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Q: Mixing Zoloft and tramadol ( No Answer,   4 Comments )
Subject: Mixing Zoloft and tramadol
Category: Health
Asked by: discostu-ga
List Price: $10.00
Posted: 25 Apr 2003 05:40 PDT
Expires: 25 May 2003 05:40 PDT
Question ID: 195235
I am looking for statistics.
1. How many people are prescribed and are currently taking the
following medications: Tramadol & Zoloft.
2. What percentage of these people have had adverse reactions?
3. Do PHYSICIANS generally consider this mix safe?


Request for Question Clarification by mvguy-ga on 25 Apr 2003 08:16 PDT
Do you want the number of people taking Tramadol and the number of
people taking Zoloft, or are you looking specifically for the number
of people who take both drugs?  Thanks.

Clarification of Question by discostu-ga on 25 Apr 2003 08:31 PDT
I am looking for the number of people on both (concommitant)

Thank you.
There is no answer at this time.

Subject: Re: Mixing Zoloft and tramadol
From: drbrains-ga on 27 Apr 2003 17:20 PDT
I don't believe you're likely to get an answer to the first two
questions.  There's no nationwide registry of who is on what drug -
although you'd be surprised at what large chain pharmacies keep track
of; they sell the info to big drug companies for a tidy sum.

Drug companies are required to keep track of adverse events once the
drug has been approved, although most do not care to make that
information public when they are not required to do so, for obvious

Here is what Epocrates Pro, a Palm application for doctors, has to say
about tramadol and sertraline (Zoloft):

"Caution advised; combo may increase risk of serotonin syndrome,
seizures (additive effects; hepatic metabolism inhibited)"

I personally wouldn't prescribe them together after reading something
like that.

But in my practice, I don't use tramadol at all.  I don't like it.  I
find it addictive, expensive, has bizarre drug interactions like this
one, and in the final analysis I suspect it's working at opiate
receptors like the regular opiates, so I tend to prefer a good old
narcotic like Percocet.

This isn't to be construed as advice for any specific situation or
patient; only a physician who is treating an individual patient can be
expected to make the right treatment decisions for that patient.
Subject: Re: Mixing Zoloft and tramadol
From: discostu-ga on 28 Apr 2003 06:02 PDT
Thank you for your comment,. I assume from your statement you are
doctor. My probelm is this. Tramadol works great for me. However I
have found the intereaction you spoke about. My primary care physician
told me "there is a remote chance of a seizure mixing the two, but it
is rare". I have checked with pharmacists around the net and have
received so much conflicting info it would make your head spin. Do you
find that seziures are a risk or is it usually just for people with a
history of both? Have you seen people on both? Is it common? I realize
that you are a doctor and would be willing to pay you for your info.

Thank you.
Subject: Re: Mixing Zoloft and tramadol
From: hollygolightly-ga on 28 Apr 2003 21:02 PDT
I agree with the doctor. Trash the Ultram and get yourself a good old,
true narcotic. But stay away from Percocet; the acetaminophen makes it
too risky to abuse. Your best bet is a pure opiate with no aspirin or
acetaminophen. But NOT Demerol; one of its metabolites, normeperidine,
is extremely toxic when the drug is taken for prolonged periods or at
high doses. My choice is either morphine sulphate or Dilaudid. If you
start taking either of these, you'll probably no longer need an SSRI
like Zoloft. Although you'll probably need a good stool softener.
Subject: Re: Mixing Zoloft and tramadol
From: jxc-ga on 04 May 2003 04:38 PDT
I take it that your interest is more in regard to the possible
interactions of Zoloft and Tramadol than statistics. In order to
provide a little background information:

Zoloft (also known as Sertraline hydrochloride) is a
serotonin-specific re-uptake inhibitor (SSRI) commonly used as an

Tramadol (also marketed as Tramal, Ultram, Ultracet, or Zydol) is a
relatively new analgesic (pain-killer) which acts by binding to
mu-opioid receptors and inhibiting the reuptake of noradrenaline and
serotonin. It was first introduced in Germany in 1977 and approved for
oral use in the US in 1995.

1. How many people are prescribed and are currently taking the
following medications: Tramadol & Zoloft.

Worldwide numbers on these statistics do not exist.

In the US, the Food and Drug Administration ( ) is
responsible for collecting safety information on all approved drugs
and is the most likely source of statistics on adverse reactions. You
can search for Tramadol or Sertraline from their website.

2. What percentage of these people have had adverse reactions? 

A MEDLINE search of papers describing tramadol and sertraline use
reveals only 2 case reports. Your local library can help you obtain

	1. Sauget D.  Franco PS.  Amaniou M.  Mazere J.  Dantoine T.
	[Possible serotonergic syndrome caused by combination of tramadol
	and sertraline in an elderly woman]. [French] [Letter] Therapie.
	57(3):309-10, 2002 May-Jun. 
	UI: 12422548 

	2. Mason BJ.  Blackburn KH. Possible serotonin syndrome associated
	with tramadol and sertraline coadministration. [Journal Article]
	Annals of Pharmacotherapy.  31(2):175-7, 1997 Feb. 
	UI: 9034418 

Unfortunately I do not have copies or access to either of these two
papers at this time. Nevertheless, part of the abstract from the
second paper describes:

	CASE SUMMARY: A 42-year-old woman developed atypical
	chest pain, sinus tachycardia, confusion, psychosis, sundowning,
	agitation, diaphoresis, and tremor. She was taking multiple
	medications, including tramadol and sertraline. The tramadol
	dosage had recently been increased, resulting in what was believed
	to be serotonergic syndrome.

A MEDLINE search of Tramadol and SSRIs is more revealing, with
relevant articles:


MEDLINE <1966 to April Week 4 2003>
1. Lange-Asschenfeldt C.  Weigmann H.  Hiemke C.  Mann K. Serotonin
syndrome as a result of fluoxetine in a patient with tramadol abuse:
plasma level-correlated symptomatology. Journal of Clinical
Psychopharmacology.  22(4):440-1, 2002 Aug.
UI: 12172351 

2. Gonzalez-Pinto A.  Imaz H.  De Heredia JL.  Gutierrez M.  Mico JA.
Mania and tramadol-fluoxetine combination. American Journal of
Psychiatry.  158(6):964-5, 2001 Jun.
UI: 11384912 

3. Ripple MG.  Pestaner JP.  Levine BS.  Smialek JE. Lethal
combination of tramadol and multiple drugs affecting serotonin.
[Review] [13 refs] American Journal of Forensic Medicine & Pathology. 
21(4):370-4, 2000 Dec.
UI: 11111800 

The death of a 36-year-old alcoholic man who died after developing
seizure activity while being treated with tramadol, as well as with
venlafaxine, trazodone, and quetiapine, all of which interact with the
neurotransmitter serotonin, is reported. The decedent, who had a
history of chronic back pain, alcoholism, depression, mild
hypertensive cardiovascular disease, and gastritis, had just been
discharged from the hospital after 4 days of alcohol detoxification
treatment. During the admission, no withdrawal seizures were noted.
The morning after discharge, a witness observed the decedent
exhibiting seizure activity and then collapsing. An autopsy was
performed approximately 6 hours after death, and the anatomic findings
were consistent with seizure activity and collapse, which included
biting injuries of the tongue and soft-tissue injuries of the face.
Toxicologic analysis identified tramadol, venlafaxine, promethazine,
and acetaminophen in the urine; tramadol (0.70 mg/L) and venlafaxine
(0.30 mg/L) in the heart blood, and 0.10 mg of tramadol in 40 ml of
submitted stomach contents. No metabolites, such as acetate, acetone,
lactate, and pyruvate, were found in the specimens that would be
characteristically found in a person with alcohol withdrawal syndrome.
The threshold for seizures is lowered by tramadol. In addition, the
risk for seizure is enhanced by the concomitant use of tramadol with
selective serotonin reuptake inhibitors or neuroleptics, and its use
in patients with a recognized risk for seizures, i.e., alcohol
withdrawal. The cause of death in this individual was seizure activity
complicating therapy for back pain, depression, and alcohol withdrawal
syndrome. The data in Adverse Event Reporting System of the Food and
Drug Administration from November 1, 1997 to September 8, 1999 was
reviewed along with a MEDLINE search from 1966 to the present. This
case appears to be the first reported death caused by seizure activity
in a patient taking tramadol in combination with drugs that affect
serotonin. [References: 13]
Office of the Chief Medical Examiner for the State of Maryland,
Baltimore 21201-1020, USA.

4. Reus VI.  Rawitscher L. Possible interaction of tramadol and
antidepressants.[comment]. American Journal of Psychiatry. 
157(5):839, 2000 May.
UI: 10784494 
Comment on: Am J Psychiatry. 1999 Apr;156(4):660-1; PMID: 10200754

5. Kesavan S.  Sobala GM. Serotonin syndrome with fluoxetine plus
tramadol. Journal of the Royal Society of Medicine.  92(9):474-5, 1999
UI: 10645303 
Department of Medicine, Huddersfield Royal Infirmary, UK.

6. Lantz MS.  Buchalter EN.  Giambanco V. Serotonin syndrome following
the administration of tramadol with paroxetine. International Journal
of Geriatric Psychiatry.  13(5):343-5, 1998 May.
UI: 9658268 

7. Egberts AC.  ter Borgh J.  Brodie-Meijer CC. Serotonin syndrome
attributed to tramadol addition to paroxetine therapy. International
Clinical Psychopharmacology.  12(3):181-2, 1997 May.
UI: 9248876 
Netherlands Pharmacovigilance Foundation, Tilburg, The Netherlands.

8. Mason BJ.  Blackburn KH. Possible serotonin syndrome associated
with tramadol and sertraline coadministration. Annals of
Pharmacotherapy.  31(2):175-7, 1997 Feb.
UI: 9034418 

OBJECTIVE: To report a possible case of serotonin syndrome associated
with coadministration of tramadol hydrochloride and sertraline
hydrochloride. CASE SUMMARY: A 42-year-old woman developed atypical
chest pain, sinus tachycardia, confusion, psychosis, sundowning,
agitation, diaphoresis, and tremor. She was taking multiple
medications, including tramadol and sertraline. The tramadol dosage
had recently been increased, resulting in what was believed to be
serotonergic syndrome. DISCUSSION: Serotonin syndrome is a toxic
hyperserotonergic state that develops soon after initiation or dosage
increments of the offending agent. Patients may differ in their
susceptibility to the development of serotonin syndrome. The (+)
enantiomer of tramadol inhibits serotonin uptake. Tramadol is
metabolized to an active metabolite, M1, by the CYP2D6 enzyme. If this
metabolite has less serotonergic activity than tramadol, inhibition of
CYP2D6 by sertraline could have been a factor in the interaction.
CONCLUSIONS: Clinicians should be aware of the potential for serotonin
syndrome with concomitant administration of sertraline and tramadol.
College of Pharmacy, Idaho State University, Boise, USA.


MIMS reports:

"Adverse Reactions Adverse reactions that may occur after
administration of tramadol resemble those known to occur with opioids.
Adverse reactions were recorded in 13,802 patients from trials with
different formulations of tramadol. The nature and incidence of
reactions (in CIOMS format where very common > 1/10; common > 1/100
and < 1/10; uncommon greater than or equal to 1/1,000 and < 1/100;
rare greater than or equal to 1/10,000 and < 1/1,000; and very rare
less than or equal to 1/10,000) were as follows.

"Cardiovascular. Uncommon: orthostatic dysregulation (tendency to
collapse, and cardiovascular collapse) and tachycardia, flushing.
Rare: increase in blood pressure, bradycardia.

"Respiratory. Very rare: worsening of asthma (causality not
established), respiratory depression (when the recommended doses are
considerably exceeded and other respiratory depressant substances are
administered concomitantly).

"Gastrointestinal. Very common: nausea. Common: vomiting,
constipation. Uncommon: dyspepsia, diarrhoea, abdominal pain,
flatulence, urge to vomit. Rare: changes in appetite. Very rare:
elevated liver enzymes.

"Neurological. Very common: dizziness. Common: autonomic nervous
effects (mainly dry mouth, perspiration), headache, sedation,
asthenia, fatigue. Uncommon: trembling. Rare: elevated mood, sensory
effects, convulsions, hallucinations, confusion, coordination
disturbance, sleep disturbance, motor system weakness.

"Hypersensitivity and skin. Common: sweating. Uncommon: skin
reactions, pruritus, rash. Rare: shock reactions, anaphylaxis,
allergic reactions.

"Genitourinary. Rare: micturition disorders (difficulty in passing
urine and urinary retention).

"Special senses. Rare: visual disturbance (blurred vision). 

"The incidence of CNS irritation (dizziness), autonomic nervous
effects (perspiration), orthostatic dysregulation (tendency to
collapse and cardiovascular collapse) and tachycardia, and nausea/
urge to vomit/ vomiting can be increased with rapid intravenous
administration and also tends to be dose dependent. No tests of
significance have been performed.

"Drug abuse and dependence. Although tramadol can produce drug
dependence of the mu-opioid type (like codeine or dextropropoxyphene)
and potentially may be abused, there has been little evidence of abuse
in clinical experience to date. In clinical trials, tramadol produced
some effects similar to an opioid, and at supratherapeutic doses was
recognised as an opioid in subjective/ behavioural studies. Tolerance
development has been reported to be relatively mild and withdrawal,
when present, is not considered to be as severe as that produced by
other opioids. Symptoms of withdrawal reactions, similar to those
occurring during opiate withdrawal, may occur as follows: agitation,
anxiety, nervousness, insomnia, hyperkinesia, tremor and
gastrointestinal symptoms. Part of the activity of tramadol is thought
to be derived from its active metabolite, which is responsible for
some delay in onset of activity and some extension of the duration of
mu-opioid activity. Delayed mu-opioid activity is believed to reduce a
drug's abuse liability."

3. Do PHYSICIANS generally consider this mix safe?

Certainly review of current pharmacopoeias suggest that the use of
serotonin metabolism modifying drugs (including SSRIs and MAOIs) are
not recommended.

(MIMS - )
	<Other serotonergic drugs.> Coadministration of sertraline with
	other drugs which enhance serotonergic neurotransmission, such
	as tryptophan or fenfluramine or 5HT agonists, should be
	undertaken only with caution and avoided whenever possible due
	to the potential for pharmacodynamic interaction (see Interactions)

	<Use with other serotonergic agents.> The presence of another drug
	that increases serotonin by any mechanism should alert the treating
	doctor to the possibility of an interaction. In isolated cases there
	have been reports of serotonin syndrome in a temporal connection
	with the therapeutic use of tramadol in combination with other
	serotonergic medicines such as selective serotonin reuptake
	(SSRIs). Signs of serotonin syndrome may be, for example, confusion,
	agitation, fever, sweating, ataxia, hyperreflexia, myoclonus and
	diarrhoea. Withdrawal of the serotonergic medicines usually brings
	about a rapid improvement. Drug treatment depends on the nature
	and severity of the symptoms.

As a medical doctor and a regular prescriber of Tramadol, I must say
that I choose not to use it when a patient is on a Zoloft or any other
SSRI due to the potential risk of developing a serotonin-syndrome, and
that is the consensus opinion of my colleagues. Otherwise, Tramadol is
also known to reduce seizure threshold (i.e. make seizures slightly
more likely) so I generally also avoid it in patients with a known
history of epilepsy or other seizure disorder.

On the other hand, I find that Tramadol is generally quite effective,
and has surprisingly little side effects. Certainly nausea is the most
common one I see. It seems generally safer than a straight-out opiate
like Morphine especially in that patients are less likely to run into
breathing difficulties (respiratory depression).



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