Documenti di Didattica
Documenti di Professioni
Documenti di Cultura
MANAGEMENT
32
Philip M. Becker
255
Downloaded from ClinicalKey.com at ClinicalKey Global Flex Package Trial June 07, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
256
Respiratory
Depression
Emesis
Physical
Dependence
+++
++
++
++
++
++
++
++
++
++
++
++
Morphine
++
++
+++
++
++
++
++
Oxycodone
++
++
+++
++
++
++
++
Oxymorphone
++
++
+++
+++
+++
Propoxyphene
Tramadol
+/to
+/to
Drug
Analgesia
Sedation
Antitussive
Codeine
Hydrocodone
Hydromorphone
++
Levorphanol
++
Methadone
++
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
Downloaded from ClinicalKey.com at ClinicalKey Global Flex Package Trial June 07, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
257
Peak
(hr)
Duration of
Action (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
Downloaded from ClinicalKey.com at ClinicalKey Global Flex Package Trial June 07, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
258
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
Downloaded from ClinicalKey.com at ClinicalKey Global Flex Package Trial June 07, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
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
Downloaded from ClinicalKey.com at ClinicalKey Global Flex Package Trial June 07, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
260
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
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
Downloaded from ClinicalKey.com at ClinicalKey Global Flex Package Trial June 07, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.
References
1. Willis T. The London Practice of Physick. London,
Bassett, Dring, Harper, and Crook, 1692.
2. Ekbom K. Restless legs: A clinical study. Acta Med
Scand Suppl 1945;158:1-123.
3. Ekbom KA. Restless legs syndrome. Neurology 1960;
10:868-873.
4. Kaplan PW, Allen RP, Buchholz DW, Walters JK.
A double-blind, placebo-controlled study of the treatment of periodic limb movements in sleep using carbidopa/levodopa and propoxyphene. Sleep 1993;
16:717-723.
5. Lauerma H, Markkula J. Treatment of restless legs syndrome with tramadol: An open study. J Clin Psychiatry
1999;60:241-244.
6. Kavey N, Walters AS, Hening W, et al. Opioid treatment of periodic movements in sleep in patients without restless legs. Neuropeptides 1988;11:181-184.
7. Walters AS, Wagner ML, Hening WA, et al. Successful
treatment of the idiopathic restless legs syndrome in a
randomized double-blind trial of oxycodone versus
placebo. Sleep 1993;16:327-332.
8. Trzepacz PT, Violette EJ, Sateia MJ. Response to opioids
in three patients with restless legs syndrome. Am J
Psychiatry 1984;141:993-995.
9. Ondo WG. Methadone for refractory restless legs syndrome. Mov Disord 2005;20:345-348.
10. Walters AS. Review of receptor agonist and antagonist
studies relevant to the opiate system in restless legs
syndrome. Sleep Med 2002;3:301-304.
261
Downloaded from ClinicalKey.com at ClinicalKey Global Flex Package Trial June 07, 2016.
For personal use only. No other uses without permission. Copyright 2016. Elsevier Inc. All rights reserved.