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).

Contraindications

Duloxetine is contraindicated in patients with a known hypersensitivity to duloxetine or any of the inactive ingredients. Concomitant use in patients taking monoamine oxidase inhibitors is contraindicated. In clinical trials, duloxetine use was associated with an increased risk of mydriasis; therefore, its use should be avoided in patients with uncontrolled narrow-angle glaucoma.

Goals and duration of treatment

Efficacy in patients with diabetic peripheral neuropathy has not been systematically studied in placebo-controlled trials beyond 12 weeks, but a 1-year, open-label safety study showed long-term safety and efficacy in relief of pain. Duloxetine has no effect on the course of the disease, either favorable or detrimental. Pain severity, but not variables related to diabetes or neuropathy, may predict the effects of duloxetine in diabetic peripheral neuropathic pain.

A study using computerized visual attention test on fibromyalgia patients has shown that an improvement in an attentional test is a reliable predictor of the response to treatment with duloxetine even without any improvement in the perception of pain (24).

Dosing

For diabetic peripheral neuropathic pain, duloxetine should be administered at a total dose of 60 mg/day given once a day, without regard to meals. According to a Cochrane Database review of controlled clinical trials, duloxetine 60 and 120 mg daily are effective for treating pain in diabetic peripheral neuropathy and fibromyalgia, but 20 mg daily is not (17). There is no evidence that a dose of 120 mg/day confers any additional benefits.

For major depressive disorder, total dose of 40 to 60 mg/day is given as 20 mg twice or three times daily without regard to meals. There is no evidence that doses greater than 60 mg/day confer any additional benefits.

Special considerations

Pediatric. Safety and effectiveness of duloxetine in the pediatric population have not been established. Antidepressants in general increased the risk of suicidal thinking and behavior in short-term studies in children and adolescents with major depressive disorder and other psychiatric disorders.

Geriatric. No dose adjustment based on age is recommended for elderly patients.

Pregnancy. Evidence indicates that duloxetine is unlikely to be a major teratogen but may be associated with a small increased risk of cardiac malformations and an increased risk of postpartum hemorrhage (12). However, duloxetine should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Neonates exposed to selective serotonin and norepinephrine reuptake inhibitors late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Excretion of duloxetine in breast milk is less than 1% of the maternal dose. Therefore, duloxetine can be safely administered to a woman who is breastfeeding her infant.

Anesthesia. No study has investigated the possible interaction of duloxetine with anesthetic agents.

Patients with clinically evident hepatic insufficiency have decreased duloxetine metabolism and elimination. It is recommended that duloxetine not be administered to patients with any hepatic insufficiency.

Duloxetine is not recommended for patients with end-stage renal disease requiring dialysis or patients with severe renal impairment.

Interactions

Duloxetine is metabolized by cytochrome P450 isoenzymes CYP 1A2 and CYP 2D6 and, thus, presents a risk of interactions with other drugs. Duloxetine metabolism is affected by inhibitors of CYP1A2 and concomitant use of the following drugs leads to higher concentrations of duloxetine: fluvoxamine, cimetidine, and quinolone antimicrobials such as ciprofloxacin and enoxacin.

Duloxetine is a moderate inhibitor of CYP2D6 and coadministration with other drugs that are extensively metabolized by this enzyme and that have a narrow therapeutic index should be done cautiously. However, no significant effects of duloxetine on the metabolism of other drugs have been reported. Coadministration of duloxetine does not significantly increase the concentration of the parent drug or the parent drug/metabolite ratio of either risperidone or aripiprazole (09).

Concomitant use of duloxetine and bupropion in elderly patients can cause delirium. Both drugs are cytochrome P450 2D6 inhibitors, which may result in a higher level of hydroxybupropion (18). Secondary analysis of randomized controlled trial has shown that duloxetine-treated patients with high emotional functioning are more likely to experience reduction of pain due to oxaliplatin-induced peripheral neuropathy (28).

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.