duloxetine

MECHANISM: Potent inhibitor of presynaptic serotonin (SERT) and norepinephrine (NET) transporters, increasing synaptic 5-HT and NE. Weak effect on dopamine reuptake. Minimal activity at histaminic, muscarinic, and alpha-adrenergic receptors, so it has fewer anticholinergic, antihistamine, and orthostatic effects than TCAs. Analgesic effect comes from enhancing descending inhibitory pain pathways (serotonin and norepinephrine in the dorsal horn), and it is independent of the antidepressant effect.

INDICATIONS: Major depressive disorder; generalized anxiety disorder; diabetic peripheral neuropathic pain (first-line, with pregabalin/gabapentin, TCAs); fibromyalgia; chronic musculoskeletal pain (e.g., osteoarthritis, chronic low back pain). Stress urinary incontinence is approved in Europe, because increased NE/5-HT in Onuf's nucleus raises urethral sphincter tone, but it is not FDA-approved in the US.

PHARMACOKINETICS: Metabolized by CYP1A2 and CYP2D6. It is a moderate CYP2D6 inhibitor, so it can raise levels of TCAs, metoprolol, and antipsychotics. Avoid with strong CYP1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin). Half-life is about 12 hours.

ADVERSE EFFECTS: Nausea (most common), dry mouth, constipation, insomnia or somnolence, dizziness, sweating, and sexual dysfunction (delayed orgasm, decreased libido). Dose-related increase in blood pressure and heart rate from NE effects. Hepatotoxicity (avoid in heavy alcohol use or chronic liver disease). Urinary hesitancy or retention. Increased bleeding risk (impaired platelet serotonin uptake), especially with NSAIDs or anticoagulants. Hyponatremia/SIADH, particularly in the elderly. Discontinuation syndrome with abrupt cessation (dizziness, "brain zaps," nausea, irritability), so taper. Boxed warning for increased suicidality in children, adolescents, and young adults.

SEROTONIN SYNDROME: Risk is higher with MAOIs, linezolid, triptans, tramadol, meperidine, St. John's wort, and other serotonergic drugs. It presents with the triad of mental status changes, autonomic instability (hyperthermia, tachycardia), and neuromuscular hyperactivity (clonus, hyperreflexia, tremor). Treatment is to stop the offending agents, give supportive care and benzodiazepines, and give cyproheptadine (5-HT2A antagonist) if needed. Do not start within 14 days of stopping an MAOI.

CONTRAINDICATIONS/CAUTIONS: Concurrent MAOI use; uncontrolled narrow-angle glaucoma; severe renal impairment (CrCl <30); hepatic impairment; uncontrolled hypertension. It can precipitate mania in bipolar disorder.

HIGH-YIELD COMPARISONS: Venlafaxine is another SNRI. It causes more dose-dependent hypertension at higher doses, and desvenlafaxine and levomilnacipran are related. Milnacipran is used for fibromyalgia. SSRIs have a narrower mechanism and no significant pain indication. TCAs (amitriptyline, nortriptyline) also treat neuropathic pain, but they have more anticholinergic effects, cardiac toxicity (QRS widening) and lethality in overdose. SNRIs are generally safer in overdose.

BOARD PEARL: A patient with depression and comorbid diabetic neuropathy or fibromyalgia: choose an SNRI such as duloxetine. For depression with obesity or sexual dysfunction concerns, bupropion is an alternative. For a patient with uncontrolled hypertension, be cautious with SNRIs.