DuloxetineRx

Trade Names: Cymbalta

Drug Class: Antidepressant, serotononin/norepinephrine reuptake inhibitor (SNRI)

Preparations: 20-, 30-, 60 mg capsules

Dose: Fibromyalgia and chronic musculoskeletal pain:  30 mg once daily for a week then increase to 60 mg once daily if tolerated. Doses of 120 mg/day in clinical trials did not offer additional benefit (but increased side effects).
Depression: Initially 40-60 mg daily either as a single dose or in divided doses; usual maintenance 60 mg daily

Indications: Fibromyalgia, chronic musculoskeletal pain, major depression, anxiety disorder, diabetic neuropathy

Mechanism of Action: Increases synaptic concentrations of serotonin and norepinephrine

Contraindications: Hypersensitivity. Avoid for at least 14 days after patient has received an MAOI. Avoid in patients with uncontrolled narrow-angle glaucoma.

Precautions: May increase suicidality, particularly in adolescents. Risk of serotonin syndrome. Seizures reported. Avoid  with hepatic disease or severe renal impairment. Caution with  hypertension, seizures, gastroparesis.  If discontinuing, reduce dose gradually over weeks or months to prevent withdrawal symptoms. Can exacerbate prostatism. Discontinue if any signs suggestive of Stevens Johnson syndrome.

Pregnancy Risk: C

Adverse Effects
Common: Nausea, constipation, headache, fatigue, dry mouth, dizziness, palpitations, insomnia, difficulty with urination, dry mouth, weight loss
Less common: Hypertension, mild increase in LFTs, orthostatic hypotension, withdrawal syndrome with abrupt discontinuation (nausea, vomiting, diarrhea, anxiety, dizziness, sleep disturbances), erectile  dysfunction, worsen glucose control in diabetes
Rarely: Severe skin reactions, fractures, inappropriate ADH and  hyponatremia, increased bleeding, fulminant hepatitis, serotonin syndrome, mania

Drug Interactions
Alcohol: Increased risk of elevated LFTs
MAOIs and serotonergic drugs: Risk of serotonin syndrome with concomitant use with other serotonergic drugs including triptans, tricyclic antidepressants, fentanyl, lithium,tramadol, tryptophan, buspirone and St. John’s Wort, and with drugs that impair metabolism of serotonin such as MAOIs and linezolid and methylene blue.
Catecholamines: Increased risk of arrhythmia and hypertension
Clonidine: May attenuate antihypertensive effect
CYP1A2 inhibitors: Strong inhibitors (e.g., ciprofloxacin, fluvoxamine, enoxacin) increase duloxetine levels many fold and should be avoided.
CYP2D6 inhibitors: Strong inhibitors (e.g.,  bupropion, paroxetine, fluoxetine, quinidine)  increase duloxetine levels.
CYP2D6 substrates: Duloxetine inhibits CYP2D6 and can increase levels of CYP2D6 substrates (e.g., many antipsychotics and antidepressants, metoprolol, dextromethorphan and others).

Patient Instructions: Avoid alcohol use. Increased risk of suicide; contact physician for suicidal thoughts or change in behavior. Patients should be advised of the risk factors for serotonin syndrome and symptoms that may include mental changes (e.g., agitation, hallucinations, delirium), increased heart rate and labile blood pressure, dizziness, sweating, flushing, fever, tremor, rigidity, nausea, vomiting, diarrhea. Monitor blood pressure.  Slow taper for discontinuation to prevent withdrawal symptoms.

Comments: Modestly more effective than placebo in fibromyalgia clinical trials; withdrawal for adverse effects was more common with duloxetine than placebo in fibromyalgia  (19.6% vs. 11.8%) and OA (16.3% vs. 5.6%).

Clinical Pharmacology: Well absorbed, hepatic metabolism by CYP1A2 and CYP2D6, half-life 12 hours

Cost: $$$

BIBLIOGRAPHY

Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database Syst Rev 2014;1:CD007115. PMID: 24385423.

Arnold LM, Lu Y, Crofford LJ, et al. A double-blind, multicenter trial comparing duloxetine with placebo in the treatment of fibromyalgia patients with or without major depressive disorder. Arthritis Rheum. 2004;50:2974-84. PMID: 15457467.