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CLINICAL SCIENCE OF RESTLESS LEGS SYNDROME: C.

MANAGEMENT

Opioid Agents in the Treatment


of Restless Legs Syndrome

32

Philip M. Becker

Opioid medications prove particularly beneficial


in patients with severe restless legs syndrome
(RLS) or who have developed complications,
such as augmentation, on other therapy. Although addiction and side effects require close
monitoring, it is of interest that neither frequent
addiction nor major complications have yet been
reported in RLS patients who are treated with
opioids.
Reports of the benefit of opioids for the symptoms of RLS and periodic limb movements of
sleep go back at least 300 years. Sir Thomas
Willis1 recommended laudanum for a condition
that would likely meet current diagnostic criteria
for restless legs syndrome. In 1945, Ekbom2
reported on the benefits of codeine and morphine in his seminal paper about RLS. He offered
further support for the use of opioids in his
paper of 1960.3 Research studies that have
often involved only a small number of RLS
patients support the use of various opioids,
including propoxyphene,4 tramadol,5 oxycodone,6-8 hydrocodone,6 and methadone.8,9 This
chapter reviews the properties of opioid agents
and the limited literature on their use in RLS,
highlighting the benefits and risks of this pharmacological class in the management of RLS.

Brief History and Properties


of Opioid Agents
The terms narcotic, opiate, and opioid agents are
often used interchangeably to describe this class
of medication. Opioid is the preferred terminology as it is more specific for drugs acting on the
opioid receptor. The terms narcotic and opiate
have developed more general figurative uses,
referring to things that soothe, dull, or reduce
pain. Derivatives of the seed pod of Papaver somniforum, the opium poppy, have been used for
centuries to treat pain, manage gastrointestinal
disorders, enhance mood, reduce cough, and to
promote sleep.
The naturally derived opioids include opium,
laudanum, codeine, and morphine. As technology allowed for refinement of the active therapeutic components of the poppy, the potency

of medication increased. The addictive properties


of opium led a Chinese emperor to ban the substance and resultant smoking houses or opium
dens in 1700. History shows that addiction
becomes an issue with any agent that has a
high affinity to the endogenous central nervous system opiate receptors. The U.S. Drug
Enforcement Administration classifies therapeutic opioids in schedule II and schedule III with
the intent to limit access and to monitor manufacture and use. Criminal penalties are in place
when opioids are diverted or abused.
Throughout the 1900s, increasingly more
potent opioid agents were developed. More
recently, antagonists and partial agonist-antagonist agents became available. Schedule III agents
include hydrocodone and codeine, which are
usually formulated with aspirin and acetaminophen. Schedule II agents include oxycodone,
fentanyl, hydromorphone, levorphanol, methadone, and morphine. The DEA has placed heroin
on schedule I, indicating no therapeutic role for
the substance. Naloxone and naltrexone are
opioid antagonists that reverse opioid overdosage (and are also used for various addictive
disorders), whereas buprenorphone is an agonist-antagonist that has seen increasing use to
manage heroin addiction and chronic pain.
Table 32-1 rates the physiological effects of
the most common therapeutic opioids.

Opioid Agents as Analgesics


Relief of acute and chronic pain remains the
primary therapeutic role of opioid agents.
The human body naturally produces its own
opioid-like substances that function as neurotransmitters. The endogenous opioids include
endorphins, enkephalins, and dynorphin. Endogenous opioids modulate reactions to pain,
hunger, and thirst and are also involved in
mood control, immune response, and other
processes. Exogenous opioids such as morphine
bind to the same receptors as endogenous
opioids. There are three types of receptors
that are widely distributed throughout the
brain: mu, delta, and kappa receptors. These G

255
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256

CLINICAL SCIENCE OF RESTLESS LEGS SYNDROME

TABLE 32-1 Pharmacological Effects of Common Therapeutic Opioid Agents


Constipation

Respiratory
Depression

Emesis

Physical
Dependence

+++

++

++

++

++

++

++

++

++

++

++

++

Morphine

++

++

+++

++

++

++

++

Oxycodone

++

++

+++

++

++

++

++

Oxymorphone

++

++

+++

+++

+++

Propoxyphene

Tramadol

+/to

+/to

Drug

Analgesia

Sedation

Antitussive

Codeine

Hydrocodone

Hydromorphone

++

Levorphanol

++

Methadone

++

+, mild; ++ moderate; +++ severe.

proteincoupled receptors influence the opening


of Na+ channels through second messengers,
reducing the excitability of neurons that signal
pain and inducing euphoria.
The analgesic properties of opioids correlate
well with the binding coefficient of a particular
agent to the mu and delta receptors. Kappa receptors have an inhibitory role and have been associated with the psychomimetic effects of certain
opioids, particularly meperidine. Opioids produce their therapeutic effect on the mu and
delta receptors of the neurons in the spinal
cord, thalamus, and somatosensory cortex. Opioids block L-glutamateinduced depolarization
of NMDA neurons by impairing the Na+ influx
triggered at the postsynaptic membrane. These
depressant effects of opioids are antagonized by
naloxone.
It is unknown whether the same pain control
mechanisms account for the benefit of opioid
agents in RLS patients. Clinical practice indicates
that the most effective opioid agents in controlling RLS are the moderate to high-potency
formulations that are commonly used for
severe chronic pain.
The euphoric effect of opioids appears to
involve another mechanism involving the
GABA-inhibitory interneurons of the ventral
tegmental area. By activation of mu receptors,
exogenous opioids reduce the release of GABA.
Normally, GABA inhibits the release of dopamine in the nucleus accumbens. By inhibiting
this inhibitor, an opioid increases the amount
of available dopamine, leading to euphoria
and reinforcement in drug-seeking behavior.
Perhaps this downregulation of GABA and

upregulation of dopamine might explain


some component of therapeutic benefit for
RLS patients.
Table 32-2 describes the pharmacokinetics
and compares the relative potencies of the
common opioid analgesics.

Experimental Manipulation
of Opioid Activity in Restless
Legs Syndrome
Walters10 has reviewed the literature on opioid
receptors, agonists, and antagonists in RLS.
Studies have shown differing influences of the
antagonist naloxone on the symptom presentation in RLS. Hening and colleagues11 reported on
the benefit to five RLS patients when they were
successfully treated with various opioid agents.
Naloxone, a mu receptor antagonist, was given
parenterally to two patients on opioid therapy
and resulted in reappearance of RLS symptoms.
A more recent study by Winkelmann and associates12 did not demonstrate an influence of opiate
receptor blockade on RLS symptoms in untreated
patients. In a double-blind, placebo-controlled
crossover design, eight drug-nave RLS subjects
received naloxone and metoclopramide, a dopamine antagonist. Neither agent provoked the presentation of RLS symptoms. Winkelmann and
colleagues concluded that any mechanism for
RLS must be in specific dopaminergic or opioidergic pathways rather than a generalized change
in neurotransmitter function.12
In 1991, Montplaisir and colleagues13 reported on a single severe RLS patient who was

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OPIOID AGENTS IN THE TREATMENT OF RESTLESS LEGS SYNDROME

257

TABLE 32-2 Pharmacokinetics of Opioid Agonists by Analgesic Potency


Onset
(min)

Peak
(hr)

Duration of
Action (hr)

Adult Halflife (hr)

Interval of
Dosing (hr)

Oral Dose
(mg)

Codeine

15 to 30

1=2

to 1

4 to 6

2 to 3

3 to 6

200

Propoxyphene

30 to 60

2 to 2.5

4 to 6

3.5 to 15

4 to 8

130 to 150

Tramadol (+M1
metabolite)

30 to 60

2 to 2.5

4 to 8

6 to 7

6 to 8

50 to 200

Hydrocodone

15 to 30

1=2

to 1

4 to 6

3 to 4.5

3 to 6

30

Morphine

15 to 60

1=2

to 1

3 to 6

2 to 4

3 to 6

60

Oxycodone

15 to 30

1=2

to 1

4 to 6

3 to 4

3 to 6

30

Hydromorphone

15 to 30

1=2

to 1

4 to 6

2 to 4

3 to 6

7.5

Oxymorphone

5 to 15

1=
2

to 1

3 to 6

ND

4 to 6

10

Levorphanol

30 to 90

1=2

to 1

4 to 8

12 to 16

8 to 12

Methadone

30 to 60

1=
2

to 1

>8 (chronic)

15 to 30

6 to 12

20

Fentanyl
transdermal
(conversion from
oral opioids)

180 to
240

20

48 to 72

7 to 24

72

25 mg/hr patch

Low Potency

Moderate Potency

High Potency

High Potency +
Long Acting

Note: milligram dosing is a comparison for pain relief (not RLS efficacy).
ND, no or insufficient data.

studied in the sleep laboratory while medicationfree, while taking codeine sulfate, and while
taking codeine sulfate and pimozide. When the
patient was treated with codeine sulfate, RLS
complaints and periodic leg movements of
sleep showed a statistically significant reduction.
When the codeine-treated patient received
pimozide, a dopamine antagonist, the RLS symptoms that were measured by the forced immobilization test worsened even though the sleep
parameters and PLMS remained unchanged.
Montplaisir and colleagues opined that the
primary neurotransmitter system in the etiology
of RLS was dopaminergic in origin with the
opiate pathway modulating the dopamine
effect.13
There have been two case reports of the development of RLS during opioid withdrawal.
Scherbaum and associates14 identified two
opioid addicts who developed transient RLS
during withdrawal of opioids. Both were successfully treated with levodopa/benserazid. The
authors then completed a chart review of 120
opioid-dependent patients who had undergone

opioid detoxification. Fifteen of the 120 patients


identified symptoms that suggested transient RLS
during detoxification.14 In another study involving abrupt discontinuation of tramadol that
had taken for 1 year, a single subject developed
a variety of withdrawal symptoms that included
symptoms of RLS.15 Tramadol and its M1 metabolite are weak mu receptor agonists with serotoninergic and norepinephric activity. In an
open-label trial, tramadol demonstrated significant benefit in 10 of 12 RLS patients.5 In the
single case report by Freye and Levy,15 it is uncertain whether the symptoms of RLS were present
before initiation of tramadol.

Opioid Agents in the Treatment


of Restless Legs Syndrome
The practice guidelines of the American
Academy of Sleep Medicine identify the benefit
of opioids in the treatment of RLS.16 A more
recent treatment algorithm that has been proposed by the Medical Advisory Board of the
Restless Legs Syndrome Foundation includes

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258

CLINICAL SCIENCE OF RESTLESS LEGS SYNDROME

opioid therapy for any severity level of RLS.


This 2004 algorithm considers opioid agents
to have a particular role in patients who have
failed first-line therapy with dopamine agonists
or as initial therapy in patients who have severe
to very severe RLS.17 The algorithm recommends close monitoring of patients who are
treated with opioid agents to avoid complications or addiction.
Most published reports of opioids in the
treatment of RLS have used open-label trials.
Reports of small sample size of codeine,2,3 oxycodone,6-8 hydrocodone,6,8 propoxyphene,4
tramadol,5 and methadone8,9 demonstrate
efficacy in managing RLS symptoms. The limitations of these reports of efficacy include
small sample size and the lack of placebo
control. The response to placebo is fairly high
in large-scale studies that have been done
with carbamazepine,18 ropinirole,19,20 and
pramipexole.21
There are only two placebo-controlled trials in
a small number of patients that demonstrate the
efficacy of oxycodone and propoxyphene.
Walters and associates22 reported in 1993 on
the benefits of oxycodone in RLS. In a doubleblind, randomized, crossover trial that compared
oxycodone and placebo; 10 of 11 moderatesevere RLS patients chose oxycodone as their preferred agent for therapy. Using 2 weeks of treatment with a 3-day withdrawal but no washout
period, this crossover trial reported on daily
ratings of leg sensation, restlessness, and daytime
alertness. A statistically significant improvement
was shown in all parameters for oxycodone
(mean dose of 15.9 mg/day), including the findings of reduced periodic leg movements in sleep,
arousals, and a better sleep efficiency on two
nights of polysomnography.7
In 1993, Kaplan, Allen, Buchholz, and
Walters4 reported the changes in periodic leg
movements in sleep (PLMS) in six patients who
had been previously identified with PLMS and
were treated in a double-blind, crossover trial
with placebo, propoxyphene, and levodopa.
The low potency, mu receptor agonist propoxyphene at 100 and 200 mg showed a small reduction of the leg movements on home actigraphy
and improvement in arousal. But the patients
did not show a statistically significant reduction
of periodic leg movements of sleep on laboratory polysomnography. Compared with propoxyphene, levodopa demonstrated superior
improvement in home actigraphy, sleep laboratory, and alertness measures.4
There are no published reports on the comparative efficacy of different opioids.

Management Strategies
for Restless Legs Syndrome
Symptoms With Opioids
When selecting a therapy for RLS, the most effective agents with the least amount of side effects
would prove ideal. The bulk of evidence to date
supports dopamine agonists as the most efficacious and least problematic therapy for the
largest number of patients. It is estimated that
60% to 80% of RLS patients initially respond
to levodopa, ropinirole, pramipexole, and
others. The long-term therapy with dopaminergic agents is often limited by side effects,
particularly augmentation. As described in
Chapter 31 on dopaminergic treatment, augmentation to dopaminergic agents varies from
9% up to 80% depending on medication, symptom severity, length of treatment with selected
dopaminergic medications. Opioid medications in general have not been found to produce
augmentation with the singular exception of the
mixed opioid medication tamadol.23
Clinicians must first recognize that opioids are
efficacious and can generally be used with limited complications.24 Treatment algorithms recognize that opioids can be considered as first-line
therapy under special circumstances, but opioids
are more commonly considered appropriate for
patients who have developed side effects on
other therapy or have very severe RLS. The patient
with severe RLS is believed to have a higher likelihood of earlier presentation of augmentation.
Opioids may also have a role in combination
therapy, reducing side effects when high dosage
of any medication is needed to alleviate
symptoms.
First-line therapy for patients with intermittent
symptoms of RLS most commonly begins
with levodopa, a dopamine agonist, or sedativehypnotic agents. Occasionally, patients with
intermittent symptoms may find benefit from
low-potency opioid agents such as tramadol 50
to 100 mg, propoxyphene hydrochloride 65 mg
or napsylate 100 mg, or codeine 30 to 60 mg at
bedtime. These agents are often formulated with
acetaminophen or aspirin. Such opioid agents
have the benefit of rapid onset of action and limited side effect, including reduced abuse potential
compared with higher-potency opioids.
Various strategies with opioid therapy are
available when adverse effects to dopamine agonists present. Infrequently, moderate or severe
RLS patients are unable to tolerate even a low
dosage of ropinirole, pramipexole, or levodopa.
Although low-potency opioid agents might be
considered, it is more likely that patients will

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OPIOID AGENTS IN THE TREATMENT OF RESTLESS LEGS SYNDROME

respond to moderate-potency agents such as hydrocodone or oxycodone. Hydrocodone or oxycodone at 5 mg, 7.5 mg, or 10 mg PO at bedtime
is usually well tolerated and offers benefit for the
urge to move, motor restlessness and sleep. The
primary disadvantage of hydrocodone or oxycodone is a half-life of 3 to 4 hours that may be
insufficient to sustain benefit in patients with
symptoms that develop in the evening or later
in the night. Two or more doses of hydrocodone
or oxycodone may be required to cover evening
and nighttime symptoms.
For the most severe patient, high-potency
opioids such as hydromorphone, time-released
oxycodone, levorphanol, fentanyl patch, or
methadone are considerations. Severity is
defined by symptom intensity, frequency, and
time of presentation during the day. Often the
most intense symptoms of RLS are found in
patients who have afternoon or evening symptoms. In such patients, longer-acting oral
opioids such as levorphanol 1 to 8 mg/day or
methadone 5 to 40 mg/day in divided dosages
are considered most appropriate. Fentanyl
transdermal patch may have a role in very
severe RLS patients with 24-hour symptoms.
After establishing the requirement of oral
dosing of another opioid throughout the 24
hours, a fentanyl transdermal patch at an
absorption rate of 25 to 50 mg/hr is applied
once every 48 to 72 hours. The clinician
needs to review an appropriate reference for
the conversion table for fentanyl and the various oral opioid agents. As high-potency, shortacting opioids tend toward higher euphoric
effect, hydromorphone and time-released oxycodone should be reserved for unique circumstances and the clinician should exercise greater
caution when prescribing these agents.
In a study of comparative efficacy of different
medications,24 Becker examined the response of
different opioids in a subset of 18 severe RLS
patients using the earliest version of the RLS
Rating Scale. These patients had been treated
with levorphanol tartrate, a high-potency and
long-acting synthetic opioid, at an average
dosage of 3.2 mg/day for a mean of 5.1 years.
Due to a change in DEA manufacturing license,
levorphanol was abruptly unavailable, leading to
a naturalistic study of the therapeutic efficacy of
propoxyphene, hydrocodone, and hydromorphone in these severe RLS patients who had
responded well to levorphanol. Propoxyphene
up to 185.3 mg/day offered only mild benefit to
these severe patients. When hydrocodone at a
mean dosage of 18.2 mg/day was offered, the
patients experienced a moderate degree of

259

improvement. On initiation of hydromorphone


at a mean dosage of 7.06 mg/day, the patients
rated themselves to be moderately or more
improved. As 4 of the 18 patients had not previously received a dopamine agonist, they
received pramipexole and reported excellent benefit. Figure 32-1 shows the changes in rating on
the RLS scale at baseline and with the various
opioid agents.

Fear of Addiction and Adverse


Events When Using Opioids in
Restless Legs Syndrome
Fear of addiction is the greatest concern for
patients and their physicians when opioids are
prescribed. Addiction represents drug-seeking
behavior that arises from physical and psychological dependence. It is estimated that approximately 6% of the adult population is prone to
addiction. The physician must exercise the
greatest caution with addiction prone patients.
If a patient has had previous problems of abuse
or misuse of psychoactive agents such as
alcohol, sedative/hypnotics, stimulants, depressants, and/or opioids, the use of opioids is best
avoided and other treatments for RLS should
be considered.
The interaction of an opioid with the mu and
delta receptors predicts the risk for physical
dependence. When tolerance develops, dosage
escalation ensues to produce the desired physiological effect, leading to physical dependence.
On abrupt discontinuation of medications, withdrawal occurs, resulting in sweating, shaking,
headache, drug craving, nausea, vomiting,
abdominal cramping, diarrhea, inability to
sleep, confusion, agitation, depression, anxiety,
and other behavioral changes.
Psychological dependence is of concern in
predisposed individuals. The risk of psychological dependence increases with the use of
short-acting and high-potency agents. It leads to
drug-seeking behaviors that include seeing multiple physicians for prescriptions, use of different
pharmacies, frequent lost or missing prescriptions or pills, or dosage escalation based on need
for symptom control (It is really bad. I really
needed more of the pills, Doc.).
When considering the question of psychological dependence, the physician must be aware
of the potential for insufficient dosing by patient
and physician. The issue of dosage escalation
in psychological dependence presumes that
an expected therapeutic dosage was obtained.
It is the natural tendency of the patient and

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260

CLINICAL SCIENCE OF RESTLESS LEGS SYNDROME

35

IRLS Rating

30

26.67

25
18.43

20
14.31

15
10

8.5

8.75

11.17

5
0
levorphanol
hydrocodone

pramipexole
propoxyphene

hydromorphone
Base

FIGURE 32-1. Comparative efficacy of different opioids in 18 severe RLS patients. The summed score of the International
RLS Study group rating scale 22 (IRLS) for this group of patients while on the indicated therapies. Lower scores indicate
better therapeutic effect. For guidance of results, the following gives a suggested correlation between IRLS score and
severity of RLS symptoms:
Mild = 0 to 10
Moderate = 11 to 20
Severe = 21 to 30
Very severe = 31 to 40

physician to use the lowest potential dosage at


the lowest frequency when initiating therapy. In
such circumstances, inadequate dosing of effective therapy for RLS can occur. When a low
dosage of the opioid agent (or a lower-potency
opioid agent) has offered temporary benefit for
1 to 8 weeks, the physician should recognize that
the therapeutic level to treat RLS has not been
attained. Dosage increase would then be appropriate. In general, the patients without addiction
potential eventually reach a dosage that results
in sustained relief of RLS symptoms and the
same therapeutic dosage of opioid will be maintained over time.
Walters and colleagues22 offer support and
guidance about the long-term uses of opioids
for RLS. They reported on 113 RLS patients
from three centers who had received opioid therapy either alone or in combination with other
treatments. Of the 36 patients who received
opioids as their sole therapy, 20 continued on
stable doses of opioid medication for a mean
of 5.9 years. Only one of the 36 patients was
discontinued from therapy because of concerns
regarding addiction. Seven patients who had
been treated for 1 to 15 years underwent polysomnography. Three of the seven patients
either developed or showed an exacerbation of
sleep apnea. The authors recommended that
patients taking chronic opioid therapy should
be closely monitored for sleep disordered
breathing.

Serious adverse effects of opioids include respiratory depression, particularly in patients who
have underlying lung disease. As noted earlier,
exacerbation of sleep apnea would be of concern.
Any patient who reports the new or worsening
symptoms of daytime sleepiness should receive
polysomnography. In particular, the sleepiness
should become a concern when the half-life
of an opioid agent would indicate insufficient
serum levels to cause sleepiness. Some patients
are particularly sensitive to the constipating side
effects, appetite suppression, or nausea/emesis
that can occur with opioids. Less frequently,
patients experience itching, depression, personality changes, or cognitive disturbance.

Conclusion
Opioid agents can be very effective in managing
the symptoms of RLS. Opioid agents prove particularly beneficial for patients who have developed augmentation on dopamine agonists or
have experienced problematic side effects from
any other therapy. The most severe patients
with RLS are appropriate candidates for opioid
agents as first-line therapy. Although patients
can benefit from moderate potency agents such
as hydrocodone and oxycodone, high-potency
levorphanol or methadone offer a longer
therapeutic benefit with manageable side effects.
If a patient has misused other psychoactive
agents, addiction, physical dependence, and

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OPIOID AGENTS IN THE TREATMENT OF RESTLESS LEGS SYNDROME

psychological dependence are risks and opioid


therapy should be avoided. For any patient who
has used opioids for months or years, a taper of
medication must occur to avoid withdrawal.
Long-term use also requires monitoring for
adverse events, particularly daytime sleepiness
or exacerbation of respiratory disturbance,
including upper airway resistance syndrome or
obstructive sleep apnea. Although the prescription of opioids requires respect for their risks
and the acceptance of regulatory monitoring,
physicians should recognize that up to 20% of
their patients with RLS will significantly benefit
from either monotherapy or combination therapy with opioids.

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