What is Cymbalta (duloxetine) used for and what are its side effects?

Cymbalta (Duloxetine): Clinical Uses and Side Effects

FDA-Approved Indications

Duloxetine is FDA-approved for major depressive disorder, generalized anxiety disorder (adults and children ≥7 years), diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain in adults. 1

Primary Clinical Applications for Pain Management

Neuropathic Pain Conditions

• Duloxetine 60 mg daily is first-line therapy for diabetic peripheral neuropathic pain, demonstrating a 65% increased likelihood of achieving ≥50% pain reduction compared to placebo (NNT = 5-6) 2, 3
• The American Diabetes Association recommends duloxetine as a primary treatment option, with efficacy sustained up to one year in open-label trials 3
• For chemotherapy-induced peripheral neuropathy (CIPN), duloxetine is the only drug with large randomized trial evidence showing moderate benefit, with 59% pain reduction versus 38% with placebo 2
• Duloxetine demonstrates greater effectiveness for platinum-based CIPN compared to taxane-induced neuropathy 2

Chronic Musculoskeletal Pain

• For knee osteoarthritis affecting multiple joints or inadequately controlled with topical NSAIDs, duloxetine 60 mg daily is recommended as second-line therapy 2, 3
• The CDC recommends starting with topical NSAIDs first for single or few affected joints, then escalating to duloxetine when pain control is incomplete 3
• Duloxetine shows small to moderate benefits at 3-6 months and 6-12 months, with greater effectiveness in patients >65 years and specifically for knee (not hip) osteoarthritis 3
• For chronic low back pain unresponsive to exercise and nonpharmacologic approaches, duloxetine demonstrates small improvements and can be considered alongside NSAIDs 2

Fibromyalgia

• Duloxetine produces small to moderate improvements in pain, function, and quality of life in fibromyalgia patients 2
• The NNT for ≥50% pain reduction is 8 at 12 weeks and maintains efficacy through 28 weeks 4, 5
• Duloxetine is FDA-approved and recommended as first-line treatment for fibromyalgia 2

Dosing and Administration

Standard Dosing Protocol

• Start at 30 mg once daily for one week, then increase to 60 mg once daily to minimize nausea 3
• Maximum effect typically requires 60 mg daily; 60 mg once daily appears equally effective as 60 mg twice daily 3
• For pain conditions, 60 mg and 120 mg daily are effective, but 20 mg daily is not 4, 5
• Improvements in pain may be apparent after 1-2 weeks at 60 mg daily 6

Administration Guidelines

• Take daily (not as needed) with or without food 3, 1
• Swallow capsules whole—do not chew, crush, open, or mix with liquids as this affects drug delivery 1
• If a dose is missed, take as soon as remembered unless near the next scheduled dose; never double dose 1

Common Side Effects

Most Frequent Adverse Events

• Nausea is the most common side effect and the primary reason for discontinuation 3, 4, 5
• Other common effects include dry mouth, sleepiness, fatigue, constipation, loss of appetite, increased sweating, and dizziness 1, 7
• Approximately 16% of patients discontinue due to adverse effects, with most side effects being mild to moderate 4, 5
• Adverse events are dose-dependent, more common at 120 mg than 60 mg daily 4

Specific Population Considerations

• In older adults (≥65 years), adverse events may be more severe but can be attenuated with lower doses and slower titration 2, 3
• In children and adolescents, common side effects include nausea, decreased weight, and dizziness; height and weight should be monitored during treatment 1
• A small increase in A1C has been reported in diabetic patients treated long-term with duloxetine versus placebo 2

Serious Side Effects and Warnings

Critical Safety Concerns

• Liver damage: Monitor for itching, right upper abdominal pain, dark urine, yellow skin/eyes, or elevated liver enzymes 1
• Avoid heavy alcohol use as concomitant use with duloxetine may cause severe liver injury 1
• Blood pressure changes: Monitor blood pressure before and throughout treatment; duloxetine may increase blood pressure or cause orthostatic hypotension with dizziness, fainting, and increased fall risk, especially in elderly 1

Serotonin Syndrome

• Life-threatening condition requiring immediate medical attention 1
• Symptoms include agitation, hallucinations, coordination problems, muscle twitching, racing heartbeat, blood pressure changes, sweating, fever, nausea, vomiting, diarrhea, muscle rigidity, tremor, or seizures 1
• Risk increases when combined with triptans, other antidepressants (SSRIs, SNRIs, MAOIs, tricyclics), tramadol, fentanyl, amphetamines, or supplements like tryptophan or St. John's Wort 1

Bleeding Risk

• Increased risk of bleeding or bruising, especially when combined with warfarin, NSAIDs, or aspirin 1

Other Serious Reactions

• Severe skin reactions (blisters, peeling rash, mouth sores, hives) may require hospitalization and are potentially life-threatening 1
• Seizures or convulsions can occur 1
• Low sodium levels, particularly in elderly, causing headache, weakness, confusion, or memory problems 1
• Urinary retention: decreased urine flow or inability to pass urine 1
• Visual problems: eye pain, vision changes, swelling or redness around the eye (some patients may benefit from preventative eye examination) 1

Psychiatric Risks

• Manic episodes: greatly increased energy, severe insomnia, racing thoughts, reckless behavior, unusually grand ideas, excessive happiness or irritability, rapid speech 1
• Increased risk of suicidal thoughts and behaviors, particularly in children, adolescents, and young adults—close monitoring is essential 1

Discontinuation Guidelines

Tapering Protocol

• Never stop duloxetine abruptly—always taper over at least 2-4 weeks for patients treated longer than 3 weeks to avoid withdrawal symptoms 3
• Discontinuation symptoms include anxiety, irritability, fatigue, sleep problems, headache, sweating, dizziness, electric shock-like sensations, vomiting, nausea, and diarrhea 1
• When switching from another antidepressant, the initial antidepressant may need dose reduction first to avoid side effects 1

Important Drug Interactions

Contraindicated or Cautious Combinations

• Do not use with MAOIs or thioridazine (Mellaril can cause serious heart rhythm problems or sudden death) 1
• Avoid potent CYP1A2 inhibitors (like ciprofloxacin, enoxacin) as duloxetine is metabolized by this pathway 1, 7
• Use caution with drugs metabolized by CYP2D6 (duloxetine is a moderate inhibitor), particularly those with narrow therapeutic index like propafenone, flecainide, quinidine 1, 7
• Monitor closely when combined with other serotonergic drugs, anticoagulants, or NSAIDs 1

Special Populations

Pregnancy and Breastfeeding

• Notify healthcare provider immediately if pregnant or planning pregnancy during treatment 1
• Duloxetine passes into breast milk and may harm the baby—discuss feeding options with provider 1

Cardiovascular Safety

• Unlike tricyclic antidepressants, duloxetine does not produce clinically important electrocardiographic changes or blood pressure alterations in most patients 3
• However, monitor blood pressure throughout treatment due to potential for both hypertension and orthostatic hypotension 1

Clinical Pearls

• Duloxetine is for chronic pain conditions, not acute injuries 3
• The drug requires daily administration for effectiveness; it is not an as-needed medication 3
• Most adverse events occur early in treatment and are mild to moderate in severity 7, 4
• Serious adverse events are rare in clinical trials 4, 5
• Do not drive or operate heavy machinery until you know how duloxetine affects you, as it can cause sleepiness and impair decision-making 1