Medscape - Venlafaxine and Serious Withdrawal Symptoms: Warning to Drivers

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[sSRI-Research] Medscape - Venlafaxine and Serious Withdrawal

Symptoms: Warning to Drivers

 

 

 

 

This Medscape article is FYI. Venlafaxine is marketed by Wyeth

Pharmaceuticals Inc. under the trade name, Effexor, in the United

States . This med has a notoriously short half-life and abrupt,

spontaneous, and serious withdrawal problems. The writer warns about

driving a car or use heavy or dangerous machinery while trying to

discontinue this medication. <emphasis added>

 

 

 

 

http://www.medscape.com/viewarticle/506427

--

 

Venlafaxine and Serious Withdrawal Symptoms: Warning to Drivers

 

 

Daniel M. Campagne, PhD Medscape General Medicine. 2005;7(3):22.

©2005 Medscape

Posted 07/06/2005

 

Abstract

Venlafaxine is a widely used serotonin- and norepinephrine-reuptake

inhibitor-type antidepressant that causes serious adverse effects in

at least 5% of cases. Serious withdrawal symptoms may occur within

hours of cessation or reduction of the usual dosage and may affect

motor and coordination skills to such a degree that patients should be

explicitly urged either to adhere to a strict medication routine or

not to drive a car. Recent clinical evidence about withdrawal symptoms

is presented that may indicate incidents in noradrenergic activity

irrespective of dosage.

 

Keywords: Venlafaxine, withdrawal, discontinuance syndrome, serotonin,

adrenaline, seizures, drivers.

 

Objective: To present clinical information and a brief review of

severe venlafaxine withdrawal symptoms that may occur within hours

after cessation and affect the ability to drive a motor vehicle or use

heavy or dangerous machinery.

 

Method: Review of own and third-party clinical records. Search in

PubMed and other databases with terms: venlafaxine, discontinuation,

withdrawal, syndrome, serotonin, noradrenaline, noradrenergic,

serotonergic, seizures, epilepsy.

 

Serotonin, Noradrenaline Withdrawal

Venlafaxine hydrochloride (Effexor, Dobupal) is a

phenylethylamine-derivative antidepressant and anxiolytic agent that

acts as a serotonin- and noradrenaline-reuptake inhibitor (SNRI). It

is used primarily in major depressive disorder, with labeled uses

including generalized anxiety disorder and social phobia. Nonlabeled

uses include depressive symptom remission, obsessive-compulsive

disorder, and chronic pain syndromes.

 

Most selective serotonin-reuptake inhibitors (SSRI) and SSNRIs are

reported to cause serious adverse effects in approximately 5% of

patients, according to its manufacturer.[1] Venlafaxine is no

exception. Among the adverse effects are a number of withdrawal

symptoms that form " discontinuance syndromes, " sometimes mistakenly

identified with what Sternbach in 1991 proposed as the " serotonin

syndrome " .[2] Venlafaxine's half-life is only 4 hours. Its primary

metabolite, O-desmethylvenlafaxine, has a half-life of 10 hours. In

the past 10 years, a number of clinical reports of severe venlafaxine

withdrawal symptoms have been published, and for the most part these

effects are duly reflected in generally available information. Widely

consulted drug information services, such as Medscape DrugInfo,

American Hospital Formulary Service Drug Information, and First

DataBank, list the following withdrawal symptoms as " serious " :

agitation, anorexia, anxiety, confusion, impaired coordination,

diarrhea, dizziness, dry mouth, dysphoric mood, fasciculation,

fatigue, headaches, hypomania, insomnia, nausea, nervousness,

nightmares, sensory disturbances (including shock-like electrical

sensations), somnolence, sweating, tremor, vertigo, and vomiting.

 

Patient hand-outs contain several useful warnings and physicians know

that, because any psychoactive drug may impair judgment, thinking, or

motor skills, patients should be cautioned about operating hazardous

machinery, including automobiles, until they are reasonably certain

that venlafaxine does not adversely affect their ability to engage in

such activities. Venlafaxine is structurally similar to phencyclidine

and thus should not be discontinued abruptly. If the drug has been

administered for longer than 1 week, the dose should be tapered over 7

to 10 days to prevent a withdrawal syndrome (headache, nausea,

dizziness, insomnia, and nervousness).[3]

 

However, little mention is found of the possibly severe effects of

abrupt discontinuation or postponing ingestion of the daily dose for

as little as 8 to 12 hours. Although a patient may have established

that taking the drug does not noticeably affect the ability to drive a

car or operate machinery, taking the drug in the evening if it is

usually taken in the morning or forgetting to take the daily dose just

once may induce sudden and severe disturbances in physical and mental

condition that most definitely can impair normal functioning.

 

Recent Case Histories: Withdrawal Effects Are Not Dose-Dependent

Case 1: Standard Dose. Female, white, age 35, no other pathologies,

diagnosed for major depressive disorder with anger attacks. Treated

with extended-release venlafaxine 150 mg for 4 months with concurrent

psychotherapy, with positive results: Beck's Depression Inventory

score reduced from 38 to 14; functionality restored.

 

The patient ran out of medication on a Thursday and could not get in

touch with her doctor until the next Monday. On Friday, only 12 hours

after the usual time of taking the medication, she felt a noticeable

change in mood, dizziness, and nausea. She experienced a sensation in

her head as if electrical discharges " popped " and could not

concentrate to the extent that she was unable to drive her car back

from where she had gone. By Friday evening (18 hours after cessation),

the " popping " in her head had become worse and she vomited after

dinner. Depression symptoms reappeared acutely, and she could not stop

crying. At first, she did not equate these symptoms to the missed dose

of venlafaxine, but thought she might have contracted the flu.

However, the symptoms continued and intensified over the weekend and

only reduced when, on Monday, she started again on venlafaxine. She

was inadvertently given the lower dose of 75 mg, which did not quite

restore her mood to the previous level, although the " electrical

popping " sensation in her head stopped and the nausea was reduced.

 

Case 2: High Dose. (Provided by J. Garcia Campayo, MD, PhD, Dept of

Psychiatry, Miguel Servet Hospital, University of Zaragoza, Spain)

 

Female, white, age 43, first diagnosis of major depressive disorder of

moderate intensity; maternal history of depressive disorder.

Successfully treated with 225 mg of venlafaxine (75-75-75) for 12

months with no adverse effects. The patient decided she could do

without the medication and stopped taking it abruptly. Withdrawal

effects appeared within a day and included headaches, dizziness, and

instability, with a sense of losing balance (although she did not

actually fall down), sense of sparks and electrical discharges in her

head, and intense anxiety. When treatment at the original level was

reinstated and progressively reduced over a period of 2 weeks, the

symptoms disappeared.

 

Case 3: Low Dose. (Provided by N. Mjellem, MD, PhD, CEO World

Federation of Biological Psychiatry, Oslo, Norway)

 

Physician (psychiatrist), female, white, age 54, major depressive

disorder (recurrent). Took 37.5 mg venlafaxine daily for 3 weeks.

Experienced side effects while taking the low doses of the medication,

such as aggressive and paranoid behavior after limited consumption of

alcohol, frequent headaches, and tinnitus. The last symptom made her

work situation difficult, so she tapered the medication at 18.75 mg

over a 2-week period. Neurologic symptoms appeared during the tapering

phase, including lasting severe dizziness and short, intense feelings

of electrical currents in her head, causing disorientation.

 

The symptoms disappeared, only to reappear 2 weeks after termination

was complete and persisted for some weeks more.

 

These cases illustrate 2 important aspects of venlafaxine medication

that warrant specific warning to patient and physician:

 

1.. Several of the documented withdrawal effects do not fit

with a " serotonin-discontinuance syndrome, " but point to a

" noradrenaline-mediated withdrawal syndrome. "

 

 

2.. Venlafaxine withdrawal symptoms can be severe. Even a

relatively short delay in taking the daily dose could severely impair

motor skills.[4-8] At present this is insufficiently reflected in

patient handouts and the physician may not sufficiently point out the

need for a strict adherence to a fixed medication routine.

 

 

 

 

As regards 1: A Role for Noradrenaline

Sternbach's review and interpretation of the data concentrated on a

toxic and potentially fatal condition that commonly results from the

interaction between serotonergic agents and monoamine-oxidase

inhibitors. Later reports indicate that co-administration of other

psychotropic and nonpsychotropic agents that influence the

serotoninergic system can cause the serotonin syndrome.[9] This

interaction is hypothesized to hyperactivate central (1A) serotonin

(5-hydroxytryptamine [5-HT]) receptors, causing changes in mental

status, restlessness, myoclonus, hyperreflexia, diaphoresis,

shivering, and tremor. In the early stages, this toxic state can be

resolved by discontinuing the serotonergic agent or through use of

5-HT receptor antagonists. Cyproheptadine and chlorpromazine have been

suggested for more severe cases.[10] A recent animal study[11] found

limited efficacy of pretreatment with 5-HT (2A) antagonists, although

such therapy is considered clinically effective.[12] The former study

found that noradrenaline levels increased along with increased

serotonin, but to a significantly lower level in the animals

pretreated with the 5-HT (2A) antagonists. The results of the

study[11] may also suggest that increased noradrenaline levels

contribute to the severity of the condition. However, during

withdrawal of venlafaxine, both serotonin and noradrenaline levels

decrease instead of increase, ruling out toxic levels of serotonin and

noradrenaline as a probable cause of the withdrawal symptoms, that can

be hypothesized to result from a (too) rapid deprivation of

neurotransmitter levels. Which neurotransmitters apart from 5-HT (2A)

antagonists are involved may be deduced from some of the less

often-reported withdrawal symptoms, such as the " electrical discharges

in the head. " These symptoms are similar to preseizure symptoms in

epilepsy, and there is now evidence of the relevant role of the

noradrenergic system in modulating seizures,[13] providing further

evidence that noradrenergic and/or serotonergic deficits may

contribute to epilepsy and depression.[14] Although this does not

necessarily establish a link between epileptiform manifestations and

venlafaxine withdrawal, it does suggest that some of the

venlafaxine-withdrawal symptoms are more likely to be caused by a lack

of noradrenergic than of serotonergic action, contrary to the commonly

accepted theory.[15] A hypothesis worth investigating is whether the

" electrical discharges in the head " are the result of a " bursting "

activity of noradrenergic receptors in the absence of a hitherto

customary neurotransmitter presence. Among the few case reports

available, a recent report again attributes this symptom to a

serotonin effect, possibly confounding the withdrawal effects of

venlafaxine with a serotonin syndrome.[5] In this case, the authors

refer to the " buzz " noted upon withdrawal in approximately 5% of

patients treated with SSRIs and hypothesize that the sensations may be

a form of paresthesias. However, the clinical evidence they provide

gives contradictory information. Their patient no.1 was taken off

venlafaxine but given fluoxetine, whereupon the brain shocks started,

so the symptoms appeared to be caused either by venlafaxine withdrawal

or by an unlikely serotonin syndrome. Their patient no.2 was gradually

tapered from venlafaxine but given citalopram and also experienced the

shocklike sensations. Finally, they cite the case of a 72-year-old

woman in whom venlafaxine withdrawal symptoms were readily relieved by

sertraline, but not by maprotiline, and 3 other cases that were

" treated successfully by fluoxetine. " The authors rightfully indicated

that " an unexplained aspect of our two patients is that the addition

of an SSRI, which theoretically would result in an increase of

serotonin, did not alleviate withdrawal symptoms... "

 

The 3 case reports presented here suggest that this specific

venlafaxine withdrawal symptom appears irrespective of dosage.

Although venlafaxine in the lower daily dose range (18.75 to 75 mg)

blocks reuptake of serotonin more than reuptake of noradrenaline, all

SSRIs and SSNRIs affect both serotonin and noradrenaline levels,

depending on their specificity. The particular withdrawal effect

discussed here compares more closely to preseizure signs than to

paresthesias, and thus could be attributed to noradrenergic more than

serotoninergic action.

 

As regards 2: The Need for a Warning to Drivers

As discussed, withdrawal symptoms occur in patients who have received

both low and high doses of venlafaxine and result in a discontinuance

syndrome with several manifestations, especially severe dizziness and

disorientation, that are incompatible with driving a car or using

heavy or dangerous machinery. Although standard warnings are given

that taking the drug may affect those abilities, and patients are also

generally advised not to stop the medication abruptly, severe

withdrawal symptoms, such as confusion, impaired coordination, sensory

disturbances, vertigo, delirium, strokelike symptoms, and

depersonalization, may occur only hours after reduction or cessation

and should warrant a specific " warning to drivers. " Whenever

venlafaxine is not taken at the usual time or in the usual quantity,

special caution is warranted. Even when the dosage is being tapered,

the physician should instruct the patient to beware of these symptoms,

because the recommended tapering period of 2 weeks is not necessarily

sufficient. Cases have been documented in which even tapering over a

period of 3 months was insufficient.[16]

 

Conclusions

Venlafaxine is a widely used antidepressant. The World Health

Organization asserts that SSRI and SSRNI antidepressants cause

dependence and that discontinuation symptoms can be troublesome and

persist notwithstanding taper therapy.[17] The specific symptoms that

can result from venlafaxine reduction or discontinuation as reviewed

here seriously impair driving ability and should be prevented by

strict dosage discipline and adequate warnings.

 

References

1.. US Food and Drug Administration: Letter to Wyeth

Pharmaceuticals about violation of FDA regulations. March 18, 2004.

Available at: http://www.fda.gov/cder/warn/2004/Effexor.pdf Accessed

June 20, 2005.

2.. Sternbach H. The serotonin syndrome. Am J Psychiatry.

1991;148:705-713. Abstract

3.. Ellingrod VL, Perry PJ. Venlafaxine: a heterocyclic

antidepressant. Am J Hosp Pharmacy. 1994;51:3033-3046.

4.. Pinzani V, Ginies E, Robert L, Peyriere H, Abbar M, Blayac

JP. Venlafaxine withdrawal syndrome: report of six cases and review of

the literature. Rev Med Interne. 2000;21:282-284. Abstract

5.. Parker G, Blennerhassett J. Withdrawal reactions

associated with venlafaxine. Aust N Z J Psychiatry. 1998;32:291-294.

Abstract

6.. Reeves RR, Mack JE, Beddingfield JJ. Shock-like sensations

during venlafaxine withdrawal. Pharmacotherapy. 2003;23:678-681. Abstract

7.. van Noorden MS, Vergouwen AC, Koerselman GF. Delirium

during withdrawal of venlafaxine. Ned Tijdschr Geneeskd.

2001;29:146:1236-1237.

8.. Haddad PM, Devarajan S, Dursun SM. Antidepressant

discontinuation withdrawal symptoms presenting as 'stroke'. J

Psychopharmacol. 2001;15:139-141. Abstract

9.. Houlihan DJ. Serotonin syndrome resulting from

coadministration of tramadol, venlafaxine, and mirtazapine. Ann

Pharmacother. 2004;38:411-413. Epub 2004 Jan 23

10.. Jaunay E, Gaillac V, Guelfi JD. Serotonin syndrome. Which

treatment and when? Presse Med. 2001;17:30:1695-1700.

11.. Nisijima K, Shioda K, Yoshino T, Takano K, Kato S.

Diazepam and chlormethiazole attenuate the development of hyperthermia

in an animal model of the serotonin syndrome. Neurochem Int.

2003;43:155-164. Abstract

12.. Pan JJ, Shen WW. Serotonin syndrome induced by low-dose

venlafaxine. Ann Pharmacother. 2003;37:209-211. Abstract

13.. Giorgi FS, Ferrucci M, Lazzeri G, et al. A damage to

locus coeruleus neurons converts sporadis seizures into

self-sustaining limbic status epilepticus. Eur J Neurosci.

2003;17:2593-2601. Abstract

14.. Jobe PC, Dailey JW, Wernicke JF. A noradrenergic and

serotonergic hypothesis of the linkage between epilepsy and affective

disorders. Cit Rev Neurobiol. 1999;13:317-356.

15.. Gutierrez MA, Stimmel GL, Aiso JY. Venlafaxine: a 2003

update. Clin Ther. 2003;25:2138-2154. Abstract

16.. Sierra Santos L, Raigal Martin Y, Ortega Garcia A,

Berriochoa Martinez de Pison C, Aparicio Jabalquinto G: Venlafaxina y

sindrome de discontinuación. Atencion Primaria. 1999;24:617-618.

17.. Selective serotonin re-uptake inhibitors and withdrawal

reactions. WHO Drug Information. 1998;12:3, 136.

 

 

 

 

Daniel M. Campagne, PhD, Faculty of Psychology, Department of

Personality, Evaluation and Psychological Treatments, Universidad

Nacional de Educación a Distancia, Madrid, Spain; Head, Department of

Psychology, Clínica Bella Medica, Altea, Spain. Email:

danplaton

 

 

Disclosure: Daniel M. Campagne, PhD, has declared no relevant

financial relationships.