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Venlafaxine is marketed under the tradenames Efexor^® in the UK, Efexor^®, Efectin^®, Effexor XR^® and Efectin ER^®

Description of compound

The chemical structure of venlafaxine is designated (R/S)-1-[2-(dimethylamino)-1-(4 methoxyphenyl)ethyl] cyclohexanol hydrochloride or (±)-1-[a [a- (dimethylamino)methyl] p-methoxybenzyl] cyclohexanol hydrochloride and it has the empirical formula of C₁₇H₂₇NO₂. It is a white to off-white crystalline solid. Venlafaxine is structurally and pharmacologically related to the analgesic tramadol, but not to any of the conventional antidepressant drugs, including tricyclic antidepressants, SSRIs, MAOIs, or reversible inhibitors of monoamine oxidase (RIMAs).^[1]

Mechanism of action

Venlafaxine is a bicyclic antidepressant, and is usually categorized as a serotonin-norepinephrine reuptake inhibitor (SNRI), but it has been referred to as a serotonin-norepinephrine-dopamine reuptake inhibitor.^[2]^[3] It works by blocking the transporter "reuptake" proteins for key neurotransmitters affecting mood, thereby leaving more active neurotransmitter in the synapse. The neurotransmitters affected are serotonin (5-hydroxytryptamine) and norepinephrine (noradrenaline) Additionally, in high doses it weakly inhibits the reuptake of dopamine.^[4]

Pharmacokinetics

Venlafaxine is well absorbed with at least 92% of an oral dose being absorbed into systemic circulation. Venlafaxine is extensively metabolized in the liver via the CYP2D6 isoenzyme to O-desmethylvenlafaxine, which is just as potent a serotonin-norepinephrine reuptake inhibitor as the parent compound, meaning that the differences in metabolism between extensive and poor metabolizers are not clinically important. Steady-state concentrations of venlafaxine and its metabolite are attained in the blood within 3 days. Therapeutic effects are usually achieved within 3 to 4 weeks. No accumulation of venlafaxine has been observed during chronic administration in healthy subjects. The primary route of excretion of venlafaxine and its metabolites is via the kidneys.^[5] The half-life of venlafaxine is relatively short, therefore patients are directed to adhere to a strict medication routine, avoiding missing a dose. Even a single missed doses can result in the withdrawal symptoms.^[6]

Indications

Approved

Venlafaxine is used primarily for the treatment of depression, generalized anxiety disorder, obsessive compulsive disorder, social anxiety disorder, and panic disorder in adults.^[5]

Off-label / investigational uses

Many doctors are starting to prescribe venlafaxine "off label" for the treatment of diabetic neuropathy (in a similar manner to duloxetine) and migraine prophylaxis (in some people, however, venlafaxine can exacerbate or cause migraines). Studies have shown venlafaxines effectiveness for these conditions.^[7]^[8] It has also been found to reduce the severity of 'hot-flashes' in menopausal women.^[9]^[10]

Substantial weight loss in patients with major depression, generalized anxiety disorder, and social phobia has been noted, but the manufacturer does not recommend use as an anorectic either alone or in combination with phentermine or other amphetamine-like drugs.^[5]

Venlafaxine is not approved for the treatment of depressive phases of bipolar disorder. As this has some potential danger, as venlafaxine can induce mania, mixed states, rapid cycling and/or psychosis in some bipolar patients, particularly if they are not also being treated with a mood stabilizer.^[5]

Contraindications

Venlafaxine is not recommended in patients hypersensitive to venlafaxine. It should also not be used in concurrence with a monoamine oxidase inhibitor (MAOI). Venlafaxine should not be used in children. Caution should also be used in those with a seizure disorder.^[5]

Pregnancy, labor and delivery

There are no adequate and well controlled studies with venlafaxine in pregnant women. Therefore, venlafaxine should only be used during pregnancy if clearly needed. There have been some reports of effects on new born infants. In view of the possibility of severe discontinuation syndrome and the difficulties this presents, use of venlafaxine for pregnant women is not generally indicated.

Dose range

Prescribed dosages are typically in the range of 75 to 225 mg per day, but higher dosages are sometimes used for the treatment of severe or treatment-resistant depression. Because of its relatively short half-life of 5 hours, venlafaxine should be administered in divided dosages throughout the day. The extended release version (largely manufactured on spheronization equipment) eliminates this problem and has largely replaced the original in use.

Available forms

Effexor is distributed in pentagon-shaped peach-colored tablets of 25 mg, 37.5 mg, 50 mg, 75 mg, and 100 mg. There is also an extended-release version distributed in capsules of 37.5 mg (gray/peach), 75 mg (peach), and 150 mg (brownish red).

Venlafaxine Extended Release (XR)

Venlafaxine extended release is chemically the same as normal venlafaxine. The extended release version (sometimes refered to as controlled release) controls the release of the drug into the gut over a longer period of time than normal venlafaxine. This results in a lower peak plasma concentration. Studies have shown that the extended release formula has a lower incidence of patients suffering from nausea as a side effect resulting in a lower number of patients stopping their treatment due to nausea.^[11]

Effectiveness

Venlafaxine is an effective anti-depressant for many persons; however, it seems to be especially effective for those with treatment-resistant depression. Some of these persons have taken two or more antidepressants prior to venlafaxine with no relief. Patients suffering with severe long-term depression typically respond better to venlafaxine than other drugs. However, venlafaxine has been reported to be more difficult to discontinue than other anti-depressants. In addition, a September 2004 Consumer Reports study ranked venlafaxine as the most effective among six commonly prescribed antidepressants. However, this should not be considered a definitive finding, since responses to psychiatric medications can vary significantly from individual to individual.

Adverse effects

As with most antidepressants, lack of sexual desire can be a very disturbing side-effect for some persons. Venlafaxine can raise blood pressure at high doses, so it is usually not the drug of choice for persons with high blood pressure.

It has a higher rate of treatment emergent mania than many modern antidepressants, and many people find it to be a more activating medication than other antidepressants. Paradoxically, some users find it highly sedating and find that it must be taken in the evening.

The energizing effect of the drug may come unwanted to some, possibly leading to an increased anxiety / depressed mind state. While the specific modality of effect is not well understood, a Black Box Warning has been issued with Effexor and with other SSRI and SNRI anti-depressants advising of risk of suicide. Thoughts of suicide (suicide ideation) as potential risk of suicide as shown in studies by Wyeth and reported on their datasheet for effexor were twice that of placebo (4% compared to 2%, however, no suicides occurred in these trials.^[5] The black box warnings advise physicians to carefully monitor patients for suicide risk at start of usage and whenever the dosage is changed. There is an additional risk if a physician misinterprets patient expression of adverse effects such as panic or akithesia as symptomatic of depression or obsessive compulsive disorder and increases the dose thereby worsening the adverse effects. Careful assessment of patient history is therefore absolutely essential as a failsafe measure or the risk of suicide is compounded. As for other anti-depressants, caution is advisable if a patient has comorbid risk factors such as drug abuse. Family members should be advised of this potentially fatal side effect so they may bring the patient to a hospital emergency for surveillance and protection. Patients who are at high risk for suicide are not generally selected for studies, therefore actual risk in specific groups is not fully understood. As the black box warnings indicate, caution is needed so that patients at risk are protected.

Another risk is Serotonin syndrome. This is a serious effect that can be caused by interactions with other drugs and is potentially fatal.^[12]

Common side effects

Less common to rare side-effects

Dose dependency of adverse events

A comparison of adverse event rates in a fixed-dose study comparing venlafaxine 75, 225, and 375 mg/day with placebo revealed a dose dependency for some of the more common adverse events associated with venlafaxine use. The rule for including events was to enumerate those that occurred at an incidence of 5% or more for at least one of the venlafaxine groups and for which the incidence was at least twice the placebo incidence for at least one venlafaxine group. Tests for potential dose relationships for these events (Cochran-Armitage Test, with a criterion of exact 2-sided p-value <= 0.05) suggested a dose-dependency for several adverse events in this list, including chills, hypertension, anorexia, nausea, agitation, dizziness, somnolence, tremor, yawning, sweating, and abnormal ejaculation.[Wyeth Monograph]

Physical and Psychological Dependency

In vitro studies revealed that venlafaxine has virtually no affinity for opiate, benzodiazepine, phencyclidine (PCP), or N-methyl-D-aspartic acid (NMDA) receptors. It has no significant CNS stimulant activity in rodents. In primate drug discrimination studies, venlafaxine showed no significant stimulant or depressant abuse liability.^[5]

Notwithstanding these in-vitro and non-human research findings, some patients using venlafaxine may become dependent on this drug. This is especially noted if a patient misses a dose but can still occur even when reduction of dosage is done with a doctor's care. Patients may still experience withdrawal symptoms described as severe discontinuation syndrome. Patients commonly recognize the link between noncompliance or stopping their medication and discontinuation symptoms and often describe their experience as dependence or "addiction".^[13] The term "addiction" has a number of meanings, some authorities wish to reserve this term for drugs causing euphoria such as the opiates, cocaine, and some tranquillizers but the term is used in other context that is equally valid semantically. Many other drugs can cause withdrawal symptoms but are not associated with addiction or dependence, for example, anticonvulsants, beta-blockers, nitrates, diuretics, centrally acting antihypertensives, sympathomimetics, heparin, tamoxifen, dopaminergic agents, antipsychotics, and lithium.^[13] However, as venlafaxine has direct impact on mood (i.e. anti-depressant), it may be difficult to discontinue taking a drug that is thought to or may improve mental well-being.^[14] This occurs especially with patients who have side effects from the drug and wish to stop using it. It is important that prescribing doctors explain the details of this drug to patients with care.

Severe discontinuation (withdrawal) syndrome

Sudden discontinuation of venlafaxine has a high risk of causing potentially severe withdrawal symptoms.^[15] The high risk of withdrawal symptoms may reflect venlafaxines short half-life.^[13] Missing even a single dose can induce discontinuation effects in some patients.^[6] Discontinuation is similar in nature to those of SSRIs such as Paroxetine (Paxil® or Seroxat®).

Venlafaxine has, along with the general group of SSRI and SNRI anti-depressants, been the subject of controversy as to efficacy and safety. A petition is on the internet containing anecdotal comments regarding the severe side effects of venlafaxine, severe withdrawal difficulties, and that these effects were not communicated to them by their physicians. While this petition is not a scientifically designed study that has been evaluated by statistical analysis, the common complaints as expressed by this large number of users do carry the weight of preponderance of numbers and deserve attention and concern in relation to the prescribing of venlafaxine.

Overdose

Most patients overdosing with venlafaxine develop only mild symptoms. However, severe toxicity is reported with the most common symptoms being CNS depression, serotonin toxicity, seizure, or cardiac conduction abnormalities.^[16] Venlafaxines toxicity appears to be higher than other SSRIs, with a fatal toxic dose closer to that of the tricyclic antidepressants than the SSRIs. Doses of 900 mg or more are likely to cause moderate toxicity.^[1] Deaths have been reported following large doses.^[17]^[18]

Management of Overdosage

There is no specific antidote for venlafaxine and management is generally supportive, providing treatment for the immediate symptoms. Administration of activated charcoal can prevent absorption of the drug. Monitoring of cardiac rhythm and vital signs is indicated. Seizures are managed with benzodiazepines or other anti-convulsants. Due to venlafaxines high volume of distribution, forced diuresis, hemodialysis, exchange transfusion, or hemoperfusion are unlikely to be of benefit in hastening the removal of the drug.^[19]

Footnotes

^ ^a ^b Whyte I, Dawson A, Buckley N (2003). "Relative toxicity of venlafaxine and selective serotonin reuptake inhibitors in overdose compared to tricyclic antidepressants". QJM 96 (5): 369-74. PMID 12702786.
^ [No Authors listed]. Acute Effectiveness of Additional Drugs to the Standard Treatment of Depression. ClinicalTrials.gov. Retrieved on 23 June 2005.
^ Goeringer K, McIntyre I, Drummer O (2001). "Postmortem tissue concentrations of venlafaxine". Forensic Sci Int 121 (1-2): 70-5. PMID 11516890.
^ Wellington K, Perry C (2001). "Venlafaxine extended-release: a review of its use in the management of major depression.". CNS Drugs 15 (8): 643-69. PMID 11524036.
^ ^a ^b ^c ^d ^e ^f ^g Effexor Medicines Data Sheet. Wyeth Pharmaceuticals Inc (2006). Retrieved on 17 September 2006.
^ ^a ^b Parker G, Blennerhassett J (1998). "Withdrawal reactions associated with venlafaxine". Aust N Z J Psychiatry 32 (2): 291-4. PMID 9588310.
^ Rowbotham M, Goli V, Kunz N, Lei D (2004). "Venlafaxine extended release in the treatment of painful diabetic neuropathy: a double-blind, placebo-controlled study". Pain 110 (3): 697-706. PMID 15288411.
^ Ozyalcin S, Talu G, Kiziltan E, Yucel B, Ertas M, Disci R (2005). "The efficacy and safety of venlafaxine in the prophylaxis of migraine". Headache 45 (2): 144-52. PMID 15705120.
^ Mayo Clinic staff (2005). Beyond hormone therapy: Other medicines may help. Hot flashes: Ease the discomfort of menopause. Mayo Clinic. Retrieved on 19 August 2005.
^ Schober C, Ansani N (2003). "Venlafaxine hydrochloride for the treatment of hot flashes". Ann Pharmacother 37 (11): 1703-7. PMID 14565812.
^ DeVane CL. (2003). "Immediate-release versus controlled-release formulations: pharmacokinetics of newer antidepressants in relation to nausea". J Clin Psychiatry 64 (Suppl 18): 14-9. PMID 14700450.
^ Adan-Manes J, Novalbos J, López-Rodríguez R, Ayuso-Mateos J, Abad-Santos F (2006). "Lithium and venlafaxine interaction: a case of serotonin syndrome". J Clin Pharm Ther 31 (4): 397-400. PMID 16882112.
^ ^a ^b ^c Haddad P (2001). "Antidepressant discontinuation syndromes". Drug Saf 24 (3): 183-97. PMID 11347722.
^ Double D (1997). "Prescribing antidepressants in general practice. People may become psychologically dependent on antidepressants". BMJ 314 (7083): 829. PMID 9081020.
^ Fava M, Mulroy R, Alpert J, Nierenberg A, Rosenbaum J (1997). "Emergence of adverse events following discontinuation of treatment with extended-release venlafaxine". Am J Psychiatry 154 (12): 1760-2. PMID 9396960.
^ Blythe D, Hackett L (1999). "Cardiovascular and neurological toxicity of venlafaxine". Hum Exp Toxicol 18 (5): 309-13. PMID 10372752.
^ Mazur J, Doty J, Krygiel A (2003). "Fatality related to a 30-g venlafaxine overdose". Pharmacotherapy 23 (12): 1668-72. PMID 14695048.
^ Banham N (1998). "Fatal venlafaxine overdose". Med J Aust 169 (8): 445, 448. PMID 9830400.
^ Hanekamp B, Zijlstra J, Tulleken J, Ligtenberg J, van der Werf T, Hofstra L (2005). "Serotonin syndrome and rhabdomyolysis in venlafaxine poisoning: a case report.". Neth J Med 63 (8): 316-8. PMID 16186642.

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