tofranil
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Synonyms | |||
Imipramine hydrochloride, marketed under the brand name Tofranil, represents one of the foundational tricyclic antidepressants (TCAs) developed in the 1950s. As a dibenzazepine derivative, it primarily functions as a potent serotonin and norepinephrine reuptake inhibitor, though its pharmacology extends to significant anticholinergic and antihistaminic effects. We initially used it for major depressive disorder, but over decades of clinical application, its utility expanded to include enuresis in children, neuropathic pain conditions, and adjunct treatment for certain anxiety disorders. The drug’s complex receptor profile means dosing requires careful titration and monitoring, particularly regarding cardiac conduction parameters. I remember my first year in psychopharmacology rotation, Dr. Chen handing me the PDR entry for imipramine saying “Learn this one cold - it’s where modern psychopharmacology began.”
Tofranil: Effective Symptom Management for Depression and Beyond - Evidence-Based Review
1. Introduction: What is Tofranil? Its Role in Modern Medicine
Tofranil, the brand name for imipramine hydrochloride, stands as the prototype tricyclic antidepressant that revolutionized psychiatric treatment in the late 1950s. Historically significant as the first TCA with demonstrated antidepressant efficacy, Tofranil continues to hold formulary status despite the development of newer antidepressant classes. What is Tofranil used for in contemporary practice? While its primary indication remains major depressive disorder, experienced clinicians frequently utilize Tofranil for treatment-resistant depression, childhood enuresis unresponsive to behavioral interventions, and various chronic pain syndromes. The medical applications extend to off-label uses including panic disorder, migraine prophylaxis, and adjunctive treatment for certain eating disorders. Interestingly, we still occasionally reach for TCAs like Tofranil when patients fail multiple trials of SSRIs - there’s something about that broad receptor activity that sometimes works when more selective agents don’t.
2. Key Components and Bioavailability of Tofranil
The composition of Tofranil centers on imipramine hydrochloride as the active pharmaceutical ingredient. Available in 10, 25, and 50 mg tablets for oral administration, the standard release form ensures predictable absorption throughout the gastrointestinal tract. The bioavailability of Tofranil demonstrates considerable interindividual variation (approximately 30-60% oral bioavailability) due to extensive first-pass metabolism, primarily mediated by cytochrome P450 2C19, 2D6, and 3A4 isoenzymes. Imipramine undergoes demethylation to its active metabolite desipramine, which possesses distinct noradrenergic activity that becomes clinically relevant during chronic administration. The pharmacokinetics are further complicated by the drug’s high protein binding (approximately 90%) and substantial volume of distribution, contributing to its long elimination half-life of 8-16 hours. We always check CYP2D6 status in patients who show either exaggerated side effects at low doses or minimal response at high doses - the pharmacogenetics really matter with this one.
3. Mechanism of Action of Tofranil: Scientific Substantiation
Understanding how Tofranil works requires examining its complex neuropharmacology. The primary mechanism of action involves potent inhibition of presynaptic serotonin and norepinephrine transporters, increasing synaptic concentrations of these monoamines. However, Tofranil’s effects on the body extend far beyond reuptake inhibition, with significant antagonism at muscarinic M1, histamine H1, and alpha-1 adrenergic receptors explaining its characteristic side effect profile. The scientific research indicates that chronic administration leads to downstream adaptations including beta-adrenergic receptor downregulation and enhanced serotonergic neurotransmission, which may correlate more closely with therapeutic effects than acute neurotransmitter changes. From a practical standpoint, I explain to residents that Tofranil is like a broad-spectrum antibiotic in psychopharmacology - it hits multiple systems, which can be advantageous for complex presentations but requires careful management of collateral effects.
4. Indications for Use: What is Tofranil Effective For?
Tofranil for Major Depressive Disorder
FDA-approved for depression since 1959, Tofranil demonstrates robust efficacy for moderate to severe major depressive episodes. Multiple meta-analyses confirm comparable efficacy to contemporary antidepressants with potential advantages for melancholic and treatment-resistant subtypes. The therapeutic effects typically emerge over 2-4 weeks, with full response often requiring 6-8 weeks of adequate dosing.
Tofranil for Nocturnal Enuresis
For pediatric nocturnal enuresis, Tofranil represents second-line pharmacotherapy when alarm therapy fails. The treatment effect appears mediated through anticholinergic actions reducing bladder contractility combined with altered sleep architecture. Dosing for enuresis typically involves 25-50 mg administered 1-2 hours before bedtime, with careful attention to cardiovascular monitoring in pediatric populations.
Tofranil for Neuropathic Pain Conditions
The utility of Tofranil for neuropathic pain conditions like diabetic neuropathy, postherpetic neuralgia, and fibromyalgia is well-established in pain literature. Dosing for analgesia typically occurs at lower ranges (25-100 mg daily) than required for antidepressant effects, with benefit often apparent within 1-2 weeks of initiation.
Tofranil for Anxiety Disorders
While not FDA-approved for anxiety, substantial evidence supports Tofranil for treatment of panic disorder with agoraphobia. The drug demonstrates particular benefit for reducing anticipatory anxiety and phobic avoidance, though initial activation may temporarily exacerbate anxiety symptoms - we always start low and go slow with anxious patients.
5. Instructions for Use: Dosage and Course of Administration
Proper instructions for use of Tofranil emphasize gradual titration and consistent timing of administration. The standard approach involves initiating therapy at lower doses with weekly increases based on tolerability and therapeutic response.
| Indication | Initial Dosage | Therapeutic Range | Administration Timing |
|---|---|---|---|
| Depression in adults | 25-50 mg daily | 100-300 mg daily | Single bedtime dose or divided doses |
| Geriatric depression | 10-25 mg daily | 50-100 mg daily | Bedtime administration |
| Pediatric enuresis (age 6+) | 25 mg daily | 25-75 mg daily | 1-2 hours before bedtime |
| Neuropathic pain | 10-25 mg daily | 25-100 mg daily | Bedtime administration |
The course of administration typically continues for 6-9 months after symptom remission in depression before considering gradual taper. How to take Tofranil safely involves consistent timing relative to meals (with food to minimize GI upset) and awareness that sedation may impact morning functioning if dosed too close to waking hours. We typically monitor therapeutic levels (imipramine + desipramine) with target range of 150-300 ng/mL for refractory cases.
6. Contraindications and Drug Interactions with Tofranil
Absolute contraindications for Tofranil include recent myocardial infarction, uncompensated heart failure, and known hypersensitivity to tricyclic compounds. Relative contraindications encompass narrow-angle glaucoma, significant prostatic hypertrophy, severe constipation, and preexisting conduction abnormalities. The side effects profile prominently features anticholinergic manifestations (dry mouth, constipation, blurred vision, urinary retention) along with orthostatic hypotension, sedation, and weight gain.
Critical drug interactions with Tofranil involve:
- MAOIs (risk of serotonin syndrome)
- Other serotonergic agents (additive serotonin toxicity)
- QTc-prolonging medications (increased arrhythmia risk)
- CYP2D6 inhibitors (fluoxetine, paroxetine, bupropion) increasing Tofranil levels
- Antihypertensives (potential attenuation of effect)
- CNS depressants (additive sedation)
Regarding special populations, Tofranil during pregnancy carries FDA Category C designation, with decisions requiring careful risk-benefit analysis. The drug excretes into breast milk in low concentrations, though most experts consider compatible with breastfeeding when monitoring infant for sedation.
7. Clinical Studies and Evidence Base for Tofranil
The clinical studies supporting Tofranil span six decades, beginning with Kuhn’s seminal 1958 report establishing antidepressant efficacy. Subsequent randomized controlled trials consistently demonstrate superiority over placebo for major depression, with meta-analyses showing response rates approximately 60-70% versus 30% for placebo. The scientific evidence for enuresis includes multiple pediatric trials showing complete response in 50-70% of children, though relapse rates approach 50% upon discontinuation.
For neuropathic pain, multiple systematic reviews confirm Tofranil’s efficacy, with NNT values of 2-3 for various neuropathic pain conditions. The effectiveness in panic disorder was established in several landmark studies during the 1980s, demonstrating significant reduction in panic frequency and phobic avoidance comparable to alprazolam without dependence concerns.
Physician reviews consistently note Tofranil’s value in treatment-resistant depression, with STAR*D analysis suggesting TCAs remain effective options after multiple SSRI failures. The evidence base, while older than contemporary antidepressants, remains robust and clinically relevant.
8. Comparing Tofranil with Similar Products and Choosing Quality Medication
When comparing Tofranil with similar antidepressants, several distinctions emerge. Versus SSRIs, Tofranil demonstrates comparable efficacy with different side effect profile - more anticholinergic effects but potentially less sexual dysfunction and emotional blunting. Among TCAs, Tofranil occupies an intermediate position between more serotonergic agents like clomipramine and more noradrenergic compounds like desipramine.
Which Tofranil alternative might be better depends on individual patient factors:
- For predominantly noradrenergic symptoms (fatigue, anhedonia): desipramine or nortriptyline
- For obsessive-compulsive features: clomipramine
- For minimal anticholinergic burden: secondary amine TCAs
- For simplified dosing: SSRIs or SNRIs
How to choose quality generic imipramine involves verifying FDA therapeutic equivalence ratings and consistency in manufacturer when possible. Some hospital systems preferentially contract with established manufacturers (Teva, Mylan) for consistency in bioavailability.
9. Frequently Asked Questions (FAQ) about Tofranil
What is the recommended course of Tofranil to achieve therapeutic results?
For depression, full therapeutic effect typically requires 4-8 weeks at adequate dosing (usually 150-300 mg daily in adults). Maintenance therapy continues for 6-9 months after remission before considering gradual taper over 2-4 weeks.
Can Tofranil be combined with SSRIs?
Combining Tofranil with SSRIs requires extreme caution due to CYP450 inhibition increasing Tofranil levels 2-4 fold. If absolutely necessary, Tofranil dosing should be reduced by 50-75% with close therapeutic drug monitoring and ECG surveillance.
How long does Tofranil stay in your system?
The elimination half-life ranges 8-16 hours for imipramine and 12-24 hours for desipramine. Complete clearance requires approximately 5 half-lives (3-5 days), though metabolites may be detectable longer.
Does Tofranil cause weight gain?
Yes, Tofranil commonly causes weight gain of 5-15 pounds through histaminergic effects on appetite and potential metabolic changes. This effect tends to be more pronounced than with SSRIs.
Is Tofranil safe for elderly patients?
Tofranil can be used in geriatric patients with appropriate dose reduction (often 50-100 mg daily maximum) and enhanced monitoring for orthostasis, cognitive effects, and cardiac conduction changes.
10. Conclusion: Validity of Tofranil Use in Clinical Practice
The risk-benefit profile of Tofranil supports its continued role in contemporary psychopharmacology, particularly for treatment-resistant conditions and specific indications like enuresis and neuropathic pain. While newer antidepressants offer improved safety margins, Tofranil retains unique therapeutic advantages in selected clinical scenarios. The validity of Tofranil use persists when prescribed by knowledgeable clinicians who appreciate its complex pharmacology and monitoring requirements.
I had this patient, Miriam, 68-year-old retired teacher with treatment-resistant depression who’d failed six adequate antidepressant trials. Her daughter brought her in basically as a last resort before considering ECT. We started imipramine at 25 mg hs, and I’ll be honest - the first two weeks were rough. Significant orthostasis, dry mouth so bad she carried water everywhere, and some confusion in the mornings. My resident wanted to discontinue, argued we were causing more harm than good in an elderly patient. But something about her affect - the crushing anhedonia seemed slightly less intense even with the side effects. We pushed through with aggressive management of the anticholinergic symptoms - pilocarpine for the dry mouth, scheduled fluids and compression stockings for the orthostasis. By week 6 at 125 mg, she came in and actually smiled - first genuine affect I’d seen in the 4 months I’d been following her. She said “I’m reading books again, doctor. I forgot what that felt like.” We did serial ECGs, monitored levels, had her daughter help with medication organization. Eighteen months later, she’s maintained on 100 mg, gardening again, traveling to see grandchildren. Not perfect - still needs artificial tears and watches salt intake - but functional. That case taught me that sometimes these old drugs earned their reputation for a reason, even if they’re fussier to manage. The key is knowing which patient has the specific biology that might respond and being willing to manage the side effect profile aggressively. We recently tried to taper her to zero, but at 25 mg the anhedonia and morning dread started creeping back, so we settled on 75 mg maintenance. Sometimes the goal isn’t medication-free, it’s life-functional. Her daughter sent me a card last Christmas with a photo of Miriam with her great-grandchild - “Thank you for giving us back our mother.” That’s why we still keep Tofranil in the arsenal.