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SRIs and Upper Gastrointestinal Bleeding
SRIs and Upper Gastrointestinal Bleeding -- Posted by Roman Bystrianyk on 12-01-04 18:02
http://www.healthsentinel.com/briefs.php?id=26&title=SSRIs+and+Upper+Gastrointestinal+Bleeding&event=briefs_print_list_item
Francisco José de Abajo, Luis Alberto García Rodríguez, Dolores
Montero, "Association between selective serotonin reuptake inhibitors
and upper gastrointestinal bleeding: population based case-control
study", BMJ (British Medical Journal), October 23, 1999, Vol. 319,
Num. 0, pp. 1106-1109
"Objective: To examine the association between selective serotonin
reuptake inhibitors and risk of upper gastrointestinal bleeding.
Design: Population based case-control study. Setting: General
practices included in the UK general practice research database.
Subjects: 1651 incident cases of upper gastrointestinal bleeding and
248 cases of ulcer perforation among patients aged 40 to 79 years
between April 1993 and September 1997, and 10 000 controls matched for
age, sex, and year that the case was identified. Interventions: Review
of computer profiles for all potential cases, and an internal
validation study to confirm the accuracy of the diagnosis on the basis
of the computerised information. Main outcome measures: Current use of
selective serotonin reuptake inhibitors or other antidepressants
within 30 days before the index date. Results: Current exposure to
selective serotonin reuptake inhibitors was identified in 3.1% (52 of
1651) of patients with upper gastrointestinal bleeding but only 1.0%
(95 of 10 000) of controls, giving an adjusted rate ratio of 3.0 (95%
confidence interval 2.1 to 4.4). This effect measure was not modified
by sex, age, dose, or treatment duration. A crude incidence of 1 case
per 8000 prescriptions was estimated. A small association was found
with non-selective serotonin reuptake inhibitors (relative risk 1.4,
1.1 to 1.9) but not with antidepressants lacking this inhibitory
effect. None of the groups of antidepressants was associated with
ulcer perforation. The concurrent use of selective serotonin reuptake
inhibitors with non-steroidal anti-inflammatory drugs increased the
risk of upper gastrointestinal bleeding beyond the sum of their
independent effects (15.6, 6.6 to 36.6). A smaller interaction was
also found between selective serotonin reuptake inhibitors and low
dose aspirin (7.2, 3.1 to 17.1). Conclusions: Selective serotonin
reuptake inhibitors increase the risk of upper gastrointestinal
bleeding. The absolute effect is, however, moderate and about
equivalent to low dose ibuprofen. The concurrent use of non-steroidal
anti-inflammatory drugs or aspirin with selective serotonin reuptake
inhibitors greatly increases the risk of upper gastrointestinal
bleeding."
"In the past few years several case reports have shown an association
between selective serotonin reuptake inhibitors such as fluoxetine and
bleeding disorders. Most of the patients had mild bleeding disorders,
for example, ecchymoses, purpura, epistaxis, or prolonged bleeding
time but several had more serious conditions such as gastrointestinal
haemorrhage, genitourinary bleeding, and intracranial haemorrhage."
"The release of serotonin from platelets has an important role in
regulating the haemostatic response to vascular injury. Serotonin is
not synthesised in platelets but is taken up from the circulation by
serotonin transporters on the platelets, which are similar to those in
the human brain. At therapeutic doses fluoxetine and other selective
serotonin reuptake inhibitors have consistently been shown to block
this reuptake of serotonin by platelets leading to a depletion of
serotonin after several weeks of treatment. It is possible that these
drugs impair haemostatic function, at least under certain conditions,
and thereby increase the risk of bleeding. We tested this hypothesis
with data from an ongoing case-control study, which was set up to
estimate the risk of ulcer complications from non-steroidal
anti-inflammatory drugs."
"The source population was all patients aged 40 to 79 years between
April 1993 and September 1997, with at least 2 years' enrolment with
their general practitioner. Patients with cancer, oesophageal varices,
Mallory-Weiss disease, alcoholism, liver disease, or coagulopathies
were excluded."
"Overall, 1651 patients had upper gastrointestinal bleeding and 248
had ulcer perforation. Fifty two (3.1%) patients with upper
gastrointestinal bleeding were current users of selective serotonin
reuptake inhibitors; among controls the proportion of current users
was 1.0% (95 of 10 000) resulting in an adjusted rate ratio of 3.0
(2.1 to 4.4) (table 1). The effect measures were hardly modified by
sex (relative risk 3.2 for men and 3.0 for women) or age group (2.9
for patients aged less than 70 years and 3.4 for patients aged 70
years or older).The rate ratio associated with non-selective serotonin
reuptake inhibitors was 1.4 (1.1 to 1.9). No association was found
with antidepressants that have no action on the serotonin reuptake
mechanism (table 1). None of the three groups of antidepressants was
associated with ulcer perforation (selective serotonin reuptake
inhibitors: relative risk 1.3, 0.4 to 3.7; non-selective serotonin
reuptake inhibitors: 0.4, 0.2 to 1.1; others: 1.3, 0.2 to 10.1)."
"The risk of upper gastrointestinal bleeding was increased with all
selective serotonin reuptake inhibitors although with clomipramine
this was only marginal. After exclusion of trazodone the drug with the
greatest relative risk the relative risk with selective serotonin
reuptake inhibitors was 2.9 (2.0 to 4.2). The exclusion of
clomipramine slightly increased the relative risk to 3.3 (2.2 to 4.9).
Among non-selective serotonin reuptake inhibitors amitriptyline
significantly increased the risk of upper gastrointestinal bleeding. A
trend was noted with imipramine and lofepramine but dothiepin had no
effect."
"The concurrent use of selective serotonin reuptake inhibitors with
non-steroidal anti-inflammatory drugs greatly increased the risk of
upper gastrointestinal bleeding (15.6, 6.6 to 36.6) showing a more
than multiplicative interaction (relative excess risk due to
interaction 10.3). The relative risk of concurrent use of
non-steroidal anti-inflammatory drugs with non-selective serotonin
reuptake inhibitors compared with non-use was 4.6 (2.8 to 7.9), which
roughly represents the sum of their respective effects (relative
excess risk 0.2). An interaction was also observed between selective
serotonin reuptake inhibitors and aspirin (7.2, 3.1 to 17.1; relative
excess risk 3.5)."
"Selective serotonin reuptake inhibitors increase the risk of upper
gastrointestinal bleeding by threefold but they do not affect the risk
of ulcer perforation. The absolute risk of upper gastrointestinal
bleeding is estimated as 1 case per 8000 prescriptions, a risk similar
to that of low dose ibuprofen. The risk with all selective serotonin
reuptake inhibitors is similar suggesting a class effect linked to
their mechanism of action. Compatible with this hypothesis is the
suggestion that some non-selective serotonin reuptake inhibitors may
also increase the risk of upper gastrointestinal bleeding although to
a lesser extent than selective serotonin reuptake inhibitors. This
effect is not influenced by sex, age, dose, or duration of use but is
greatly potentiated by the concurrent use of non-steroidal
anti-inflammatory drugs and to a lesser extent low dose aspirin."
"The release of serotonin from platelets seems to be an important step
in platelet aggregation especially in the presence of collagen,
thrombin, and ADP. Therefore a depletion of serotonin from platelets
would be expected to impair the haemostatic response to vascular
injury. The low frequency of this effect, however, indicates that only
in certain circumstances would impaired aggregation be clinically
patent, probably when alternative mechanisms are unable to compensate
for the effect."
"With the exception of fluvoxamine all selective serotonin reuptake
inhibitors were associated with upper gastrointestinal bleeding.
Trazodone presented the greatest risk although its confidence interval
overlapped with that of the other inhibitors. This finding is
unexpected because trazodone is the inhibitor with the weakest effect
on the serotonin reuptake mechanism. Interestingly, this drug is a
potent blocker of 5-HT2 receptors, the stimulation of which is thought
to mediate the platelet aggregation induced by serotonin release."
"One of the most singular findings of our study was the interaction
between selective serotonin reuptake inhibitors and non-steroidal
anti-inflammatory drugs. This may have public health implications
owing to the high prevalence of use of both groups of drugs in most
countries."
Authors Note:
The original NSAIDs have been known for years to be killing thousands
of people each year since their initial introduction. As reported in
the American Journal of Medicine, over 100,000 people are hospitalized
each year and at least 16,500 die each year from gastrointestinal (GI)
bleeding. These figures are considered conservative and they are only
figures for NSAIDs being used to treat arthritis. It also doesn't
include the number of people who die of other complications of NSAID
use such as congestive heart failure. A true analysis of the number of
deaths world wide from NSAIDs would be overwhelming.
In this study we see that SSRIs (Prozac, Luvox, etc.) alone triple the
chances of upper GI bleeding. This is of great importance since an
ever-increasing number of people are being prescribed these
medications. Still worse is when these medications are combined with
aspirin (which is being recommended for a theoretical better
cardiovascular health) the chances of upper GI bleeding increase to
over 7 times. This is of high significance in the elderly since often
times antidepressants are being prescribed while people are taking
aspirin for better cardiovascular health as well as arthritis,
headaches, and aches and pains. Even worse is when SSRIs are combined
with prescription NSAIDs the chances of upper GI bleeding increases to
an enormous 15 fold! This is a major health problem that impacts
people across the world since there is a high prevalence of using
these types of medications together.
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