DULOXETINE IS SAFE AND EFFECTIVE ANTIDEPRESSANT IN DEPRESSION AND FIBROMYALGIA

Duloxetine is a safe and effective antidepressant in depression and fibromyalgia or ion. Linear pharmacokinetics of duloxetine makes this drug is safe and easy to prescribe as laxprincipla property of a drug with linear pharmacokinetics or first order is that they are not dose-dependent.

The Agency for Healthcare Research and Quality (AHRQ) (formerly the Agency for Health Care Policy and Research) has identified three major objectives for the treatment of MDD with antidepressants:

Remission of depressive symptoms.
Return of the patient’s normal social
Occupational functioning.
Prevention of recurrence or relapse.

The American Psychiatric Association
The American College of Physicians
The American Society of Internal Medicine

Recommend three phases of antidepressant treatment:
Acute
Continuation
Maintenance.

Clinically, remission means the complete relief of an individual’s depressive symptoms.

When measured during a clinical trial, remission of depressive symptoms may correspond to a score of 7 or less on the 17-item Hamilton Depression Rating Scale (HAMD17). 

Compared with remission, a response to antidepressant treatment is defined as a 50% reduction in the HAMD17 score.

Even though a patient may exhibit a response, may still meet diagnostic criteria for MDD.

Patients who respond to treatment but do not achieve remission have a much greater risk of relapse.

The goal of the acute treatment phase is complete remission of a patient’s depressive symptoms.

The recommended length of the acute treatment phase may vary for each individual patient but is approximately six to eight weeks.

Treatment during the continuation phase lasts 16–20 weeks after acute-phase remission and may help prevent symptom relapse during a vulnerable period following asymptomatic recovery. 

Maintenance treatment should be considered for patients who may be at risk for recurrence of a major depressive episode.

The optimal length of maintenance therapy is not known, but indefinite treatment may be required for some patients

Duloxetine is a potent serotonin/norepinephrine reuptake inhibitor (SNRI) with antidepressant properties that may also assist patients who have a neuropathic component to their pain and fibromyalgia. 

The dual reuptake inhibition of both serotonin and norepinephrine is likely what makes duloxetine an effective agent in major depressive disorder (MDD) because both neurotransmitters contribute to the pathology of depression.

Specifically, serotonin levels affect:
Impulsivity
Aggression
Appetite
Sexual function.

Norepinephrine levels affect:
Cognitive function
Mood
Emotion
Increased levels may lead to anxiety and irritability.

The concurrent increase in serotonin and norepinephrine seen with duloxetine is thought to contribute to an increased efficacy and faster onset compared with more selective serotonin agents. It also may explain the activation that can occur when an SNRI is initiated, and it may contribute to the discontinuation syndrome that manifests when a patient abruptly stops serotoninergic or norepinephrine receptor-acting medications.

Duloxetine is often used in the treatment of neuropathic pain because the pathophysiology of this type of pain has been linked to that of depression.

The exact mechanism of central pain inhibition is unknown, but it may be related to the potentiation of adrenergic and serotoninergic activity in the central nervous system.

Because of this hypothesis, the tricyclic antidepressants traditionally have been used to reduce neuropathic pain because they inhibit presynaptic reuptake of serotonin, norepinephrine, and to a lesser extent, dopamine.

As duloxetine also affects the levels of these neurotransmitters, it should also help reduce neuropathic pain. In fact, it is the first drug approved by the US Food and Drug Administration for the treatment of diabetic peripheral neuropathic pain.

Given these indications, duloxetine is likely the right drug for a patient who is experiencing both depression and neuralgic pain secondary to fibromyalgia.

However, an important consideration when selecting the right drug for the right person at the right time is the side-effect profile, as tolerability will play a significant role in patient compliance and adherence.

An increased amount of serotonin and norepinephrine in the synapse can lead to the development of adverse effects.

Serotonin commonly results in sleep disturbances, gastrointestinal upset, and sexual dysfunction. Norepinephrine can be responsible for slight increases in blood pressure and pulse rate.

A review of clinical trials examining duloxetine in MDD revealed that the incidence of these adverse effects is dose related. Specifically, the incidence of nausea was higher in patient groups receiving higher doses of duloxetine. This finding likely holds true for other side effects commonly associated with duloxetine.

Three of the more common adverse effects associated with duloxetine are dizziness, somnolence, and fatigue. Another review of clinical trials of duloxetine in MDD demonstrated that the incidence of dizziness was 10.7%, compared with 5.3% for placebo; somnolence was 7%, compared with 3% for placebo; and fatigue was 8%, compared with 4% for placebo. All differences were statistically significant.

It is important to note that these side effects may be more pronounced in patients whose dose has been titrated upward too quickly.

Drug interactions also should be considered when treating a patient with duloxetine because the drug is extensively hepatically metabolized, primarily by the cytochrome P450-2D6 system (CYP2D6), with a smaller portion metabolized by CYP1A2.

A moderately potent inhibitor of CYP2D6, duloxetine has the potential to interact with other drugs that are also metabolized by this cytochrome P450 system.

An important example that is often overlooked involves over-the-counter cough and cold medications that contain dextromethorphan. Because metabolism through CYP2D6 may be moderately inhibited in patients taking duloxetine, dextromethorphan will be metabolized to a lesser extent, resulting in decreased clearance of this drug from the body.

Other medications metabolized by the CYP2D6 system that should be avoided by patients taking duloxetine include tricyclic antidepressant drugs and phenothiazines.

Consideration of the CYP2D6 system is also important because a high degree of genetic polymorphism is associated with the enzymatic activity of this isoenzyme. Specifically, 8% of whites, 4% of African Americans, and fewer than 1% of Asians are thought to be poor metabolizers, which may also contribute to decreased clearance of duloxetine; this decreased clearance may contribute to greater side effects, including sleepiness, fatigue, and dizziness.

Careful review of a patient’s social substance abuse must also be undertaken, especially because there is some metabolism by the CYP1A2 system. When an agent is a substrate of the CYP1A2 system, a patient’s smoking status becomes an issue, as the polycyclic aromatic hydrocarbons contained in tobacco smoke are a potent inducer of the CYP1A2 system.

Thus, the medication may not act therapeutically as expected, and higher doses will be required to produce the same clinical effect. Only 7 cigarettes per day are needed to maximize this induction, and marijuana also acts as a potent inducer.

With the higher doses required comes a higher propensity for adverse effects. In addition, if a patient abruptly discontinues smoking or switches to nicotine replacement therapy, this may result in higher blood concentrations of the medication.

It is also important to avoid combining duloxetine with other serotoninergic agents (eg, selective serotonin-reuptake inhibitors, monoamine oxidase inhibitors, and triptans), as all of these agents will contribute to an increased level of serotonin available in the synapse; this pharmacodynamic interaction is referred to as  “serotonin syndrome” and is characterized by agitation, confusion, delirium, tachycardia, diaphoresis, fluctuations in blood pressure, and extrapyramidal side effects. This syndrome can develop within 2 hours, but it also can be resolved within 24 hours in 70% of cases by discontinuing the serotoninergic drugs.

Follows the premise of primum non nocere, or first do no harm.

Exactly what dose is required to achieve a therapeutic response in alleviating depression and neuropathic pain?

As with any medication, the theory of start low and go slow should be used to allow the treating team to assess safety and tolerability for the patient.

In my clinical practice, I consider dosing increases once the medication has reached pharmacologic steady state parameters plus 50%.

Thus, if a drug has a half-life of 24 hours, 5 half-lives will allow the drug to reach about 97% steady state.

This would represent 5 days plus 2.5 days or 7.5 days, or an increase every week.

Linear pharmacokinetics of duloxetine makes this drug is safe and easy to prescribe as laxprincipla property of a drug with linear pharmacokinetics or first order is that they are not dose-dependent.

The best determination and predictor of tolerance and response is ultimately a discussion with the patient and the caregivers.

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