Opioid Agents in the Treatment of Restless Legs Syndrome

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Chapter 32 Opioid Agents in the Treatment of Restless Legs Syndrome

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,68 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 protein–coupled 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-glutamate–induced 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-naïve 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 studied in the sleep laboratory while medication-free, 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

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