Venlafaxine (Effexor)

Based on "Essential Psychopharmacology"
written by Stephen M. Stahl, MD, PhD

History

Venlafaxine was first synthesized in the early 1980s by researchers at Wyeth Pharmaceuticals. Wyeth scientists -- John Yardley, Morris Husbands, and Eric Muth -- recognized venlafaxine’s promise as an important antidepressant and pressed forward with its development. Wyeth launched venlafaxine for the treatment of depression in the United States in early 1994 under the trade name Effexor.

The medicine was originally launched in an immediate release formulation. The extended-release (XR) formulation was approved by the FDA in 1997. The advantage of the XR formulation, besides once-daily dosing, is a slightly lower rate of nausea during the beginning of therapy.

Generic formulations of venlafaxine immediate-release entered the market in 2007.

FDA approved indications

• Major depressive disorder
• Generalized anxiety disorder (GAD)
• Social anxiety disorder
• Panic disorder

Off-label & Investigational uses

• post-traumatic stress disorder (PTSD) 15
• migraine prophylaxis16
• fibromyalgia17
• tension-type headache18
• chronic pain syndromes19
• premenstrual dysphoric disorder (PMDD)20
• diabetic neuropathy21
• hot flashes22
• bipolar depression24
• chronic fatigue syndrome
• irritable bowel syndrome (IBS)
• attention-deficit hyperactivity disorder (ADD/ADHD) 25
• cocaine dependence26

Venlafaxine for fibromyalgia
Venlafaxine is a promising treatment for fibromyalgia symptoms. Venlafaxine 75 mg/day appears to be effective in alleviating the pain and disability associated with fibromyalgia17, 38. This effect seems to be independent of its anxiolytic and antidepressant properties. Blockade of both norepinephrine and serotonin reuptake might be more effective than blockade of either neurotransmitter alone in the treatment of fibromyalgia.

Analgesic potential of Venlafaxine
Venlafaxine is gaining interest as a potential treatment for various pain syndromes. This medication combines the norepinephrine-reuptake inhibiting effects of TCAs with the serotonin-reuptake inhibiting effects of the SSRIs, without the anticholinergic side effects. It appers to be effective in diabetic neuropathy and neuropathic back pain21,32. Venlafaxine is modestly effective in the treatment of atypical facial pain33. The results of clinical study have shown long-term efficacy and effectiveness of venlafaxine XR for treatment of chronic pain with associated major depressive disorder34.

Venlafaxine "pros" and "cons"

Advantages:

• Venlafaxine appears more effective than SSRIs, and at least as effective as tricyclic antidepressants, in the treatment of major depression36
• Often effective for depression unresponsive to SSRIs 2,7
• High therapeutic success rate5
• Effective for treatment-resistant depression6
• Quick onset of antidepressant and anxiolytic activity28,29
• Higher remission rates than with fluoxetine and paroxetine13
• Memory improving effects27
• Provides protection against a renewed occurrence of depressive symptoms (recurrence prevention)
• Low potential for pharmacokinetic drug interactions due to minimal inhibition of liver CYP450 isoenzymes

Disadvantages:

• High risk of withdrawal syndrome. Withdrawal symptoms occur rapidly and may be very severe 3. Withdrawal symptoms may occur after missing a single dose due to venlafaxine's short half-life.
• High rate of treatment emergent mania and hypomania 23
• More toxic than SSRIs in overdose. Toxicity appears to be higher than with other SSRIs, with a fatal toxic dose closer to that of the tricyclic antidepressants 4, 10. Doses of 900 mg or more are likely to cause moderate toxicity.
• Elevation of blood pressure 37. The risk of sustained high blood pressure increases from 3% to 7% at dosages of 100-225 mg/day (for IR formulation) and to 13% at dosages above 300 mg/day 11. In the studies of the XR formulation with maximum dosage of 225 mg/day, the increased risk was only 3%.
• Highest rate of nausea and vomiting 30
• Highest risk of suicide 31

Mechanism of action

Venlafaxine is a phenethylamine bicyclic derivative. It blocks the reuptake of serotonin, noradrenaline and, to a lesser extent, dopamine. The reuptake effects of venlafaxine are dose dependent. At low doses (< 150 mg/day) it acts only on serotonergic transmission, like the SSRIs. At moderate doses (>150 mg/day) venlafaxine acts on serotonergic and noradrenergic systems, whereas at high doses (>300 mg/day) it affects serotonergic, noradrenergic and dopaminergic neurotransmission 14.

The combination of the effects on the reuptake mechanisms appears to be responsible for the antidepressant action of the drug.

Venlafaxine has negligible affinity for muscarinic, adrenergic, or histamine receptors.

Analgesic action
Venlafaxine has an analgesic effect that is independent of its antidepressant activity. The results of clinical studies suggest that the opioidergic system has a role in the analgesic effect of venlafaxine 8. Antinociceptive effect of venlafaxine is influenced by opioid receptor subtypes (mu-, kappa1- kappa3- and delta-opioid receptor subtypes) combined with the alpha2-adrenergic receptor. This opioid profile may be one of the explanations to venlafaxine efficacy in severe depression, unlike the SSRIs and other antidepressants which lack opioid activity 9. Time to clear out of the system

Venlafaxine has elimination half-life about 5 ± 2 hours and its active metabolite O-desmethylvenlafaxine (ODV) has a half-life of about 11 ± 2 hours. It may take 4 to 5 days for venlafaxine to clear out of the system.

The clearance of venlafaxine is slightly (15%) lower following multiple doses than following a single dose.

Onset of action

Steady-state concentrations of both venlafaxine and ODV in plasma were attained after approximately 3 days of multiple dose therapy.

While most people taking venlafaxine become aware of some lessening of depression within two to four weeks, there are some who experience relief within the first week and others who only experience relief after a couple of months of therapy.

Venlafaxine (Effexor) withdrawal

Abrupt discontinuation and even gradual tapering of venlafaxine is associated with high incidence of withdrawal symptoms. Severe discontinuation reactions may make cessation of the drug extremely difficult. Venlafaxine discontinuation symptoms include:

• agitation
• anorexia
• anxiety
• confusion
• coordination impaired
• diarrhea
• dizziness
• dry mouth
• dysphoric mood
• fasciculation
• fatigue
• headaches
• hypomania
• insomnia
• nausea
• nervousness
• nightmares
• shock-like sensations
• somnolence
• sweating
• tremor
• vertigo
• vomiting

In order to minimise the chance of withdrawal problems, it is suggested that venlafaxine should be withdrawn very gradually by reducing the dose very slowly over a period of weeks, or months in cases where the symptoms are severe.

Venlafaxine & alcohol

Venlafaxine has not been shown to increase the impairment of mental and motor skills caused by alcohol.

Venlafaxine (Effexor) abuse & dependence

Venlafaxine is not a controlled substance. It has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. While venlafaxine has not been systematically studied in clinical trials for its potential for abuse, there was no indication of drug-seeking behavior in the clinical trials.

However, there is some evidence that large doses of venlafaxine may produce amphetamine-like effects 35. So, when treating patients with a history of alcohol or drug abuse, physicians should consider the potential of venlafaxine for abuse.

Further reading

• Venlafaxine (Effexor) versus ...
• Venlafaxine vs Amitriptyline
• Venlafaxine vs Paroxetine
• Venlafaxine vs Sertraline

References

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Published: March 31, 2008
Last updated: October 21, 2017