++
Depression is
one of the largest psychological issues comorbid with chronic pain.
For example, major depression is found in 8% to 50% of
patients with chronic pain, and dysthymia may be seen in greater
than 75% of patients with chronic pain. In most cases of
chronic pain, a patient will be prescribed an antidepressant or
will already be taking one. Antidepressants often serve a dual role: treating
a mood disorder as well as independently addressing pain symptoms.
For these reasons, an awareness of available antidepressants as
well as an understanding of their purported mechanism of action
is important.
++
Effective medical treatments for depression have been available
since the late 1950s. The earliest forms of currently used antidepressants
were tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors
(MAOIs), each with inhibitory actions on norepinephrine (NE) and
serotonin (5-HT) reuptake. These were the drugs of choice for treating
depression until the 1980s when the selective serotonin reuptake
inhibitors (SSRIs) were found to possess substantial antidepressant efficacy.
The SSRIs have revolutionized treatment of depression by offering
efficacy with greatly reduced side-effect profiles. Over the past
decade, numerous atypical antidepressants have been developed, including
norepinephrine and dopamine reuptake inhibitors (NDRIs), serotonin-norepinephrine
reuptake inhibitors (SNRIs), and serotonin-2 (5-HT2) antagonist/reuptake
inhibitors (SARIs). These newer agents are currently undergoing
clinical trials to assess relative efficacy compared with standard
TCAs and SSRIs.
++
It is notable that antidepressants are useful for many disorders
other than depression, especially for anxiety disorders and neuropathic
pain. Anxiolysis with antidepressants is discussed in the following
sections. The history of antidepressants as analgesics began in
1960, just 2 years after imipramine was reported to be an antidepressant.
When first reported to be analgesic, TCAs were thought to work by
relieving the depression component of pain. It is now well known
that relieving depression by any method is likely to decrease pain.
Not all antidepressants, however, have independent analgesic properties.
++
Amitriptyline was the first TCA described to have analgesic properties
that are independent of antidepressant properties (suggested to
relieve migraine via vasodilatory mechanism). There is now a convincing
body of controlled data as well as extensive, long-standing clinical
experience supporting TCA analgesia that is independent of antidepressant
actions. Although SSRIs have been suggested to be useful for pain
by anecdotal reports, at present there is no controlled data to support
this. The only controlled trial to date did not show independent
analgesia.2 Since reduction of depression can reduce
pain, separating this antidepressant effect from other intrinsic,
independent effects of these drugs is a difficult but critical part
of clarifying analgesic effects.
+++
Cyclic Antidepressants
(TCAs)
++
TCAs are approved
by the U.S. Food and Drug Administration (FDA) for the treatment
of major depressive disorders and secondary depression in other
disorders. Other approved uses of TCAs include treating obsessive-compulsive
disorder (clomipramine) and enuresis (imipramine). TCAs are also
useful in treating generalized anxiety, panic disorder, agoraphobia,
bulimia, attention deficit hyperactivity disorder (ADHD), and chronic
pain.
++
Although this class includes tricyclics and heterocyclics, they
are generally referred to as tricyclics (TCAs). They are named for
their three-ring structure, that is, two benzene rings connected by
a double-carbon bond. The tertiary amines (amitriptyline, imipramine)
have two methyl groups on the terminal nitrogen atom of the side
chain. Demethylation of these results in the secondary amines nortryptiline
and desipramine, respectively. In general, the secondary amines
have less anticholinergic side-effects than do the tertiary amines.
Table 63-1 lists the common tricyclics divided by secondary and
tertiary amine groups.
++
++
There exists some question about the precise mechanism of how
tricyclics combat depression. All tricyclics inhibit both serotonergic
and noradrenergic reuptake; and these effects are seen early, but
clinical benefits often begin 2 to 3 weeks after initiation of treatment.
In other words, side effects are seen right away, whereas clinical
benefits take several weeks to emerge.
++
This disparity raises questions about the exact relationship
between NE/5-HT reuptake inhibition and the antidepressant
effects of TCAs. Downregulation of β-adrenergic
receptors correlates temporally with onset of action, but this is
likely a marker for the role of second-messenger systems and neuronal
gene regulation in the therapeutic mechanism of TCAs.
++
There is no dispute that relief of depression also relieves some
chronic pain. Therefore, TCAs relieve pain as an antidepressant,
but also may offer independent analgesia, perhaps by other mechanisms
such as its blockade of sodium channels rather than by their well-described
inhibitory effects on NE/5-HT reuptake. Still, some endorse
the idea that because serotonin has been implicated as the major
neurotransmitter in descending inhibitory tracts, TCAs relieve pain
by making more serotonin available.
++
TCAs as analgesics rarely offer complete analgesia, and TCA side
effects are common due to the antagonist effects on the cholinergic,
adrenergic, and histaminergic systems. These agents are compelling
analgesics, particularly with comorbid depression or insomnia. Reasonable
goals for using TCAs as analgesics include decreased pain intensity
from unbearable to bearable. Some mild side effects may be unavoidable
in exchange for analgesia.
++
There are some common misconceptions about TCAs as analgesics.
For instance, there probably is not a therapeutic window, whereby
analgesia is diminished above and below threshold dosages. Another
misconception is that analgesia requires only low dosages of TCA.
Evidence suggests that analgesia is maximized with increased doses
as well as with time. The time course of analgesic TCAs varies between
1 and 120 days, suggesting that initial early analgesia is maximized
over time. Duration of TCA analgesia also persists over time with
maintenance of therapy.
++
TCAs are typically lipophilic, and thus easily pass through the
blood–brain barrier. They are widely distributed in major
organs including lung, heart, brain, and liver. Eighty-five to 95% of the
drug is protein bound, although individual differences can cause
up to a four-fold variation in amount of free drug. All TCAs undergo
first-pass hepatic metabolism; intermediate stages involve demethylation,
oxidation, and glucuronide conjugation. As mentioned earlier, the
demethylated daughter metabolites have fewer side effects. For instance,
nortriptyline and desipramine have fewer anticholinergic side effects
than amitriptyline and imipramine, respectively. Demethylated metabolites
are usually biologically active with plasma half-lives often greater
than two times that of the tertiary amine parent compound. Thus,
the washout period is usually a week or more.
++
Because hepatic clearance involves the P450 enzyme system, drug
interactions are possible. For example, P450 enzyme inhibitors,
such as fluoxetine, cimetadine, and methylphenidate increase TCA
plasma levels. P450 enzyme inducers such as phenobarbitol, carbamazepine,
and cigarette smoking decrease TCA plasma levels. Decreased gut
absorption is also a possible cause of decreased TCA plasma levels
and may occur with use of common agents such as cholestyramine.
++
Combining TCAs with opiate agonists can lead to decreased intestinal
motility, already a problem for many patients taking opioids. Additive
anticholinergic and opioid effects on the bowels can lead to treatment-resistant
constipation or ileus.
+++
Phytochemical
Reactions
++
Serotonin syndrome may occur when St. John’s wort is
used in conjunction with TCAs (an in vitro study indicated that
St. John’s wort affected serotonin reuptake.3 In
addition, serotonin is deaminated by MAO type A, and some early
studies showed that St. John’s wort inhibits MAO type A.4 Monitor
the concurrent use of other phytochemicals such as kava or valerian,
which function as central nervous system (CNS) depressants.
++
In treating depression, all TCAs are considered equally efficacious
but have significantly different side-effect profiles. Thus, choosing
a particular TCA can be made on the basis of side-effect profile.
Some side effects such as sedation may be beneficial to some patients
with insomnia.
++
Before initiating treatment, routine laboratory screening may
include complete blood count, electrolytes, BUN, creatinine, and
liver function tests. Because tricyclics have quinidine-like properties,
can increase all intervals of the electrocardiogram (ECG), and are
potentially proarrhythmic, ECG screening may be requested.
++
As previously described, TCAs interact with multiple neurotransmitter
systems and as a result present with a wider side-effect profile
than SSRIs. TCAs may manifest all anticholinergic symptoms including
dry mucous membranes, blurred vision, constipation, urinary retention,
excessive sweating, and confusion or delirium. Antagonism of histaminic
receptors may result in sedation, weight gain, or confusion. Cardiovascular
effects result from a combination of interactions with α1-adrenergic,
muscarinic, serotonergic, and histaminic receptors as well as IA
antiarrhythmic actions of TCAs. Cardiovascular side effects include
tachycardia, orthostatic hypotension, prolonged cardiac conduction,
and arrhythmias. Sexual side effects are also seen with TCAs and include
decreased libido, impotence, erectile difficulties, ejaculatory
disturbances, and anorgasmia. As with SSRIs, TCAs may cause or exacerbate
extrapyramidal symptoms. TCAs likely decrease the seizure threshold
as well. Rare side effects include abnormalities in serum glucose levels,
syndrome of inappropriate antidiuretic hormone (SIADH), jaundice,
hepatitis, blood dyscrasias, and photosensitivity.
++
Rarely, patients may develop a discontinuation syndrome following
abrupt cessation of the TCA. Withdrawal may manifest as anxiety,
fever, sweating, myalgia, headache, nausea, vomiting, dizziness,
dyskinesia, or akathesia. Overdose with TCAs can be lethal. Toxicity
results from anticholinergic effects and CNS effects (including
seizures and coma). The most hazardous side effect is cardiac toxicity,
especially QRS complex widening. TCA overdose is a leading cause
of drug-related overdose and death. Since three to five times the
therapeutic dose of TCAs is potentially lethal, this low therapeutic
index (ratio of toxic to therapeutic dose) must make prescribers
vigilant. This is probably a large part of the reason SSRIs are
chosen as first-line antidepressants over TCAs.
+++
Dosages and
Monitoring
++
Although somewhat controversial, it is generally agreed that
plasma levels may be clinically useful when using imipramine, desipramine,
or nortriptyline. Plasma levels of nortriptyline may be especially
useful in that a therapeutic level may exist where levels >150
may be less efficacious than lower levels. As with all antidepressants,
effects are often delayed. Antidepressant effects may be seen anywhere
from 2 to 6 weeks of a trial at therapeutic dosages. Following effective
response, patients should continue the medication for 6 to 12 months to
prevent relapse.5 Dosage should not be decreased
during the maintenance phase of treatment (Table 63-1). If a patient
has had multiple recurrences of their illness, an indefinite length
of treatment may be indicated.
+++
Monoamine Oxidase
Inhibitors (MAOIs)
++
MAOIs are approved
for use in major depression, double depression (dysthymia superimposed
on major depression), psychotic depression, social phobia, and simple
phobias and are often also used to treat anxiety, panic disorder,
and obsessive-compulsive disorder. They are not considered first-line
agents in the treatment of major depression due to their high incidence
of side effects, dietary restrictions, and lethality in overdose. “Atypical” subtypes
of depression involving mood reactivity, increased appetite, hypersomnia,
leaden paralysis, and rejection sensitivity may respond better to
MAOIs than other agents.
++
MAOIs are divided into hydrazines and nonhydrazines. Hydrazines
marketed in the United States include phenelzine (Nardil) and isocarboxazid
(Marplan). The nonhydrazine is tranylcypramine (Parnate), which
closely resembles the amphetamine structure.
++
MAOIs work by binding to the enzyme monoamine oxidase, thus inhibiting
the breakdown of monamines at the synaptic junction. This results
in increased concentration and availability of the neurotransmitters
epinephrine, norepinephrine, and dopamine at various storage sites
in the central and sympathetic nervous system. This increased availability
of monoamine is what is believed to alleviate depressive symptoms.
It is important to remember that MAO inhibitors block the action
of MAO as well as other enzymes, thus causing alterations in the
hepatic metabolism of many other drugs.6
++
MAOIs may be reversible or irreversible, though only irreversible
MAOIs are available in the United States. While reversible MAOIs,
known as reversible inhibitors of monoamine activity (RIMAs), are
widely available outside of the United States, for our purposes,
we discuss only irreversible MAOIs.
++
MAOIs require up to 2 weeks to achieve maximal MAO inhibition
and clinical effects may not be seen for 2 to 4 weeks, although
an energizing effect may occur within a few days following initiation
of treatment. Table 63-2 offers some dosage guidelines for MAOIs.
Another significant difference from standard TCAs and SSRIs is that
MAOIs have a short half-life and require twice daily dosing. To
date, there are no implications of direct analgesic effect by MAOIs.
Recall that relief of depression also relieves some degree of pain.
++
++
MAOIs are rapidly and fully absorbed from the gastrointestinal
(GI) tract. They are biotransformed in the liver and excreted rapidly.
Although their half-life is very short, they have long-lasting pharmacologic
effects because they permanently bind to and deactivate enzymes.
It takes approximately 2 to 3 weeks for the body to resynthesize
monoamine oxidase; therefore, at least that long should be allowed
between drug trials.
++
Sympathomimetic amines such as tyramine exert pressor effects
on the human system; when not broken down by MAO, introduction of
exogenous tyramines can set off a hypertensive crisis. For this
reason, patients taking MAOIs should avoid foods high in tyramine
content, such as cheeses, yeast supplements, or aged alcohols. Symptoms
of a hypertensive crisis include occipital headache, neck stiffness
or soreness, dilated pupils, tachycardia or bradycardia, and constricting
chest pain. Because of this risk, MAOIs should be used with caution
in patients with cerebrovascular disease, cardiovascular disease,
or hypertension.
++
Although the stimulant effect of MAOIs is often helpful for some
patients suffering from major depression, symptoms of insomnia,
restlessness, and anxiety, they may be excessive. Other side effects
include constipation, anorexia, nausea, vomiting, dry mouth, urinary
retention, drowsiness, headache, dizziness, and weakness. As with
SSRIs and TCAs, sexual dysfunction may occur, manifested as impotence,
anorgasmia, decreased libido, ejaculation difficulties, and rarely priapism.
++
TCAs and SSRIs should be used cautiously with MAOIs: Fatalities
have been reported from patients taking fluoxetine in concert with
MAOIs. Concomitant use of MAOIs with SSRIs runs the risk of developing
serotonin syndrome. Symptoms of serotonin syndrome include CNS irritability,
myoclonus, diaphoresis, and elevated temperature. Severe cases may
result in death. Thus, patients should discontinue MAOIs for at
least 2 weeks before beginning an SSRI. Because of its particularly
persistent metabolite, fluoxetine requires MAOI discontinuation
for at least 5 weeks. Of course, SSRIs must be similarly discontinued
for prolonged periods before starting a MAOI. These dietary restrictions
should be continued for at least 10 days following discontinuation
of the MAOI as a washout period.
++
Psychostimulants and sympathomimetics should be used cautiously,
if at all, in patients taking MAOIs. Avoid using meperidine with
MAOIs, as this can cause excessive serotonin concentrations resulting
in excitation, sweating, hypertension, respiratory depression, coma,
and vasculatory collapse. It is unclear if other opiate agonists
have the same adverse pharmacodynamic effects.
+++
Phytochemical
Reactions
++
Any substances that act on the CNS, for example, kava kava, Piper
methysticum, or valerian (Valeriana officinalis), should be carefully
monitored for MAOI interactions. For the same reason, St. John’s
wort (Hypericum perforatum) should not be used with MAOIs.
+++
Dosages and
Monitoring
++
It appears that optimal antidepressant efficacy is seen when
MAOIs are given at doses that reduce MAO activity by at least 80% (see
Table 63-2 for dosages). Liver function tests should be monitored
periodically, as MAOIs are associated with hepatotoxicity. With
long-term use, MAOIs may impair their own metabolism. Unfortunately,
MAOI serum levels are not useful for guiding therapy.
+++
Selective Serotonin
Reuptake Inhibitors (SSRIs)
++
Since the introduction of fluoxetine (Prozac) in 1987, several
other selective serotonin reuptake inhibitors (SSRIs) have been
introduced and have revolutionized first-line therapy for depression (Table
63-3).
++
++
Although SSRIs were initially introduced for use in major depressive
disorder, the FDA has approved other indications for these agents,
including panic disorder, bulimia nervosa, and obsessive-compulsive
disorder. In addition, SSRIs are often used by clinicians for a
variety of other conditions, including premenstrual syndrome, chronic
fatigue syndrome, intermittent explosive disorder, and chronic pain
management.
++
SSRIs are structurally diverse.
++
SSRIs act via specific mechanisms in the central nervous system
(CNS) and may have fewer side effects than other antidepressants
as a result. The immediate effect of the SSRIs on the CNS is blockade
of the presynaptic serotonin reuptake pump. This delays presynaptic
reuptake of serotonin following its presynaptic release. Thus, serotonin
persists in the synaptic cleft, able to exert its effects on neurotransmission
for a longer duration. These effects occur almost immediately. However,
clinical antidepressant response from SSRIs is usually not observed
until 2 to 3 weeks following initiation of treatment. Other delayed
actions, such as second-messenger effects and neuronal gene regulation,
may play a role in the efficacy of SSRIs.
++
Although there are reports of SSRI-induced analgesia, these are
anecdotal. The only controlled trial by Max et al2 did
not find these agents to possess independent analgesia. It is important
to keep in mind the adage that “absence of proof is not
proof of absence,” and there exist those who suggest that
the serotonergic mechanisms of descending inhibitory pathways are
influenced by more serotonin available in the synaptic cleft.
++
SSRIs are metabolized by hepatic oxidation and their use may
affect serum levels of other hepatically metabolized drugs. This
occurs via induction and inhibition of various cytochrome P450 enzymes.
SSRIs may increase levels of tricyclic antidepressants and benzodiazepines
as well as other drugs. There may also be effects on levels of carbamazepine,
lithium, and antipsychotics. Other serotonergic drugs should be
avoided or used with caution given the possibility of causing serotonergic
syndrome. There is a report of visual hallucinations in a patient
taking fluoxetine, after using dextromethorphan.7 Dextromethorphan
is metabolized by the cytochrome P450 enzyme, which is inhibited
by fluoxetine. Although this is a single case report, prescribing
both simultaneously may require caution.
+++
Phytochemical
Reactions
++
As in other antidepressants or mood stabilizers, caution is advised
in combining these with any phytochemicals known to affect mood,
such as valerian, kava kava, or St. John’s wort.
++
Although SSRIs have limited side effects because they have minimal
effects on neurotransmitters other than serotonin, they may cause
some undesirable symptoms. Possible CNS effects include headaches,
stimulation or sedation, fine tremor, tinnitus, and rare extrapyramidal
symptoms including dystonia, akathisia, dyskinesia, and possibly
tardive dyskinesia. There are also conflicting reports regarding
SSRIs lowering the seizure threshold. Cardiovascular effects are
rare but there are reports of tachycardia, bradycardia, palpitations,
and vasoconstriction. Gastrointestinal effects include nausea, vomiting,
anorexia, bloating, and diarrhea. Rare side effects include SIADH,
jaundice, hepatitis, and bleeding disorders. The limited sedation
associated with these agents makes them ideal additions for patients
with pain on sedating analgesics.
++
Lastly, approximately 10% to 15% of patients
taking an SSRI will experience sexual side effects. This may manifest
as decreased libido, impotence, ejaculatory disturbances, and anorgasmia. Change
to another SSRI may alleviate these symptoms. However, if changing
SSRIs is not effective, a switch to another class of antidepressants
may or may not be necessary. Addition of adjunct agents to treat
sexual side effects are often helpful. These adjuncts include amantadine, bethanacol,
cyproheptadine, neostigmine, and yohimbine. Coadministration of
the antidepressant bupropion (Wellbutrin), discussed in the section
on Atypical Antidepressant, may also alleviate sexual side effects
and provide additional antidepressant efficacy.
+++
Dosages and
Monitoring
++
Other than to rule out a medical cause of the patient’s
symptoms, no initial laboratory workup is required prior to initiate
treatment with SSRIs. Although plasma concentrations of fluoxetine
plus norfluoxetine above 500 ng/mL seem to be associated
with poorer response than lower concentrations, dosage titration
is usually based on clinical response and side effects. Note that
beneficial effects are usually not seen prior to 2 to 3 weeks.
++
When SSRIs are discontinued, the dosage should be tapered slowly
to avoid withdrawal symptoms. Withdrawal is uncommon and not life-threatening,
but it may be unpleasant if it does occur. Withdrawal often includes
flulike symptoms including GI upset, vomiting, diarrhea, fever,
diaphoresis, irritability, headache, dizziness, and arthralgia.
Overdose of SSRIs alone has not been reported to cause death, and
the relative safety of SSRIs in this regard contributes to their
first-line status in the treatment of depression, where suicide
rates may be as high as 10% to 15%. Given the
incidence of depression in chronic pain patients, this relative
safety offers an advantage over other antidepressants used for pain
management. In the event of overdose, symptoms of toxicity include
nausea, vomiting, tremor, and myoclonus. Treatment is symptomatic
and supportive.
+++
Atypical Antidepressants
++
Following the introduction of SSRIs, several other classes of
antidepressants have been developed. These classes have been designed
to target specific neurotransmitter interactions at the synaptic
level. They attempt to maximize therapeutic benefits while minimizing
side effects. These classes include norepinephrine and dopamine
reuptake inhibitors (NDRIs), such as bupropion (Wellbutrin), serotonin-norepinephrine
reuptake inhibitors (SNRIs), such as venlafaxine (Effexor), and
5-HT2 antagonist/reuptake inhibitors (SARIs) represented
by trazodone and nefazodone.
++
Bupropion (Wellbutrin), an NDRI, is a weak inhibitor of noradrenergic
and dopaminergic reuptake pumps. However, it is metabolized to hydroxybupropion,
which is a powerful inhibitor of both noradrenergic and dopaminergic
pumps. This agent differs from most other antidepressants in that
it has psychostimulant properties. Thus, as well as being used for
depression, it may be useful for treating attention deficit hyperactivity
disorder . There have been no clinical trials of its efficacy in
the treatment of chronic pain; however, its stimulating properties
offer advantages in treating depression in patients on sedating
drugs such as opioids.
++
Treatment should be initiated at 75 to 100 mg once per day, starting
in the morning to avoid potential insomnia. It can then be moved
to twice daily dosing and gradually increased, though never above
450 mg/day or 150 mg in a single dose. A new sustained-release
form is available, saving the practitioner from concern about dosage
splitting. Seizures occur in approximately 0.4% of patients
at dosages less than 450 mg/day. Dosages of 450 to 600
mg/day may cause seizures in 4.0% of patients.
Therefore, doses above 450 mg/day should be avoided. Bupropion should
also be avoided in patients with seizure disorder or those taking
medications that may cause seizures. Laboratory studies are not
necessary before starting bupropion and serum levels are not clinically
useful. The most common adverse effects are headache, insomnia,
upper respiratory complaints, nausea, restlessness, agitation, and
irritability. In overdose, dosages as high as 4200 mg have been
taken without death. However, bupropion should not be given with
MAOIs, nor in patients with anorexia or eating disorders. Care should
be taken when coadministering other drugs that are hepatically metabolized
because bupropion is metabolized by the liver.
++
Venlafaxine (Effexor) is an SNRI that possesses no α1,
cholinergic, or histaminic inhibition. Venlafaxine has dose-related
degrees of inhibition of serotonin reuptake (most potent at low
doses), norepinephrine reuptake (moderate potency at higher doses),
and dopamine reuptake (least potent at highest doses). Venlafaxine
is indicated for major depression and possibly ADHD. Though there
have been no controlled trials, some anecdotal evidence points toward
efficacy in the treatment of chronic pain. Potential analgesia is
suggested by its profile of dual inhibition of serotonin and norepinephrine
reuptake that is similar to proven analgesic antidepressants such
as imipramine, amitriptyline, and desipramine. Venlafaxine differs from
these agents in its lack of anticholinergic, antiadrenergic, and
antihistiminergic side effects, a difference that has unknown bearing
on analgesia. Venlafaxine was approved by the FDA in 1999 for treatment
of generalized anxiety disorder.
++
In 1997, an extended-release formulation was approved. Although
in traditional form, venlafaxine is given in two or three divided
daily doses beginning at 75 mg/day and increased to as
high as 375 mg/day. No laboratory studies are indicated
and serum levels of venlafaxine are not clinically useful. Side
effects include nausea, headache, somnolence, dry mouth, dizziness,
nervousness, constipation, anxiety, anorexia, blurred vision, and
sexual dysfunction. No reports of fatal overdose have been reported.
Venlafaxine should not be used in conjunction with MAOIs and venlafaxine
may affect hepatic metabolism of other medications.
++
Trazodone and nefazodone are SARIs by virtue of blocking 5-HT2 receptors
as well as serotonin reuptake. These agents are used for depression
and insomnia. Their usefulness in the treatment of chronic pain
is undetermined, but given the incidence of insomnia in pain patients,
they are likely to have at least a potential adjuvant role. Trazodone
is less effective for the treatment of depression than nefazodone,
though trazodone may be more sedating. Dosages should begin as low
as 50 mg/day but can be increased to as high as 600 mg/day
in twice daily divided doses. No laboratory studies are indicated
before beginning SARIs and plasma levels are not clinically useful.
Side effects include sedation, orthostatic hypotension, dizziness, headache,
nausea, dry mouth, and GI upset. There are no anticholinergic effects
of SARIs. Rare cases of cardiac arrhythmias have been reported.
An infrequent but serious side effect is priapism (1/1000
to 1/10000), and patients should be warned of this prior
to starting treatment. There have been no reported cases of death
following overdose with SARIs taken alone. SARIs should not be used
in conjunction with MAOIs. Also, use with astemizole or terfenadine
may decrease hepatic P450 metabolism of these compounds resulting
in cardiac arrhythmias. Lastly, SARIs may increase serum levels
of triazolam (Halcion) and alprazolam (Xanax).