Duloxetine …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 03.28.2021
Released 03.28.2005
Expires For CME 03.28.2024

Duloxetine

Author: K K Jain MD†

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Duloxetine

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Introduction

Historical note and terminology

Duloxetine hydrochloride was originally developed as an antidepressant for the treatment of major depressive disorder including both the emotional and physical symptoms. Later it was found to be effective for the relief of neuropathic pain in diabetic neuropathy; it was approved for this indication by the FDA in 2004 and is the focus of this article. The generic name, duloxetine, is the most used name worldwide. Of the numerous trade names, the best known is Cymbalta.

Pharmacology

Duloxetine hydrochloride is a selective serotonin and norepinephrine reuptake inhibitor for oral administration. Its chemical designation is (+)-(S)-N-methyl-gamma-(1-naphthyloxy)-2-thiophenepropylamine hydrochloride.

Pharmacodynamics. Although the exact mechanisms of the antidepressant and central pain inhibitory action of duloxetine in humans are unknown, the antidepressant and pain inhibitory actions are believed to be related to its potentiation of serotonergic and noradrenergic activity in the CNS. Duloxetine, with dual effects on serotonin and norepinephrine, has more consistent benefits than selective serotonin antidepressants for the treatment of persistent pain associated with fibromyalgia. Most of the observed effect on pain in fibromyalgia is due to a direct analgesic effect rather than an indirect antidepressant effect. Another explanation of action of duloxetine in relieving pain is that it increases the activity of noradrenergic and serotonergic neurons in the descending spinal pathway, inhibiting the activity of dorsal horn neurons and suppressing excessive input from reaching the brain.

Preclinical studies have shown that duloxetine is a potent inhibitor of neuronal serotonin and norepinephrine reuptake and a less potent inhibitor of dopamine reuptake. Duloxetine has no significant affinity for dopaminergic, adrenergic, cholinergic, histaminergic, opioid, glutamate, and GABA receptors in vitro. Duloxetine does not inhibit monoamine oxidase. Duloxetine undergoes extensive metabolism, but the major circulating metabolites have not been shown to contribute significantly to the pharmacologic activity of duloxetine.

Pharmacokinetics. The pharmacokinetics of duloxetine is dose-dependent over the therapeutic range. Important pharmacokinetic features of duloxetine are:

• Orally administered duloxetine hydrochloride is well absorbed.
• The elimination half-life of duloxetine ranges from 8 hours to 17 hours with a mean duration of 12 hours.
• Steady-state plasma concentrations are usually achieved after 3 days.
• Elimination of duloxetine is mainly through hepatic metabolism involving P450 isozymes, CYP2D6 and CYP1A2.
• Duloxetine is highly bound to proteins in human plasma, binding primarily to albumin.
• Most (about 70%) of the duloxetine dose appears in the urine as metabolites of duloxetine and about 20% is excreted in the feces.

Pharmacogenomics. In a study on patients with major depressive disorder using duloxetine or placebo, a genome-wide association with rs76767803 upstream of STAC1 was observed in placebo-treated group, whereas suggestive associations with rs4261893, rs2303377, and rs117986340 were observed in the duloxetine-treated group (19). The finding that a variant upstream of STAC1 is associated with placebo response may have implications for optimization of treatment, clinical trial design and drug development.

Clinical trials

Most of the published clinical trials of duloxetine are in patients with depression including depression associated with neurologic disorders such as stroke and Parkinson disease. Some deal with pain associated with depression. The effect of duloxetine on reducing emotional and painful physical symptoms in patients with major depressive disorder has been demonstrated in randomized, double-blind, placebo-controlled trials.

Results of a systematic review of randomized trials of duloxetine were compared with published results of other antidepressants and showed that duloxetine is equally effective for the treatment of painful diabetic neuropathy and fibromyalgia, judged by the outcome of at least 50% pain relief over 12 weeks, and is well tolerated (30).

A pooled analysis of data from placebo-controlled trials showed that duloxetine was more effective than placebo in the management of depression regardless of whether the patients were anxious or non-anxious (21). Another pooled analysis of randomized, placebo-controlled trials of duloxetine for fibromyalgia has revealed that, besides pain reduction, improvements in fatigue, mood, and activities of daily life also make these patients feel better (11).

A 12-week open-label, randomized trial compared duloxetine, pregabalin, and duloxetine plus gabapentin for diabetic peripheral neuropathic pain management in patients with inadequate pain response to gabapentin (31). The results showed that duloxetine was noninferior to pregabalin; ie, improvement with duloxetine was no worse than that resulting from pregabalin.

Although several clinical trials have reported efficacy of duloxetine for treatment of fibromyalgia, results of one 12-week, randomized, double-blind, placebo-controlled study showed that duloxetine 30 mg per day did not significantly reduce pain severity in patients with fibromyalgia (01). However, duloxetine-treated patients reported global improvement in symptoms and function.

An open study comparing duloxetine with citalopram and sertraline for the treatment of poststroke depression showed that it was more effective for relief of anxiety (14). None of these drugs had any effect on fatigue.

An open-label, noncomparative, multicenter study showed that duloxetine was well tolerated and likely effective in the treatment of depression associated with Parkinson disease with no adverse effects on signs and symptoms of the disease (04).

In a pooled analysis of data from two randomized, double-blind, multicenter, phase 3, placebo-controlled trials on children and adolescents with major depressive disorder, neither duloxetine (investigational drug) nor fluoxetine (active control) showed a statistically significant improvement compared with placebo on the primary efficacy measure (08). The results were consistent with the known safety and tolerability profile of duloxetine.

A systematic review of clinical trials comparing duloxetine with amitriptyline showed that both antidepressants are effective in the treatment of fibromyalgia and differ according to the patient's symptoms and profile (06).

Indications

Duloxetine is indicated for the treatment of major depressive disorder and for the management of neuropathic pain associated with diabetic peripheral neuropathy. It is also approved for the treatment of fibromyalgia.

Off-label uses

Duloxetine increases neural input to the urethral sphincter, thereby relieving the symptoms of stress urinary incontinence in women. Involvement of serotonin and noradrenaline in urinary incontinence provides the scientific basis for efficacy of duloxetine. Duloxetine failed to gain US approval for stress urinary incontinence because of concerns over liver toxicity and suicidal events, but it was approved for this indication in Europe.

Duloxetine is approved only for adult patients, but it has been used for chronic pain and comorbid major depressive disorder in adolescents and children. Duloxetine has been used successfully for the management of femoral neuropathy induced by cardiac catheterization in an adolescent with coexisting reactive depression (13).

Modest effects for headache and osteoarthritic pain have been reported in open-label trials with duloxetine; these effects need to be confirmed with large, randomized studies (02).

A randomized, double-blind, placebo-controlled study provides clinical evidence of the efficacy and safety of duloxetine at a fixed dose of 60 mg once daily in the treatment of chronic low back pain, but it is not yet approved for this indication by regulatory authorities (26).

Duloxetine has been used for primary progressive freezing gait (20). An open label study has shown that duloxetine is well tolerated, safe, and effective in reducing depression as well as fatigue in multiple sclerosis patients (29).

A randomized clinical trial has shown efficacy of duloxetine for relief of pain in chemotherapy-induced peripheral neuropathy (27).

Duloxetine has been used for treatment of paclitaxel-induced peripheral neuropathy in gynecological cancer patients (22).

Duloxetine has been used successfully for treatment of severe venlafaxine withdrawal (05).

A metaanalysis of published randomized, double-blind, placebo-controlled trials to assess the efficacy and tolerability of duloxetine in treating generalized anxiety disorder showed that it is moderately effective (34).

In an open study on patients with chronic pain due to different causes, pain outcomes were compared between patients receiving spinal cord stimulation alone and in addition to duloxetine (23). At 1-year follow-up, patients receiving duloxetine and spinal cord stimulation had better pain relief than those receiving spinal cord stimulation alone.

In a small series of patients, duloxetine could attenuate pathologic laughing exhibited by stroke patients (25).

In an open study of duloxetine for patients with chronic poststroke central neuropathic pain, approximately 70% of the patients showed at least 30% reduction in Numeric Rating Scale for pain at the third week compared with baseline (15).

A study has reported that duloxetine significantly alleviates neuropathic pain induced by paclitaxel by inhibiting p53-related pathways (16).

Adverse effects

Most of the events reported in clinical trials of duloxetine were gastrointestinal, neuropsychological, and hepatic adverse effects. Duloxetine also increased blood pressure in a dose-dependent manner, but this adverse effect has not been a problem in practice. Reported adverse effects include serotonin syndrome and hyponatremia. Case reports in the literature describe hyponatremia due to inappropriate antidiuretic hormone (SIADH) secretion induced by duloxetine (10; 32). Discontinuation of duloxetine, restriction of water intake, and intravenous normal saline are used to manage hyponatremia with good prognosis for restoration of serum sodium level. Serum electrolytes should be continuously monitoring when prescribing duloxetine in patients with predisposing factors for hyponatremia.

A case has been reported of posterior reversible encephalopathy syndrome with coma and myoclonus related to hypertensive encephalopathy a few days after starting duloxetine treatment (33). The patient made a full recovery after discontinuation of duloxetine, antihypertensive therapy, and intravenous anticonvulsant therapy. Unilateral visual loss due to retrobulbar neuritis has been reported as an adverse effect of duloxetine therapy (03).

Duloxetine has no adverse effects on glycemic control in diabetes. Approximately 14% of patients who received duloxetine in the diabetic neuropathy clinical trials discontinued treatment due to an adverse event, compared with 7% of those receiving placebo. Nausea, dizziness, somnolence, and fatigue were the common adverse events reported as reasons for discontinuation and considered to be drug-related. However, a study that analyzed pooled clinical trial data in the placebo arms of controlled trials of antidepressant medications to investigate treatment-emergent adverse events in placebo arms found that they were commonly due to nocebo effect, with no evidence to associate them with adverse clinical outcomes (07).

See PDR for detailed description of adverse effects of duloxetine.

References

01: 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;28(9):775-81. PMID 22971669
02: Bellingham GA, Peng PW. Duloxetine: a review of its pharmacology and use in chronic pain management. Reg Anesth Pain Med 2010;35(3):294-303. PMID 20921842
03: Bicer T, Kosker M, Celikay O, Gurdal C. A case of retrobulbar optic neuritis caused by duloxetine. Cutan Ocul Toxicol 2016;35(3):251-3. PMID 26362493
04: Bonuccelli U, Meco G, Fabbrini G, et al. A non-comparative assessment of tolerability and efficacy of duloxetine in the treatment of depressed patients with Parkinson's disease. Expert Opin Pharmacother 2012;13(16):2269-80. PMID 23067321
05: Cutler N. Severe venlafaxine withdrawal successfully treated with a short course of duloxetine. Prim Care Companion CNS Disord 2017;19(1). PMID 28196312
06: de Farias AD, Eberle L, Amador TA, da Silva Dal Pizzol T. Comparing the efficacy and safety of duloxetine and amitriptyline in the treatment of fibromyalgia: overview of systematic reviews. Adv Rheumatol 2020;60(1):35. PMID 32641165
07: Dodd S, Schacht A, Kelin K, et al. Nocebo effects in the treatment of major depression: results from an individual study participant-level meta-analysis of the placebo arm of duloxetine clinical trials. J Clin Psychiatry 2015;76(6):702-11. PMID 26132671
08: Emslie GJ, Wells TG, Prakash A, et al. Acute and longer-term safety results from a pooled analysis of duloxetine studies for the treatment of children and adolescents with major depressive disorder. J Child Adolesc Psychopharmacol 2015;25(4):293-305. PMID 25978741
09: Hendset M, Molden E, Enoksen TB, Refsum H, Hermann M. The effect of coadministration of duloxetine on steady-state serum concentration of risperidone and aripiprazole: a study based on therapeutic drug monitoring data. Ther Drug Monit 2010;32(6):787-90. PMID 21068650
10: Hu D, Wurster S. Hyponatremia induced by duloxetine: a case report. Consult Pharm 2018;33(8):446-9. PMID 30068437
11: Hudson JI, Arnold LM, Bradley LA, et al. What makes patients with fibromyalgia feel better. Correlations between Patient Global Impression of Improvement and changes in clinical symptoms and function: a pooled analysis of 4 randomized placebo-controlled trials of duloxetine. J Rheumatol 2009;36(11):2517-22. PMID 19833743
12: Huybrechts KF, Bateman BT, Pawar A, et al. Maternal and fetal outcomes following exposure to duloxetine in pregnancy: cohort study. BMJ 2020;368:m237. PMID 32075794
13: Kachko L, Ben Ami S, Liberman A, Birk E, Kronenberg S. Duloxetine contributing to a successful multimodal treatment program for peripheral femoral neuropathy and comorbid 'reactive depression' in an adolescent. Pain Res Manag 2011;16(6):457-9. PMID 22184557
14: Karaiskos D, Tzavellas E, Spengos K, Vassilopoulou S, Paparrigopoulos T. Duloxetine versus citalopram and sertraline in the treatment of poststroke depression, anxiety, and fatigue. J Neuropsychiatry Clin Neurosci 2012;24(3):349-53. PMID 23037649
15: Kim NY, Lee SC, Kim YW. Effect of duloxetine for the treatment of chronic central poststroke pain. Clin Neuropharmacol 2019;42(3):73-6.** PMID 31085946
16: Lu Y, Zhang P, Zhang Q, et al. Duloxetine attenuates paclitaxel-induced peripheral nerve injury by inhibiting p53-related pathways. J Pharmacol Exp Ther 2020;373(3):453-62.** PMID 32238452
17: Lunn MP, Hughes RA, Wiffen PJ. Duloxetine for treating painful neuropathy or chronic pain. Cochrane Database Syst Rev 2009;7(4):CD007115. PMID 19821395
18: Ma SP, Tsai CJ, Chang CC, Hsu WY. Delirium associated with concomitant use of duloxetine and bupropion in an elderly patient. Psychogeriatrics 2017;17(2):130-2. PMID 27046219
19: Maciukiewicz M, Marshe VS, Tiwari AK, et al. Genome-wide association studies of placebo and duloxetine response in major depressive disorder. Pharmacogenomics J 2018;18(3):406-12. PMID 28696415
20: Morgante F, Fasano A. Improvement with duloxetine in primary progressive freezing gait. Neurology 2010;75(23):2130-2. PMID 21135389
21: Nelson JC. Anxiety does not predict response to duloxetine in major depression: results of a pooled analysis of individual patient data from 11 placebo-controlled trials. Depress Anxiety 2010;27(1):12-8. PMID 20013987
22: Otake A, Yoshino K, Ueda Y, et al. Usefulness of duloxetine for Paclitaxel-induced peripheral neuropathy treatment in gynecological cancer patients. Anticancer Res 2015;35(1):359-63. PMID 25550572
23: Prabhala T, Sabourin S, DiMarzio M, Gillogly M, Prusik J, Pilitsis JG. Duloxetine improves spinal cord stimulation outcomes for chronic pain. Neuromodulation 2019;22(2):215-8.** PMID 30325091
24: Schmidt G, Alvarenga R, Manhães A, Schmidt S. Attentional performance may help to identify duloxetine responders in chronic pain fibromyalgia patients. Eur J Pain 2017;21(6):977-86.** PMID 28146317
25: Shin SH, Kim YW, Kim NY. Treatment of poststroke pathologic laughing with duloxetine: a case series. Clin Neuropharmacol 2019;42(2):60-3. PMID 30724786
26: Skljarevski V, Zhang S, Desaiah D, et al. Duloxetine versus placebo in patients with chronic low back pain: a 12-week, fixed-dose, randomized, double-blind trial. J Pain 2010;11(12):1282-90. PMID 20472510
27: Smith EM, Pang H, Cirrincione C, et al. Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial. JAMA 2013;309(13):1359-67. PMID 23549581
28: Smith EM, Pang H, Ye C, et al. Predictors of duloxetine response in patients with oxaliplatin-induced painful chemotherapy-induced peripheral neuropathy (CIPN): a secondary analysis of randomised controlled trial - CALGB/alliance 170601. Eur J Cancer Care (Engl) 2017;26(2). PMID 26603828
29: Solaro C, Bergamaschi R, Rezzani C, et al. Duloxetine is effective in treating depression in multiple sclerosis patients: an open-label multicenter study. Clin Neuropharmacol 2013;36(4):114-6. PMID 23783007
30: Sultan A, Gaskell H, Derry S, Moore RA. Duloxetine for painful diabetic neuropathy and fibromyalgia pain: systematic review of randomised trials. BMC Neurol 2008;8:29. PMID 18673529
31: Tanenberg RJ, Irving GA, Risser RC, et al. Duloxetine, pregabalin, and duloxetine plus gabapentin for diabetic peripheral neuropathic pain management in patients with inadequate pain response to gabapentin: an open-label, randomized, noninferiority comparison. Mayo Clin Proc 2011;86(7):615-26. PMID 21719618
32: Wang D, Lai J, Lu S, Huang M, Hu S, Xu Y. Rapid-onset hyponatremia and delirium following duloxetine treatment for postherpetic neuralgia: case report and literature review. Medicine (Baltimore) 2018;97(46):e13178.** PMID 30431592
33: Zappella N, Perier F, Pico F, et al. Duloxetine-related posterior reversible encephalopathy syndrome: a case report. Medicine (Baltimore) 2016;95(33):e4556. PMID 27537580
34: Zhang Y, Huang G, Yang S, Liang W, Zhang L, Wang C. Duloxetine in treating generalized anxiety disorder in adults: a meta-analysis of published randomized, double-blind, placebo-controlled trials. Asia Pac Psychiatry 2016;8(3):215-25. PMID 26238298

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Duloxetine

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Duloxetine …

Duloxetine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview.
Start a Free Account
to access the full version.

Questions or Comment?

Also in This Category

Primary headache associated with sexual activity

Neuropathies associated with cytomegalovirus infection

Late-life migrainous accompaniments

Clinical evaluation of peripheral neuropathies

Drug-induced myasthenic syndromes

Headache associated with intracranial neoplasms

Hypothyroidism

Medication overuse headache

Duloxetine

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Primary headache associated with sexual activity

Neuropathies associated with cytomegalovirus infection

Late-life migrainous accompaniments

Clinical evaluation of peripheral neuropathies

Drug-induced myasthenic syndromes

Headache associated with intracranial neoplasms

Hypothyroidism

Medication overuse headache

This is an article preview.
Start a Free Account
to access the full version.