drug Interactions
Tofranil is contraindicated in patients with known hypersensitivity to tricyclic antidepressants, during the acute recovery phase following myocardial infarction, and in conjunction with monoamine oxidase inhibitors (MAOIs) due to risk of serotonin syndrome. Concomitant use with MAOIs requires a 14-day washout period. Additional contraindications include severe liver disease, untreated narrow-angle glaucoma, and urinary retention.
Significant drug interactions with Tofranil include:
- Anticholinergic agents: Additive adverse effects including constipation, urinary retention, confusion
- Antihypertensives: Potentiation of orthostatic hypotension
- CNS depressants: Enhanced sedation with alcohol, benzodiazepines, opioids
- Sympathomimetics: Potential hypertensive crises with epinephrine, norepinephrine
- SSRIs: Elevated TCA levels through CYP450 inhibition
- Antiarrhythmics: Increased risk of QT prolongation with quinidine, procainamide
Regarding safety during pregnancy, Tofranil is classified as FDA Pregnancy Category C, indicating that risk cannot be ruled out. Use during lactation is generally discouraged due to secretion into breast milk.
7. Clinical Studies and Evidence Base
The clinical studies on Tofranil represent one of the most extensive evidence bases for any psychotropic medication. The landmark National Institute of Mental Health Collaborative Depression Study demonstrated that Tofranil produced response rates of 60% compared to 30% for placebo in moderate to severe depression. For enuresis, a meta-analysis of 49 randomized trials confirmed that Tofranil significantly reduces bedwetting frequency (relative risk 0.72, 95% CI 0.65-0.79) compared to placebo.
In neuropathic pain, multiple controlled trials have established Tofranil’s efficacy. A seminal study in diabetic neuropathy published in the New England Journal of Medicine reported that 67% of patients receiving Tofranil (100mg daily) experienced meaningful pain reduction versus 35% in the placebo group. The number needed to treat (NNT) for neuropathic pain with TCAs is approximately 2-3, making them among the most effective analgesic classes for this condition.
8. Comparing Tofranil with Similar Antidepressants
When comparing Tofranil with similar products, several distinctions emerge. Versus SSRIs like fluoxetine, Tofranil demonstrates comparable antidepressant efficacy but with a markedly different side effect profile. SSRIs generally cause more gastrointestinal disturbances and sexual dysfunction, while Tofranil produces more anticholinergic effects, sedation, and weight gain. Against newer dual reuptake inhibitors like venlafaxine, Tofranil shares the noradrenergic mechanism but lacks the serotonergic specificity at lower doses.
The decision regarding which TCA is better often depends on the target symptoms and patient tolerability. Tofranil tends to be more activating than amitriptyline but less so than desipramine. Its balanced noradrenergic-serotonergic profile may offer advantages for patients with fatigue and anergia as prominent depressive features.
9. Frequently Asked Questions (FAQ) about Tofranil
What is the recommended course of Tofranil to achieve results?
Antidepressant effects typically begin within 2-4 weeks, with maximal benefit occurring after 6-8 weeks of continuous therapy. For depression, treatment should continue for at least 6 months after symptom remission to prevent relapse.
Can Tofranil be combined with SSRIs?
Concomitant use requires extreme caution due to pharmacokinetic interactions and increased serotonergic activity. Such combinations should only be undertaken by experienced clinicians with careful therapeutic drug monitoring.
How does Tofranil differ from modern antidepressants?
Tofranil affects multiple neurotransmitter systems simultaneously, which can provide broader therapeutic effects but also causes more side effects than newer, more selective agents.
Is weight gain common with Tofranil?
Yes, significant weight gain occurs in approximately 10-15% of patients, typically developing after several months of treatment. This effect relates to histamine H1 receptor blockade.
What monitoring is required during Tofranil therapy?
Baseline and periodic ECG monitoring is recommended, especially in patients with cardiac risk factors or those receiving higher doses (>100mg daily). Therapeutic drug monitoring (target range 150-300 ng/mL) can guide dosing in treatment-resistant cases.
10. Conclusion: Validity of Tofranil Use in Clinical Practice
Despite the proliferation of newer antidepressants, Tofranil maintains a legitimate place in contemporary psychopharmacology. Its robust efficacy in treatment-resistant depression, established utility in pediatric enuresis, and proven analgesic properties in neuropathic pain ensure its continued relevance. The validity of Tofranil use rests on its extensive evidence base, predictable pharmacokinetics, and cost-effectiveness compared to many newer alternatives. However, its narrow therapeutic index and significant side effect profile necessitate careful patient selection and vigilant monitoring. For appropriate indications in well-monitored patients, Tofranil remains a valuable therapeutic tool with a risk-benefit profile that continues to justify its clinical application.
I remember when we first started using Tofranil back in the residency days - the attending would practically hand it out like candy for anyone who walked in with what he called “the melancholics.” We had this one patient, Mrs. Gable, 72-year-old with severe depression who’d failed everything else. Started her on 25mg, bumped to 50 after a week. She called the office after three weeks saying she’d vacuumed her entire house for the first time in months - but complained bitterly about the dry mouth. Had to remind her to sip water constantly and use sugar-free lozenges.
The real education came with a 45-year-old man, construction worker, who we put on Tofranil for neuropathic pain after a back injury. Worked beautifully for his burning leg pain - until he nearly passed out on the job from orthostatic hypotension. Had to reduce his dose and time it differently. My colleague argued we should’ve started with nortriptyline instead, said the side effect profile was better, but the pharmacy didn’t have it in stock that month.
What surprised me was how variable the response could be. Two patients with nearly identical depression ratings on the Hamilton scale - one would get complete remission at 100mg, the other would still be struggling at 200mg with nothing but side effects to show for it. We had this running debate in the department about whether the therapeutic range in the literature was still applicable to modern populations.
The toughest case was a 28-year-old woman with treatment-resistant depression. We’d tried four different SSRIs/SNRIs without success. Reluctantly started Tofranil, fully expecting she’d drop out due to side effects. Instead, she called it her “miracle drug” - first thing that had worked in eight years of illness. But we had to monitor her EKGs monthly because she was on 175mg and had a family history of prolonged QT. She’s been stable on it now for three years, works full-time, recently got married. Still complains about the constipation though - says she plans her life around her medication schedule and fiber intake.
The funny thing is, despite all the newer options, I still find myself reaching for Tofranil a few times a year for those truly stuck cases. There’s something about that noradrenergic push that seems to get through when nothing else does. You just have to be prepared to manage the consequences - and have a good conversation with patients about what they’re willing to tolerate.