Download Opioid Withdrawal: A New Look At Medication

FEATURE
Opioid Withdrawal:
A New Look
At Medication Options
Concomitant use of central adrenergic
agonists, and dopaminergic and serotonergic
agents can minimize withdrawal symptoms.
Nabeela Ahmed, PharmD
PGY-1 Pharmacy Resident
New York University Langone Medical Center
New York, New York
Randall Horlacher, BS, PharmD
Community Practice
Harrisburg, Pennsylvania
Jeffrey Fudin, BS, PharmD, DAAPM, FCCP, FASHP
Clinical Pharmacy Specialist in Pain Management
Director, PGY2 Pain & Palliative Care Pharmacy Pain Residency
Samuel Stratton VA Medical Center
Albany, New York
O
pioid dose reduction or transition to another
opioid therapy often results in uncomfortable
signs and symptoms of withdrawal. The severity of these symptoms can fluctuate among
patients, even among those with similar body
mass index, gender, and dosage.
Several theories have been proposed regarding the contribution of noradrenergic pathways in the expression of opioid
withdrawal.1 In the central nervous system, the major clustering of norepinephrine-producing neurons is in the locus
coeruleus (LC). Levels of norepinephrine and its metabolites
are altered during opioid dependence, resulting in somatic
opioid withdrawal symptoms.1 Other studies have suggested
that alterations in the density and sensitivity of alpha and
beta adrenergic receptors plays a role.1 Still, others suggest
that a mesolimbic dopaminergic system contributes to opioid
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withdrawal symptomatology.2
In October, Practical Pain Management featured an article
by Hymes et al on the use of percutaneous electrical neurostimulation to treat withdrawal symptoms.3 In this article, the authors examine pharmaceutical ways to attenuate
withdrawal symptoms. By taking advantage of alpha- and
beta- agonists and antagonist, clincians can provide faster
tapers and less withdrawal symptoms—without adding a
new medication to patients polytherapy.
Symptoms of Opioid Withdrawal
Opioid receptor activation is mediated by 3 different opioid
receptors: delta, kappa, and mu. Symptoms of opioid withdrawal may begin 8 to 10 hours after the last dose, depending on the half-life and volume of distribution of the opioid (Table 1). The dosage form and route of administration
Opioid Withdrawal: A New Look at Medication Options
Table 1: Opioid Half-Life and Volume of Distribution
Opioid
Half-life, h
Volume of Distribution, L/Kg
16.4-27.5
430
37
430
1.7-7.2
430
26
430
1-1.5
1.5-2
3
3-6
3.22-6.43
4
3.65
4
5.02-13.5
4
16-25
3-8
3.38-4.16 minutes
96
Hydrocodone
3.8
3.3-4.7
Hydromorphone
2.5
4
Methadonea
8 - 59 (up to 190)
1-8
Morphine (IR)
2-4
2.7-5.3
Oxycodone (IR)
3.2
2.6
2.85-12.79
3
6.3
2.6-2.9
Buprenorphine (buccal)
Buprenorphine (sublingual)
Buprenorphine (injection)
Buprenorphine (transdermal)
Cocaine (smoking)
Codeine
Fentanyl (buccal)
Fentanyl (injection)
Fentanyl (sublingual tablet)
Fentanyl (transdermal)
Heroin
Oxymorphone (IR)
Tramadol
a
Large range in variable half-life due to polymorphisms.
h, hour; IR, immediate release
can influence a drug’s pharmacokinetic parameters and the onset
of withdrawal following cessation
of the drug.
The majority of opioid withdrawal
symptoms reflect increased activity of
the autonomic nervous system (ANS).
While hyperactivity of noradrenergic
neurons within the LC has been associated with somatic symptoms of opioid withdrawal, it is also noteworthy
that the LC is involved with various
neurophysiologic functions,1 including
learning processes and the emotions of
anxiety and fear. For these reasons, it
is thought that excessive activation of
the LC noradrenergic neurons not only
induces somatic symptoms of opioid
withdrawal but also causes the cognitive and emotional problems associated
with withdrawal.
The initial phase of withdrawal
includes acute symptoms such as lacrimation, rhinorrhea, yawning, and
sweating that may last 7 to 10 days as
well as symptoms that occur later, such
as restless sleep, weakness, chills, nausea and vomiting, muscle aches, and
involuntary movements. The secondary phase of withdrawal includes symptoms such as hypotension, bradycardia,
hypothermia, mydriasis, and decreased
responsiveness of the respiratory system to carbon monoxide. The secondary phase can last anywhere from
26 to 30 weeks.4
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The Clinical Opioid Withdrawal
Scale (COWS) is a tool used by clinicians to assess the degree of withdrawal a patient is experiencing based
on current symptoms.5 The COWS
reflects the assessment of 11 symptoms:, vital signs (pulse), a brief physical exam (pupil size, sweating, restlessness, runny nose or eye tearing,
achiness, GI distress, tremor, yawning, gooseflesh skin) and mental status
(irritability or anxiety).5
These symptoms are then converted
into a numeric score based on their
severity. These numbers are totaled to
form an overall score, from 0 (indicating no withdrawal symptoms) to 48
(the maximum degree of withdrawal
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Opioid Withdrawal: A New Look at Medication Options
symptoms). These scores typically are
used to determine whether buprenorphine induction is appropriate, with
mild to moderate withdrawal symptoms being the ideal time to begin
buprenorphine therapy.7
Treatment of Withdrawal
There are myriad agents that can be
used to support clinicians in their treatment of patients experiencing opioid
withdrawal. The following is a summary of agents that can attenuate withdrawal symptoms (Table 2).
Alpha-1 Antagonists
Administration of the alpha-1 antagonists phentolamine,6 phenoxybenzamine (Dibenzyline, others),6 and prazosin (Minpress, others)7 can decrease
the occurrence of somatic symptoms
associated with opioid withdrawal.
Trazodone (Oleptro, others) is a triazolopyridine derivate that is used as
an antidepressant.8 Trazodone acts as
a 5-serotonin (HT)2 receptor antagonist at high doses and inhibits the
reuptake of serotonin at the presynaptic membrane. Trazodone also weakly
inhibits alpha-2 adrenergic receptors
and strongly inhibits postsynaptic
alpha-1 receptors. Due to its ability to
inhibit alpha-1 adrenergic receptors,
we postulate that it has a role in opioid withdrawal. Interestingly, trazodone has been shown to bind to opioid receptors as well, but only at high
concentrations.8
When studied in mice, trazodone
was found to induce potent mu-1 and
mu-2 opioid receptor–mediated pain
relief. Schreiber et al evaluated the
effects of trazodone on opioid withdrawal symptoms in morphine-dependent mice who were receiving a high
dose of naloxone.9 They evaluated the
intensity of withdrawal symptoms
using 3 different behavioral measurements: rearing, jumping, and grooming and found that adding trazodone
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to naloxone in morphine-dependent
mice effectively decreased opioidwithdrawal intensity.9
Alpha-2 Agonists
Another agent that is commonly
used to attenuate opioid withdrawal
is clonidine (Catapres, Kapvay, others). The use of clonidine for opioid
withdrawal originally was proposed by
DeStefano et al.10 In addition, studies
have revealed that clonidine plays a role
in reducing the negative motivational
aspects of opioid withdrawal.11
A recent review article by Gowing et
al evaluated the evidence for alpha-2
adrenergic agonists in the management
of withdrawal symptoms in people who
are physically dependent on opioids.12
The review evaluated 25 randomized control trials consisting of 1,668
opioid-dependent patients who were
being treated with either clonidine,
lofexidine, guanfacine (Tenex, Intuniv,
others), or tizanidine (Zanaflex, others). Twelve studies compared alpha-adrenergic agonists with decreasing doses
of methadone (Dolophine, Methadose,
others), 5 studies compared alpha-2
agonists with placebo, 4 studies compared the study drug with drugs used
for specific symptom control in withdrawal, and 5 studies compared different alpha-2 adrenergic agonists to each
other. Treatment duration averaged 1 to
2 weeks (shortest duration was 3 days,
and longest duration was 30 days).
The review showed no difference in
opioid withdrawal symptoms between
those receiving central alpha-2 adrenergic agonists and those treated with
decreasing doses of methadone.12 The
chance of completing treatment also
was similar with alpha-2 adrenergic agonists and decreasing doses of
methadone. However, the duration of
treatment was longer with methadone.
There were fewer adverse effects with
methadone withdrawal signs and symptoms occurred earlier in patients taking
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alpha-adrenergic agonists. Of note,
clonidine and lofexidine were more
effective than placebo in managing
withdrawal from heroin or methadone
and were more likely to be associated
with treatment completion than placebo. The studies conclude that alpha-2
adrenergic agonists may be an alternative in treating opioid withdrawal.12
Sos et al evaluated the effects of
the alpha-2 adrenergic agonist tizanidine in patients suffering from opioid
addiction.13 In this study, 26 intravenous heroin users were divided into
2 groups; each group had the usual
detoxification treatment, but patients
in the experimental group were given
tizanidine 8 mg three times daily. A
subjective scale was used to determined severity of withdrawal using
7 key withdrawal symptoms (sweating, nervousness, insomnia, tremor,
diarrhea, muscle pain, and drug craving). The results of the study showed
that tizanidine treatment decreased the
intensity of withdrawal symptoms and
may have potential benefit in treating
opioid withdrawal.13
Although there are no studies to suggest that methyldopa is useful in the
prevention of withdrawal, because it
is a centrally acting alpha-2 agonist we
could postulate that it would provide
some benefit in this setting.12
Beta-1 Antagonists
And Beta-2 Antagonists
Propranolol (Inderal, InnoPran XL,
others) and atenolol (Tenormin, others)
have been reported to reduce somatic
signs of spontaneous opioid withdrawal
and naloxone-precipitated opioid abstinence.14 It is theorized that beta blockers can have these effects because they
block the noradrenergic hyperactivity associated with supersensitive betaadrenergic receptors that result from
adaptive changes induced by chronic
opioid exposure.19-21 Somatic symptoms, including jumping and wet dog
Opioid Withdrawal: A New Look at Medication Options
Table 2. Summary of Agents That Attenuate Opioid Withdrawal
Class
Drug
Mechanism of Action
Phentolamine
Alpha-1
Antagonists
Alpha-2
Agonists
Beta-Adrenergic
Antagonists
Phenoxybenzamine
(Dibenzyline, others)
Prazosin (Minpress, others)
Yes6
Blocks alpha-1 receptors, thus inhibiting the release of NE
during noradrenergic hyperactivity (which occurs as a result of
opioid withdrawal)
Yes7
Yes8.9
Clonidine
(Catapres, Kapvay, others)
Yes10
Lofexidine
Guanfacine (Tenex, Intuniv, others)
Stimulates central alpha-2 receptors that inhibit the release of
NE during noradrenergic hyperactivity (which occurs as a result
of opioid withdrawal)
Yes12
Yes12
Tizanidine (Zanaflex, others)
Yes13
Methyldopa
No12
Propranolol
(Inderal, InnoPran XL, others)
Yes14-16
Atenolol (Tenormin, others)
Yes14-16
Metoprolol
(Lopressor, Toprol XL, others)
Blocks beta-1 and beta-2 receptors (which become
supersensitive as a result of adaptive changes induced by
chronic opioid exposure) that inhibit release of NE during
noradrenergic hyperactivity
No
No
Carvedilol (Coreg, others)
No
Labetalol
No
Dextromethamphetamine
Yes20
Ketamine (Ketalar, others)
Yes20
Memantine (Namenda, others)
Amantadine
Blocks NMDA receptors that may have a role in increasing
the release of beta endorphins, thus attenuating withdrawal
symptoms
Dextromethorphan
Venlafaxine (Effexor, others)
Mirtazapine (Remeron, others)
Yes21
Yes22
Yes23-25
Orphenadrine (Norflex, others)
Serotonergic and
Norepinephrine
Reuptake Inhibitors
Yes6
Trazodone (Oleptro, others)
Nadolol (Corgard, others)
NMDA Receptor
Antagonists
Evidence
No26
Blocks the reuptake of serotonin, which may have a role in
decreasing the release of NE centrally, but further studies
are warranted to determine the role of serotonin in opiate
withdrawal.
Mirtazapine increases release of dopamine by inhibiting alpha-2
adrenoceptors in the cerebral cortex and by blocking 5-HTc2
receptors, which generally block prefrontal cortex release of DA.
Yes27-29
Yes30
Mirtazapine increases the release of dopamine, which may have
a role in reducing acute withdrawal symptoms and inhibiting
opioid cravings
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Opioid Withdrawal: A New Look at Medication Options
Table 2. Summary of Agents That Attenuate Opioid Withdrawal (Continued)
Increases the release of dopamine, which may have a role in
reducing acute withdrawal symptoms and inhibiting opioid
cravings. L-dopa increased aggression during opioid withdrawal,
while quinpirole decreased aggression.
Levodopa
Dopaminergic
Agonists
Levels of dopamine increases acutely during opioid
administration and then decreases after opioid withdrawal;
thus, it has been hypothesized that a decrease in dopaminergic
neurotransmission may be associated with some of the
unpleasant subjective symptoms associated with drug
withdrawal.
Quinpirole
SKF82958
Dopaminergic
Antagonists
Miscellaneous
Haloperidol (Haldol, others)
Buproprion
(Aplenzin, Buproban, others)
Yes36
Yes36
Yes37
Unknown
Droperidol
No33
Yes38
Inhibits reuptake of dopamine, and, thus, may have a role in
reducing acute withdrawal symptoms and inhibiting opioid
cravings
Yes39
DA, dopamine; NE, norepinephrine; NMDA, N-methyl-D-aspartase
shakes, were both blocked by beta-1
antagonists, whereas beta-2 antagonists
have been shown to suppress the incidence of wet dog shakes only.14
Propranolol and atenolol have been
shown to reduce withdrawal-induced
anxiety in animals.15,16 Addicts have
reported that anxiety associated with
opioid withdrawal often returns when
they are in an environment that is
associated with drug use. Harris and
Aston-Jones conducted a study to
investigate whether propranolol and
atenolol reduced somatic symptoms
and whether the medications reduced
place aversion in opioid-abstinent
rats.15,16 The most common somatic
symptoms included wet dog shakes,
teeth chatter, writhing, and vocalization
upon touch. Place aversion was tested
by injecting the rats with naloxone in
one area of the cage and then observing whether the rats avoided that area.
The investigators found that beta-adrenergic antagonists reduced somatic
symptoms and alleviated withdrawal-induced anxiety.
Beta receptors have a role in promoting consolidation and retrieval of
memory; thus, in theory, blocking this
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pathway with a beta-adrenergic antagonist would prevent such memories
from forming.17 Animal studies have
suggested that propranolol can disrupt
memory reconsolidation that previously had been associated with rewarding medications such as morphine.17-19
Such results imply that by preventing
the memory of the rewarding effects
of the medication, propranolol could
be effective for preventing relapse in
addicts.
Although a prior study by Robinson
et al showed that propranolol disrupted
memory reconsolidation associated
with morphine,18 when they tested
this theory in rats, they found that in
a setting of exposure to high doses of
morphine, propranolol was not able
to disrupt memory reconsolidation.19
This study indicates that chronic exposure to morphine markedly alters the
effects of propranolol as a reconsolidation blocking treatment.19
NMDA Receptor Antagonists
Some evidence suggests that another
mechanism responsible for tolerance to
and withdrawal from opioids involves
activation of N-methyl-D-aspartase
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(NMDA) receptors. Thus, it has been
theorized that NMDA antagonists may
decrease withdrawal symptoms.20
Bisaga et al demonstrated that the
NMDA-receptor antagonist memantine (Namenda, others) decreased
naloxone-induced symptoms of withdrawal in heroin-addicted patients.21
Amantadine, another NMDA antagonist with dopaminergic, adrenergic,
and serotonergic properties (MAO-A
inhibition), also has been theorized
to have efficacy in the treatment of
opioid-withdrawal symptoms. Amiri
et al found that amantadine plus clonidine was superior to clonidine alone
in controlling opioid-withdrawal
symptoms for a duration of 3 days in
a study involving 69 patients.22 The
mechanism of action may be due to
NMDA-receptor inhibition and MAO
inhibition, which cause an increase in
beta-endorphins. Amiri et al showed a
trend for increased withdrawal symptoms on day 3; thus, studies done with
amantadine for a longer duration are
warranted.
The antitussive dextromethorphan is another agent that, theoretically, can provide benefit for patients
Opioid Withdrawal: A New Look at Medication Options
experiencing opioid withdrawal, based
on its ability to inhibit NMDA receptors. Dextromethorphan is metabolized
to dextrophan, the pharmacologic activity of which is primarily at the NMDA
receptor. (Dextromethorphan binds to
NMDA binding sites with a 10-fold
lower affinity than dextrophan.)23
In a randomized clinical trial
involving 48 heroin addicts, dextromethorphan showed benefit in
attenuating withdrawal symptoms.
Dextromethorphan combined with
diazepam (Valium, others) had greater
efficacy compared with diazepam and
chlorpromazine combined.24
However, Rosen et al found that oral
dextromethorphan (60 mg, 120 mg, or
240 mg) did not attenuate withdrawal
symptoms in 11 subjects who experienced naloxone-precipitated withdrawal after being stabilized on oral
methadone 25 mg per day.23 Subjects
received challenges with 0.4 mg of
intramuscular naloxone on 3 different
days and were randomized to receive
either dextromethorphan or placebo.
Patients taking dextromethorphan
showed no difference in withdrawal
symptoms compared with patients taking placebo.23
Bisaga et al showed beneficial data
for withdrawal with dextromethorphan in 6 male patients who were
daily heroin users.25 The patients in
this trial were hospitalized during the
study, and all received 75 mg of dextromethorphan 5 times per day (no
other medications were given besides
hydroxyzine [Vistaril, others], acetaminophen [Tylenol, others], and ibuprofen [Advil, Motrin, others]). Two
patients dropped out of the study, but
the 4 patients who completed the study
reported a subjective difference from
previous detoxification with methadone; they all had a rapid and thorough decrease in signs, symptoms,
and craving associated with opioids
by the fourth day of treatment. Patients
received treatment for an average of 6
days and were discharged after being
free from medication for 1 day. Results
of this trial indicate that dextromethorphan may be an inpatient treatment
option in patients suffering from opioid withdrawal.25
Of note, efficacy in treating opioid
withdrawal symptoms can be expected
from dextromethorphan due to its
NMDA-antagonist properties, not
due to its effects as an opioid agonist.
Dextromethorphan’s binding affinity
to mu opioid receptors is 6,000 times
less than that of morphine; thus, we
would not see much efficacy to diminish withdrawal symptoms due to its mu
opioid–receptor activity.
Orphenadrine (Norflex, others),
a commonly used muscle relaxant, is an anticholinergic medication
with NMDA-antagonist properties.
Theoretically, orphenadrine can be
used for opioid withdrawal due to its
ability to inhibit NMDA receptors.26
Although there have been no studies
conducted to substantiate the role of
orphenadrine in opioid withdrawal,
anecdotal reports have noted benefit
from its use to mitigate such symptoms.
Serotonergic and Norepinephrine
Reuptake Inhibitors
Venlafaxine (Effexor, others) is a novel
antidepressant that blocks reuptake of
norepinephrine and serotonin. It has
been postulated to mitigate opioid withdrawal due to its serotonin reuptake–
blocking properties. In a study by Lu
et al, rats treated with chronic morphine were pretreated with venlafaxine
or not given anything before administration of naloxone.27 Pretreatment
significantly attenuated the rats’ symptoms of morphine withdrawal, including jumping, writhing, shaking, exploring, lacrimation, piloerection, irritability, and diarrhea. Venlafaxine also
attenuated morphine-induced reacquisition of conditioned place preference
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in these rats. However, because there
is limited evidence to suggest that the
serotonergic system is involved in opioid withdrawal, more studies are warranted to determine if the serotonergic properties of venlafaxine contribute to the attenuation of withdrawal
symptoms.
Although there is limited evidence
for the role of serotonergic neurotransmission in opioid dependence and
withdrawal, the selective serotonin
reuptake inhibitors (SSRI) fluvoxamine and sertraline (Zoloft, others) have
been shown to decrease the intensity
of physical signs of naloxone-induced
opioid withdrawal.28 In an experiment
conducted by Gray, naloxone increased
norepinephrine levels in the hippocampus of morphine-dependent rats 20
minutes after administration, and withdrawal-induced physical behaviors were
apparent 5 minutes after injection.28
Study animals were given either fluvoxamine or sertraline, either acutely
(after discontinuation of 8 days of therapy with morphine and right before
naloxone administration) or chronically (after daily morphine doses for 8
days). Chronic administration of both
SSRIs reduced the severity of naloxoneprecipitated opioid withdrawal syndrome and prevented naloxone-precipitated increases in hippocampal levels
of norepinephrine.
However, acute administration did
not prevented naloxone-precipitated
increases in norepinephrine in the
hippocampus. Acute administration
of SSRIs only reduced the intensity of
physical symptoms of naloxone-precipitated opioid withdrawal.28 The principal finding of the study was that fluvoxamine given once daily following
morphine prevented an increase in
norepinephrine levels and the physical behaviors of opioid withdrawal,
and reduced levels of norepinephrine
in the hippocampus of morphinedependent rats.28
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Opioid Withdrawal: A New Look at Medication Options
Theories about the ability of SSRIs to
ameliorate symptoms of opioid withdrawal suggest that increased serotonin
in the synaptic cleft can increase the
inhibitory tone of the LC, causing
lower levels of noradrenergic activity
within the LC.28 Another hypothesis
suggests that SSRIs may be involved
in increasing endogenous opioid levels, which can cause a decrease in norepinephrine levels.28,29
Mirtazapine (Remeron, others) is
an antidepressant with noradrenergic
and serotonergic properties. More specifically, mirtazapine is a potent presynaptic alpha-2 receptor antagonist,
5-HT1 receptor agonist, and 5-HT2
and 5-HT3 antagonist. A study conducted by Kang et al tested the acute
and chronic effects of mirtazapine on
rats that were given morphine for 10
days.30 The acute effects of mirtazapine were observed by administering
mirtazapine 15 minutes before naloxone. The chronic effects of mirtazapine were tested by administering mirtazapine 15 minutes before daily doses
of morphine. The experiment recorded
8 behaviors (wet dog shakes, digging,
teeth chattering, rearing, grooming,
chewing, scratching, and escape attendance) over a period of 30 minutes.
Overall, the results of the study
showed that chronic mirtazapine can
reduce the severity of withdrawal symptoms, inhibit the craving for morphine,
and may decrease the rewarding effects
of morphine in rats.30 Also, mirtazapine
caused pronounced elevation in dopamine levels. Kang et al proposed that
mirtazapine increases levels of dopamine by inhibiting alpha-2 adrenoceptors in the cerebral cortex and by
blocking 5-HTc2 receptors that generally block prefrontal cortex release
of dopamine. The rise in dopamine is
the suggested neurobiological mechanism of mirtazapine’s action for reducing acute withdrawal symptoms and
inhibiting opioid craving in rats. More
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studies are warranted to explore the
role of mirtazapine in the treatment
of opioid dependence and withdrawal
in humans.30
Dopaminergic Agonists
And Antagonists
There are contradictory data on the role
of dopamine agonists and antagonists
in morphine withdrawal.31,32 For example, amphetamine, apomorphine, and
levodopa have been shown to increase
aggression in rats undergoing morphine
withdrawal33,34 but quinpirole decreases
aggression associated with morphine
withdrawal. Furthermore, Harris and
Aston-Jones found that activation of
D2 dopaminergic receptors within the
NAc prevented some of the somatic
symptoms of opioid withdrawal.35
Radhke and Gewirtz examined the
effects of dopamine agonists on withdrawal-induced anxiety following spontaneous withdrawal from acute morphine exposure.36 They examined the
effects of intracerebrally infused dopamine-receptor agonists on the potentiation of acoustic startle reflex, which
likely represent the anxiety-like component of withdrawal. The experiments
used 2 dopamine receptor agonists,
SKF82958 (D1 receptor agonist) and
quinpirole (D2 receptor agonist), and
randomly injected either medication
during morphine withdrawal in rats.
The study found that activation of D1and D2-like receptors attenuated opioid withdrawal–induced anxiety and,
thus, support the theory that diminishing activity at both D1- and D2-like
receptors have a role in the expression
of opioid withdrawal.36
From a pharmacologic perspective, since opioid withdrawal is associated with a reduction in the release of
dopamine along the mesolimbic pathway, dopamine agonists have shown
some benefit for opioid withdrawal.
Counterintuitive to this is the fact
that some dopamine antagonists, in
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particular the butyrophenones haloperidol (Haldol, others) and droperidol,
have some benefit in withdrawal too.37
Both butyrophenone antipsychotics
block postsynaptic mesolimbic dopaminergic D2 receptors in the brain and
reduce dopaminergic neurotransmission in the 4 dopaminergic pathways.
Haloperidol has been shown to
markedly decrease morphine withdrawal-induced aggression.37 RodriguezArias et al revealed that aggressive
behavior in rats decreased when they
were administered haloperidol during
either naloxone-precipitated or spontaneous withdrawal. This study suggested that anti-aggressive effects of
haloperidol were more pronounced in
naloxone-precipitated withdrawal than
in spontaneous withdrawal.37
Sivolap and Savenkov examined 197
patients who were treated with haloperidol and droperidol following opioid
withdrawal.38 They found that withdrawal-induced psychosis was relieved
with droperidol and haloperidol, and
these 2 agents were especially helpful in the acute phase of withdrawal.
Although the exact mechanism through
which these agents attenuate symptoms
of withdrawal are unclear, it is evident
that these agents have some benefit in
opioid withdrawal.38
Miscellaneous
Bupropion (Aplenzin, Buproban, others), a norepinephrine and dopamine
reuptake inhibitor, has shown some
benefit in opioid withdrawal. Joshi et
al studied the effects of bupropion on
morphine tolerance and dependence in
mice.39 They gave mice bupropion therapy (2 or 5 mg/d) with morphine for
10 days. When naloxone was administered, the mice treated with bupropion
had less withdrawal-induced jumps.
Furthermore, acute administration of
bupropion on day 10 decreased the
incidence of naloxone-precipitated
withdrawal jumps without causing
Opioid Withdrawal: A New Look at Medication Options
tolerance to the analgesic effect. The
results of this study suggest that buproprion may have potential in opioid
withdrawal.
Although the exact mechanism for
bupropion’s efficacy in opioid withdrawal is unknown, its ability to
decrease reuptake of dopamine may
contribute to attenuation of withdrawal
symptoms.
Summary
A person’s ability to tolerate a rapid opioid taper and substantial dose reductions when converting to other opioids can, in large part, depend on their
concomitant medical therapies. These
therapies, which may have been prescribed for any number of disorders,
can directly or indirectly affect the sympathetic and parasympathetic nervous
systems. All of these factors should be
carefully considered when tapering or
switching opioids.
Authors’ Bios: At the time of this writing, Dr. Nabeela Ahmed was a PharmD
Candidate, 2015 at the Albany College
of Pharmacy and Health Sciences. She is
currently a PGY-1 Pharmacy Resident at
New York University Langone Medical
Center in New York City.
At the time of this writing, Dr. Randall
Horlacher was a PharmD Candidate,
2015 at the University at Buffalo
School of Pharmacy and Pharmaceutical
Sciences. He is currently in community
practice in Harrisburg, Pennsylvania.
Jeffrey Fudin, BS, PharmD, DAAPM,
FCCP, FASHP, is Adjunct Associate
Professor of Pharmacy Practice & Pain
Management, Western New England
University College of Pharmacy, in
Springfield, Massachusetts, He also is
Adjunct Assistant Professor of Pharmacy
Practice, University of Connecticut School
of Pharmacy, in Storrs, Connecticut,
and Clinical Pharmacy Specialist and
Director, PGY2 Pain & Palliative Care
Pharmacy Residency at the Stratton VA
Medical Center, in Albany, New York.
Dr. Fudin graduated from the Albany
College of Pharmacy & Health Sciences
with his Bachelors Degree and his
PharmD. He was awarded and completed
an American Cancer Society Sponsored
Fellowship in Oncology/Hematology at
SUNY/Upstate Medical Center shortly
after his undergraduate work.
Dr. Fudin practices as a Clinical
Pharmacy Specialist and Director, PGY-2
Pharmacy Pain Residency Programs at the
Stratton Veterans Administration Medical
Center. He is an Adjunct Associate
Professor of Pharmacy Practice at Western
New England University College of
Pharmacy; Adjunct Assistant Professor
of Pharmacy Practice at Albany College
of Pharmacy; Adjunct Assistant Professor
of Pharmacy Practice at the University
of Connecticut School of Pharmacy; and
has several other academic affiliations
including and the University at Buffalo
School of Pharmacy and Pharmaceutical
Sciences. He has been an Instructor of
Pharmacology at SAGE Graduate
School of Nursing for several years. He
is a Clinical Pharmacy Consultant to
Homedical Associates, an innovative
home-based academic patient care service dedicated to treating medically complex patients in their homes.
He is a Diplomate of the American
Academy of Pain Management, a Fellow
of the American College of Clinical
Pharmacy, and a member of several other
professional organizations. Dr. Fudin is
a Section Editor for Pain Medicine, the
official journal of AAPM. He is Founder/
Chairman of Professionals for Rational
Opioid Monitoring & Pharmacotherapy
(PROMPT), a group that advocates in
favor of safe opioid prescribing by encouraging clinician education, proactive risk
stratification, and appropriate therapeutic monitoring.
Drs. Fudin, Ahmed, and Horlacher
disclosed that their involvement with this
article was not prepared as part of their
official government duties.
Practical Pain Management readers will recognize Dr. Fudin as one of
the codevelopers of the PPM Opioid
Calculator.
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