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In the Name of GOD
Psychopharmacology for Pain
Medicine
A large percentage of patients with chronic
pain disorders have coexisting, or comorbid,
psychiatric conditions, which are the most
prevalent comorbidities in patients with
chronic pain.
This is particularly true in patients with chronic low
back pain. Patients with pain and psychiatric
comorbidity are commonly referred to pain
medicine clinics and frequently present on
psychoactive medications. Many of these
medications, such as antidepressants and
anticonvulsants, also have analgesic properties,
and are a mainstay of the drug armamentarium of
the pain physician.
Psychotherapeutic modalities, such as
cognitive behavioral therapy, relaxation
training, or biofeedback, play an
important role in the treatment of both
psychiatric and chronic painful illness,
and in some cases are the preferred
method of treatment.
As with many of the medications used in
pain medicine, psychoactive medications
with reported analgesic properties do not
always have a Food and Drug Administration
(FDA) indication for this purpose, but can
legally be prescribed for off-label use.
EPIDEMIOLOGY
Over two decades of studies of U.S. pain clinic
populations have shown that 60% to 80% of these
patients have psychiatric illnesses by DSM criteria.
Estimates are lower in persons with pain in primary
care, institutional, and community settings, but
regardless of setting, given the prevalence of
persistent pain in adults, estimated at 20% to 45%,
pain-psychiatric comorbidity constitutes an
important public health problem. Patients with
psychiatric illness report greater pain intensity,
more painrelated disability, and a larger affective
component to their pain.
The majority of patients with psychiatric
comorbidity developed their psychiatric illness after
the onset of chronic pain. Major depression alone
affects 30% to 50% of all pain clinic patients,
followed by anxiety disorders, personality
disorders, somatoform disorders, and substance
use disorders. Major depression alone affects 30%
to 50% of all pain clinic patients, followed by
anxiety disorders, personality disorders,
somatoform disorders, and substance use disorders.
MAJOR DEPRESSION
AND SUBTHRESHOLD DEPRESSION
According to the DSM-IV, major depressive
disorder (MDD) requires two key features:
depressed mood and loss of interest or
pleasure in most activities (anhedonia) for at
least 2 weeks. The lifetime risk of MDD is 7%
to 12% in men and from 20% to 25% in
women. But, the risk of major depression in
patients with pain is at least twice as high.
Suicidal thoughts reflect the severity of depressive
symptoms.
Untreated or undertreated major depression has a
lifetime risk of death through completion of suicide
of 10% to 15%.
Major depression is a serious complication of
persistent pain, and if not treated effectively, it will
reduce the effectiveness of all pain treatments.
Even low levels of depression (“subthreshold
depression”) may worsen the physical impairment
associated with chronic pain conditions and should
also be treated.
TREATMENT
Antidepressants can take up to 2 to 4 weeks for an
initial response, but all can take 4 to 8 weeks for
full clinical improvement after a typical dose is
reached, and remission may take longer.
This can be particularly the case for depressed
patients who also suffer from comorbid pain.
Patients should remain on them for 6 to 12 months
for the treatment of an initial depressive episode,
and 5 years for the treatment of a recurrent
depressive episode.
There is some evidence that pain patients with
major depression have increased treatment
resistance, particularly when their pain is not
effectively managed.
Older adults tend to respond at lower doses of
antidepressants, and dose titration should occur
more slowly in this group because of their
heightened sensitivity to side effects and toxicity.
Often, patients with chronic pain are on multiple
medications that can potentiate the side effects of
antidepressants, such as headache, nausea,
constipation, or sedation, so “starting low and going
slow” is even more important in this population.
Typically, in the initial treating period, re-evaluations
are done every 2 to 4 weeks, with dose adjustments if
indicated.
Monoamine oxidase inhibitors (MAOIs), such as
phenelzine, which are rarely prescribed anymore,
should not be prescribed with other antidepressants
concurrently. Because of the inherent risks of these
medications, they should be used only by experienced
psychopharmacologists.
SELECTIVE SEROTONIN REUPTAKE
INHIBITORS (SSRIS)
Since the introduction of fluoxetine (Prozac) in
1987, many SSRIs have been introduced.
They have an immediate effect on the blockade of
the presynaptic serotonin reuptake pump in the
central nervous system (CNS), which has been
shown in animals to increase the duration of
serotonin in the synaptic cleft, increasing the
effects of neurotransmission.
The antidepressant efficacy of SSRIs and their low
side effect profiles have made them the most
widely prescribed class of antidepressants.
However, the SSRIs have few independent pain
properties.
Pain patients whose depression responds to an SSRI
may have diminished pain that is attributable to
improvements in the affective components of their
pain, but there is little evidence supporting
independent analgesic activity of SSRIs.
While a few case reports have shown improvements
in diabetic neuropathic pain on SSRIs, double-blind,
placebo-controlled clinical trials that exclude
patients with depression have not consistently
demonstrated analgesic benefit.
Patients should begin on one-half of the usual dose
for a week and then to the standard dose, to minimize
the side effects of nausea, diarrhea, tremor, and
headache. Some patients can experience sedation or
overstimulation.
Approximately 75% to 80% of patients on SSRIs can
experience sexual side effects, such as decreased
libido, impotence, ejaculatory disturbances, or
anorgasmia. This can be particularly the case in
elderly patients who may already have diminished
libido due to possible comorbid pain and depression.
Rare side effects include dystonia, akathisia,
palpitations, a lowered seizure threshold, serotonin
syndrome, or syndrome of inappropriate antidiuretic
hormone (SIADH).
Selective Serotonin Reuptake Inhibitors (SSRIs)
Drug
Usual Start Dose
Average Dose
Maximum Dose
Citalopram (Celexa)
10 mg qd
20–40 mg qd
60 mg/day
Fluoxetine (Prozac)
10 mg qd
20–40 mg qd
80 mg/day
Fluvoxamine (Luvox)
25 mg qd
50–100 mg bid
300 mg/day
Paroxetine (Paxil)
5–10 mg qd
20–40 mg qd
60 mg/day
Sertraline (Zoloft)
25 mg qd
50–150 mg qd
200 mg/day
TRICYCLIC ANTIDEPRESSANTS (TCAs)
TCAs are one of the oldest classes of
antidepressants and they act by inhibiting both
serotonergic and noradrenergic reuptake. This
lengthens the time serotonin and norepinephrine
remain in the synaptic cleft, enhancing their
neurotransmission.
The analgesic properties of TCAs are independent of
their treatment effects on depression, thus making
them a good choice for treating depression in the
patient with chronic pain, particularly if cost is a
factor.
All TCAs are equally effective for the treatment of
depression, and the choice of a particular one is
determined by side effects.
Amitriptyline and imipramine are more sedating,
with more weight gain and orthostatic hypotension.
Other anticholinergic side effects include dry
mouth, constipation, blurred vision, urinary
retention, sexual side effects, excessive sweating,
and confusion or delirium.
TCAs also decrease the seizure threshold.
Desipramine and nortriptyline have fewer
anticholinergic side effects, and of all of the TCAs,
desipramine has the fewest anticholinergic side
effects.
Prior to initiating treatment patients should have
laboratory screening of electrolytes, BUN,
creatinine, and LFTs. TCAs also have quinidine-like
properties, are potentially proarrhythmic, and can
prolong the QTC interval.
All patients aged over 40 years or with any history
of cardiac disease should have a baseline EKG, with
particular attention to the QTC interval, checking
that it is less than 450 ms.
TCAs are strongly protein-bound (85% to 95%) and
undergo first-pass hepatic metabolism. Subsequent
stages involve demethylation, oxidation, and
glucuronide conjugation.
SSRIs and TCAs should not be prescribed at
the same time unless plasma levels are
carefully monitored.
Phenobarbital, carbamazepine, and cigarette
smoking induce the P450 enzyme system,
and thus decrease serum TCA levels.
As with SSRIs, to minimize side effects and
increase adherence initiation of TCAs should begin
at lower doses (usually 25 mg for a week) than the
target doses for antidepressant effect (typically
75–150 mg).
The elderly are more sensitive to their side effects,
and many psychiatrists begin at doses of 10 to 20
mg in this age group.
With diminished or altered metabolism of TCAs, as
well as the multiple medications older patients are
frequently taking, they are more prone to develop
toxic serum levels, and monitoring should be more
frequent.
Also, unlike the SSRIs, TCAs have
independent analgesic properties.
A series of studies by Max and others have
illustrated the analgesic properties of TCAs,
which are independent of its effects on
improving depression.
TCAs have been shown to be modestly
effective for diabetic neuropathy pain,
chronic regional pain syndrome, chronic
headache, poststroke pain, and radicular
pain.
Many patients are referred to the pain
specialist after a failed trial of TCAs at lower
doses. And yet there is a dose-response
relationship for analgesia. So even if one is
using a TCA solely for pain relief, patients
may benefit with a dose in the
antidepressant range, in conjunction with
blood level monitoring.
Tricyclic Antidepressants (TCAs)
Drug
Usual Start Dose
Average Dose
Maximum Dose
Amitriptyline (Elavil)
10–25 mg qd
75–150 mg qd
300 mg/day
Amoxapine (Asendin)
25 mg bid
75–200 mg bid
600 mg/day
Clomipramine
(Anafranil) 25 mg qd
150–250 mg qd
250 mg/day
Desipramine
(Norpramin)
10–25 mg qd
75–150 mg qd
300 mg qd
Doxepin (Sinequan)
10–25 mg qd
75–150 mg qd
300 mg qd
Nortriptyline
(Pamelor)
10–25 mg qd
75–150 mg qd
200 mg qd
Protriptyline (Vivactil)
5 mg qd
10 mg tid
60 mg/day
SEROTONIN-NOREPINEPHRINE
REUPTAKE
INHIBITORS (SNRIs)
The nontricyclic SNRIs are a newer group of
antidepressants that, like the TCAs, act by inhibiting
serotonin and norepinephrine reuptake.
This appears to be one of the mechanisms
accounting both for the higher rates of depression
remission and the analgesic efficacy associated with
TCAs and SNRIs as compared with SSRIs.
Venlafaxine, duloxetine, and, most recently,
milnacipran are the main drugs in this category and
have significantly less alpha-1, cholinergic, or
histamine inhibition. In the United States,
milnacipran (Savella®) is FDA approved for the
treatment of fibromyalgia but not depression, and
thus will not be discussed in detail.
Duloxetine (Cymbalta) is an SNRI approved for use
in the United States for diabetic peripheral
neuropathic pain, fibromyalgia, major depression,
and generalized anxiety disorder.
It is the only major psychotropic drug approved in
the United States for both pain and psychiatric
conditions, and thus it is the treatment of choice
for patients with neuropathic pain and psychiatric
comorbidity.
OTHER ANTIDEPRESSANTS
Bupropion is a noradrenergic and dopaminergic
reuptake pump inhibitor, prolonging the time
norepinephrine and dopamine remain in the
synaptic cleft.
Unlike many of the other antidepressants it has
significant psychostimulant properties.
It is used in the treatment of depression, ADHD,
and smoking cessation, at doses up to 600 mg/day.
Two studies have shown that bupropion has
independent analgesic effects in a variety of
neuropathic conditions.
Treatment should start at 75 to 100 mg in the
morning to avoid insomnia that may occur if the
drug is started at night.
After 5 days, this dose is advanced to the average
treatment dose of 100 to 150 mg bid, even for
sustained-release preparations.
At these doses there is a very slight decrease in
seizure threshold.
Doses from 450 to 600 mg/day may cause seizures
in 4% of patients, so these doses should be
avoided.
Mirtazapine is an antidepressant with
antagonism of serotonin and central
presynaptic alpha2-adrenergic receptors,
stimulating serotonin and norepinephrine
release.
This serves to potentiate serotonergic and
noradrenergic transmission, while having no
anticholinergic effects.
Trazodone is a serotonin-2
antagonist/reuptake inhibitor (SARI), and is
used for major depression and insomnia.
The sedative qualities of trazodone are so
great that few patients are able to get to high
enough of a dose to be in the effective
antidepressant range.
Miscellaneous Antidepressants
Drug
Usual Start Dose
Average Dose
Maximum Dose
Bupropion
(Wellbutrin)
75 mg bid
100–150 mg bid
600 mg qd
Duloxetine (Cymbalta) 30 mg qd
60 mg qd
120 mg
Mirtazapine
(Remeron)
15 mg qhs
30–45 mg qd
60 mg qd
Nefazodone (Serzone)
100 mg bid
150–300 mg bid
600 mg/day
Trazodone (Desyrel)
50 mg qhs
150–250 mg bid
600 mg/day
Venlafaxine (Effexor)
37.5 mg qd
75–112.5 mg bid
375 mg/day
ANXIETY DISORDERS
Anxiety disorders are a broad spectrum of
disorders, including generalized anxiety
disorder, panic disorder, obsessive
compulsive disorder, and PTSD.
There is a high prevalence rate of anxiety
disorders in chronic pain clinic populations,
with 30% to 60% of patients having anxiety
at pathological levels. Generalized anxiety
disorder is the most frequent anxiety
disorder affecting pain patients.
Patients’ situational anxiety is often anxiety about
pain and its negative consequences. Patients may
be conditioned to be excessively fearful that
activities will cause uncontrollable pain, causing
avoidance of those activities, which in some
patients can be extreme, almost phobic.
Also, pain may activate thoughts that patients are
seriously ill. Pain-specific anxiety as well as
generalized anxiety amplify pain perception and
pain complaints through several biopsychosocial
mechanisms, including sympathetic arousal with
noradrenergically mediated lowering of
nociceptive threshold, increased firing of
ectopically active pain neurons, excessive cognitive
focus on pain symptoms, and poor coping skills.
TREATMENT
Antidepressants are effective, but generally
at higher doses than what is typically
prescribed for depression.
Anxiolytics, such as benzodiazepines and
buspirone, are most useful in the initial
treatment stages to stabilize a disorder.
ANTIDEPRESSANTS
BENZODIAZEPINES (BZDs)
BUSPIRONE
These medications are useful in the treatment of
acute anxiety, panic attacks, and the stabilization
of generalized anxiety. Occasionally, anxiety
cannot be stabilized with antidepressants and
patients remain on BZDs in the long term.
BZDs bind to the BZD component of the gammaaminobutyric acid (GABA) receptor, an inhibitory
neurotransmitter. They depress the CNS at the
levels of the limbic system, brainstem reticular
formation, and cortex.
Acute anxiety or panic attacks can be treated
with short-acting BZDs, such as lorazepam
0.5 to 2 mg q6hr, prn, which has a rapid
onset of action (10 to 15 min) and a half-life
of 10 to 20 hr.
Caution should be taken in prescribing short
half-life drugs, such as alprazolam. While it
has a rapid onset of action, it typically lasts
only 2 to 3 hr and many patients have
significant rebound anxiety.
Buspirone is also an effective anxiolytic. It acts as a
serotonin agonist. It is especially useful in treating
patients with a history of substance abuse who
may abuse BZDs.
It has no addictive properties, and does not impair
psychomotor or cognitive functions. It is started at
5 mg tid and can be advanced as high as 10 mg tid.
Unlike the short-acting BZDs that deliver anxiolysis
with the first dose, buspirone requires 1 to 4
weeks of administration for antianxiety benefits to
appear. Patients can experience headache,
dizziness, paresthesias, and GI upset.
Clonazepam 0.25 to 1 mg tid, a long-acting
BZD, is often used in conjunction with a
short-acting agent or an antidepressant to
stabilize persistent anxiety or prevent acute
anxiety attacks.
Diazepam, which also has psychoactive
metabolites lasting several days, and
flurazepam, are other agents with long halflives.
Benzodiazepines (BZDs)
Drug
Onset
Half-Life (hr)
Alprazolam (Xanax)
Intermediate
6–20
Chlordiazepoxide (Librium)
Intermediate
30–100
Clonazepam (Klonopin)
Intermediate
18–50
Clorazepate (Tranxene)
Rapid
30–100
Diazepam (Valium)
Rapid
30–100
Estazolam (ProSom)
Intermediate
10–24
Flurazepam (Dalmane)
Rapid-intermediate
50–160
Lorazepam (Ativan)
Intermediate
10–20
Midazolam (Versed)
Rapid
2–3
MOOD STABILIZERS
AND ANTIEPILEPTICS
Mood stabilizers are agents that possess both
antimanic and antidepressant properties. Some of
these medications are antiepileptic drugs.
This class of medications is often used to treat
patients with chronic neuropathic pain, trigeminal
neuralgia, and headache.
Some of the medications in this class are lithium,
valproic acid (Depakote is the longer-acting brand
name formulation), carbamazepine (Tegretol®),
and lamotrigine (Lamictal®).
The anticonvulsants are frequently
prescribed in pain medicine and are
documented analgesics for a variety of
conditions, most often neuropathic pain and
headache prophylaxis.
LITHIUM
Lithium is the most commonly prescribed mood
stabilizer for bipolar disorder.
It is also used as an augmentation agent for MDD,
administered in conjunction with antidepressants.
lithium has been used as prophylaxis for chronic
daily headaches and cluster headaches.
VALPROIC ACID
Depakote is the brand name of long-acting valproic
acid, with a duration of action of 8 to 12 hr. It has
both antimanic and antidepressant effects,
although with less anti depressant effect than
lithium. It is also useful as an augmentation agent
in depression.
Depakote can also be used for the treatment of
impulsivity and aggression. Valproic acid has an
established use in migraine prophylaxis, and
neurologists have extensive experience with it in
seizure treatment. This medication should not be
given to pregnant women, as it is associated with
neural tube defects.
LAMICTAL
Lamotrigine, or Lamictal, as it is known by its trade
name, is an antiepileptic medication very
commonly prescribed for seizure control by
neurologists and for mood stabilization by
psychiatrists.
It is often prescribed for bipolar patients with
prominent depressive symptomatology and it
appears to be more effective in preventing
depression than mania.
Its mechanism for treating bipolar disorder is not
known. Lamictal has been reported to reduce
neuropathic pain in case reports.
Lamotrigine does have an established use as a
preventive agent in headache management, and a
recent systematic review concludes that it is
efficacious in reducing the frequency of migraines.
Although generally well tolerated, rash may occur
in up to 10% of individuals and Steven-Johnson
syndrome.
This medication is often started 25 mg daily for 2
weeks, then 50 mg daily for 2 weeks, 100 mg daily
for 1 week, and then 200 mg daily for most
patients.
CARBAMAZEPINE
Carbamazepine, also know as Tegretol, is an
anticonvulsant used to treat partial seizures and
generalized seizures.
Carbamazepine is a well-established mood
stabilizer and is also the first-line treatment for
trigeminal neuralgia and other neuropathic pain
disorders with a lancinating quality.
This medication is usually started at doses
between 200 and 400 mg daily in divided doses
with a therapeutic dose range of 750 to 2500 mg
daily in divided doses.
NEUROLEPTICS
Also termed “antipsychotics,” neuroleptics have
been available for almost 50 years.
They are used to treat any psychotic process, the
hallmark illness being schizophrenia, and psychotic
symptoms in depression, mania, or delirium are
also indications for their use.
Both the typical and newergeneration atypical
neuroleptics have independent analgesic
properties, and are effective analgesics for
nociceptive and neuropathic conditions.
However, based on a recent review of the
literature, there is evidence that
demonstrates a role for antipsychotics in
treating many different types of pain
including cancer pain and chronic non cancer
pain, such as fibromyalgia, chronic headache,
low back pain, musculoskeletal pain, chronic
pain in older patients, chronic facial pain,
and diabetic neuropathy.
TYPICAL NEUROLEPTICS
Typical neuroleptics act as antipsychotics
through their antagonism of dopamine
receptors, particularly the D2 receptors.
They also have actions on histaminic,
cholinergic, and alpha-1 adrenergic
receptors.
Selected Typical Neuroleptics
Drug
Usual Dose
Maximum Dose
Fluphenazine (Prolixin)
5–10 mg bid-tid
40 mg/day
Haloperidol (Haldol)
2–5 mg bid-tid
100 mg/day
Perphenazine (Trilafon)
8–16 mg bid-tid
64 mg/day
Thiothixene (Navane)
5–10 mg tid
60 mg/day
Trifluoperazine (Stelazine)
5–10 mg bid
40 mg/day
Loxapine (Loxitane)
20–50 mg bid-tid
250 mg/day
Chlorpromazine (Thorazine)
10–50 mg bid-qid
2000 mg/day
Thioridazine (Mellaril)
100–200 mg bid-qid
800 mg/day
ATYPICAL NEUROLEPTICS
The atypicals have a lesser degree of
dopamine D2 receptor antagonism and a
greater degree of D4 receptor antagonism
than the typical neuroleptics.
Additionally, they have some degree of
serotonin-2 receptor blocking.
This mixed receptor profile results in far
fewer extrapyramidal, anticholinergic, and
cardiac side effects.
The use of atypical neuroleptics in pain
medicine will continue to grow.
Case reports and retrospective studies
indicate that they may be effective as a
secondary or tertiary agents for migraine and
chronic daily headache prophylaxis.
They have been effective as abortive agents
for cluster headache.
Atypical Neuroleptics
Drug
Usual Dose
Maximum Dose
(Aripiprazole) Abilify
5 mg qd
30 mg qd
(Clozaril) Clozapine
100–300 mg qd-bid
900 mg/day
(Zyprexa) Olanzapine
5–15 mg qd
20 mg/day
(Seroquel) Quetiapine
50–150 mg bid-tid
800 mg/day
(Risperdal) Risperidone
2–4 mg qd-bid
16 mg/day
(Geodon) Ziprasidone
20–40 mg bid
160 mg/day
Thank you for your attention