Duloxetine (Cymbaltaź) for Fibromyalgia
Duloxetine (Cymbalta) is a new antidepressant with both serotonergic and noradrenergic reuptake-inhibiting properties (SNRIs). Duloxetine is indicated for the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD) (approved in February 2007), and for the management of diabetic peripheral neuropathic pain (DPNP). Duloxetine is effective in the treatment of both the emotional and painful physical symptoms of depression.
On June 2008, Cymbalta was officially approved for the management of fibromyalgia. And recently, on November 2010, Cymbalta was licensed for chronic musculoskeletal pain.
Duloxetine side effects
The most common side effects are nausea, dry mouth, constipation, insomnia, dizziness, decreased appetite, fatigue, somnolence, and increased sweating 2. Nausea usually resolves after about 7 days 4. However, insomnia may be persistent 13.
Duloxetine Efficacy for Fibromyalgia
Fibromyalgia (FM) is a perplexing and often disabling disorder, characterized by chronic musculoskeletal pain and tenderness. Fibromyalgia is not a disease per se but rather is a pain syndrome often accompanied by fatigue.
Cymbalta is approved by the FDA for the management of fibromyalgia. It improves most fibromyalgia symptoms (pain, number of tender points, stiffness) in about 60% of patients 9.
Evidence of the efficacy of duloxetine in fibromyalgia was demonstrated in good-quality randomized multicenter controlled trial, in which duloxetine (60 mg twice daily for 12 weeks) provided moderate reductions in the total score on the Fibromyalgia Impact Questionnaire and improvements in quality of life and disability scores. However, significant improvement with duloxetine occurred primarily in females, whereas a benefit was not evident in men 10.
In another randomized placebo-controlled trial more than half of patients treated with Cymbalta (60 mg once or twice daily), responded to treatment after 12 weeks, compared with 33% of those taking a placebo 11. Patients treated with Cymbalta had functional improvements on the Sheehan Disability Scale which measures disability at work, in family life and in social life, that were significantly greater than those of patients taking placebo. Cymbalta 60 mg once or twice daily directly reduced pain (75.7% and 87.5%, respectively) more than the indirect effect attributed to improvement in depressive symptoms (24.4% and 12.5%, respectively). Cymbalta also relieved the pain associated with tender points in fibromyalgia.
Latest clinical trial on Duloxetine in the treatment of fibromyalgia
Twelve-week, randomized, double-blind, placebo-controlled study evaluated the efficacy and safety of duloxetine 30 mg daily in adults with fibromyalgia 16. In this study duloxetine did not greatly reduce pain severity, however the medication produced general improvement in symptoms and function.
Dosage for Fibromyalgia
The recommended dose is 60 mg once daily. Therapy should be started with 30 mg once daily for 1 week and next increased to 60 mg once daily as needed. For some patients dosage 30 mg once daily is sufficient to get satisfactory results. The dose of 120 mg per day is also used in clinical practice 12.
- Cymbalta® has gained official FDA approval for fibromyalgia.
- Provides modest improvement in pain, physical functioning, level of fatigue, and quality of life 6, 8.
- Reasonable choice for fibromyalgia patients with depressed mood.
- Convenience of once-daily dosing.
- Lower rate of sexual side effects than with SSRIs 5
- Short-term treatment is not associated with weight gain, and may cause weight loss 14
- Although duloxetine is beneficial in the management of fibromyalgia its efficacy is relatively modest. Some clinical studies reveal no significant difference between duloxetine and placebo 6.
- Higher prevalence of drug interactions than with pregabalin, an alternative medication for FM 7. Risk of serotonin syndrome when used with serotonergic agents (e.g. triptans, tricyclic antidepressants, tramadol, tryptophan, St. John’s Wort).
- Not licensed for the treatment of FM in Europe.
- Risk of cardiovascular side effects (increased heart rate and blood pressure, changes in electrocardiogram)3
- High rate of insomnia, which may be a persistant13
- Risk of weight gain with long-term use14
- Risk of severe withdrawal symptoms1
- May worsen blood glucose control in diabetics15
- Absorption: Well absorbed. Steady state reached after 3 days.
- Bioavailability: approximately 50% (range 32%-80%); duloxetine may have 30% less bioavailability in men than women.
- Metabolism: Hepatic metabolism by CYP1A2 and CYP2D6 to numerous metabolites.
- Elimination half-life: 12 hours
- Excretion: 70% of duloxetine is eliminated in the urine as metabolites and 20% is excreted in the feces.
Mechanism of action
Duloxetine is a potent and selective serotonin and norepinephrine reuptake inhibitor, that lacks significant affinity for muscarinic, histamine1, alpha1-adrenergic, dopamine, opiate receptors, and ion channels including Na+ channels.
Alternatives medications approved by the US FDA for the treatment of fibromyalgia:
- Pregabalin (Lyrica®) -- good choice for patients with profound sleep problems
- Milnacipran (Savella®) -- good choice for patients with cognitive dysfunction
Other medications which are used "off-label" with various success are:
- Tricyclic antidepressants
- Nonsteroidal antiinflammatory drugs (NSAIDs)
Reviews, Discussions & Forums
Duloxetine reviews for pain conditions:
- 1. Petition to Cymbalta manufacturer, Eli Lilly and Company.
- 2. Hudson JI, Perahia DG, Gilaberte I, Wang F, Watkin JG, Detke MJ. Duloxetine for depression. BMC Psychiatry. 2007 Aug 28;7(1):43. PubMed
- 3. Wernicke J, Lledo' A, Raskin J, Kajdasz DK, Wang F. An evaluation of the cardiovascular safety profile of duloxetine: findings from 42 placebo-controlled studies. Drug Saf. 2007;30(5):437-55.
- 4. Greist J, McNamara RK, Mallinckrodt CH, Rayamajhi JN, Raskin J. Incidence and duration of antidepressant-induced nausea. Clin Ther. 2004 Sep;26(9):1446-55. PubMed
- 5. Schweitzer I, Maguire K, Ng C. Sexual dysfunction of contemporary antidepressants. Aust N Z J Psychiatry. 2009 Sep;43(9):795-808. PubMed
- 6. Murakami M, Osada K, Mizuno H, Ochiai T, Alev L, Nishioka K. A randomized, double-blind, placebo-controlled phase III trial of duloxetine in Japanese fibromyalgia patients. Arthritis Res Ther. 2015 Aug 22;17:224. PubMed
- 7. Ellis JJ, Sadosky AB, Ten Eyck LL, Cappelleri JC, Brown CR, Suehs BT, Parsons B. Impact of potential pregabalin or duloxetine drug-drug interactions on health care costs and utilization among Medicare members with fibromyalgia. Clinicoecon Outcomes Res. 2014 Oct 14;6:389-99. PubMed
- 8. Lunn MPT, Hughes RAC, Wiffen PJ. Duloxetine for treating painful neuropathy, chronic pain or fibromyalgia. Cochrane Database of Systematic Reviews 2014, Issue 1. Art. No.: CD007115. PubMed
- 9. Littlejohn GO, Guymer EK. Fibromyalgia syndrome: which antidepressant should we choose. Curr Pharm Des. 2006;12(1):3-9. PubMed
- 10. Arnold LM, Lu Y, Crofford LJ et al. A double-blind, multicenter trial comparing duloxetine with placebo in fibromyalgia patients with or without major depressive disorder. Arthritis Rheum 2004;50:2974-84 PubMed
- 11. Arnold LM, Rosen A, Pritchett YL, D'Souza DN, Goldstein DJ, Iyengar S, Wernicke JF. A randomized, double-blind, placebo-controlled trial of duloxetine in women with fibromyalgia with or without major depressive disorder. 2005 Dec 15;119(1-3):5-15. PubMed
- 12. Arnold LM, Clauw DJ, Wohlreich MM, Wang F, Ahl J, Gaynor PJ, Chappell AS. Efficacy of duloxetine in patients with fibromyalgia: pooled analysis of 4 placebo-controlled clinical trials. Prim Care Companion J Clin Psychiatry. 2009;11(5):237-44. PubMed
- 13. Wohlreich MM, Mallinckrodt CH, Prakash A, Watkin JG, Carter WP. Duloxetine for the major depressive disorder. Depress Anxiety. 2007;24(1):41-52. PubMed
- 14. Wise TN, Perahia DG, Pangallo BA, Losin WG, Wiltse CG. Prim Care Companion J Clin Psychiatry. 2006;8(5):269-78. PubMed
- 15. Hardy T, Sachson R, Shen S, Armbruster M, Boulton AJ. Does treatment with duloxetine for neuropathic pain impact glycemic control? Diabetes Care. 2007 Jan;30(1):21-6. PubMed
- 16. Arnold LM, Zhang S, Pangallo BA. Efficacy and safety of duloxetine 30 mg/d in patients with fibromyalgia: a randomized, double-blind, placebo-controlled study. Clin J Pain. 2012 Nov-Dec;28(9):775-81 PubMed
- 17. Vuppalanchi R, Hayashi PH, Chalasani N, et al. Duloxetine hepatotoxicity: a case-series from the drug-induced liver injury network. Aliment Pharmacol Ther. 2010 Nov;32(9) PubMed
- Generic name: Duloxetine
- Trade names: Cymbalta, Xeristar
- Dosages: 20 mg, 30 mg, 60 mg Delayed-release capsules
- Pharmacologic category: Serotonin and norepinephrine reuptake inhibitors (SNRI)
- FDA approved: August 3, 2004
- Manufacturer: Eli Lilly and Company
- Pregnancy risk factor: C
- Duloxetine is the first antidepressant to have a specific pain indication in the United States - treatment of PDN.
- Cymbalta was the first antidepressant to hit the market since the FDA began studying whether antidepressants can increase the risk of suicide, particularly when used by adolescents.
- In one study Cymbalta users were almost three times as likely to achieve relief of depression as patients given a placebo.