The Interplay of Mitochondrial Bioenergetics and Dopamine Agonists as an Effective Disease-Modifying Therapy for Parkinson's Disease.

Parkinson's disease (PD) is a progressive neurological ailment with a slower rate of advancement that is more common in older adults. The biggest risk factor for PD is getting older, and those over 60 have an exponentially higher incidence of this condition. The failure of the mitochondrial electron chain, changes in the dynamics of the mitochondria, and abnormalities in calcium and ion homeostasis are all symptoms of Parkinson's disease (PD). Increased mitochondrial reactive oxygen species (mROS) and an energy deficit are linked to these alterations. Levodopa (L-DOPA) is a medication that is typically used to treat most PD patients, but because of its negative effects, additional medications have been created utilizing L-DOPA as the parent molecule. Ergot and non-ergot derivatives make up most PD medications. PD is successfully managed with the use of dopamine agonists (DA). To get around the motor issues produced by L-DOPA, these dopamine derivatives can directly excite DA receptors in the postsynaptic membrane. In the past 10 years, two non-ergoline DA with strong binding properties for the dopamine D2 receptor (D2R) and a preference for the dopamine D3 receptor (D3R) subtype, ropinirole, and pramipexole (PPx) have been developed for the treatment of PD. This review covers the most recent research on the efficacy and safety of non-ergot drugs like ropinirole and PPx as supplementary therapy to DOPA for the treatment of PD.

Sprague Dawley rats from different vendors vary in the modulation of prepulse inhibition of startle (PPI) by dopamine, acetylcholine, and glutamate drugs.

RATIONALE: Rodent vendors are often utilized interchangeably, assuming that the phenotype of a given strain remains standardized between colonies. Several studies, however, have found significant behavioral and physiological differences between Sprague Dawley (SD) rats from separate vendors. Prepulse inhibition of startle (PPI), a form of sensorimotor gating in which a low-intensity leading stimulus reduces the startle response to a subsequent stimulus, may also vary by vendor. Differences in PPI between rat strains are well known, but divergence between colonies within the SD strain lacks thorough examination. OBJECTIVES: We explored intrastrain variation in PPI by testing SD rats from two vendors: Envigo and Charles River (CR). METHODS: We selected drugs acting on four major neurotransmitter systems that have been repeatedly shown to modulate PPI: dopamine (apomorphine; 0.5, 1.5, 3.0 mg/kg), acetylcholine (scopolamine; 0.1, 0.5, 1.0 mg/kg), glutamate (dizocilpine; 0.5, 1.5, 2.5 mg/kg), and serotonin (2,5-Dimethoxy-4-iodoamphetamine, DOI; 0.25, 0.5, 1.0 mg/kg). We determined PPI and startle amplitude for each drug in male and female Envigo and CR SD rats. RESULTS: SD rats from Envigo showed dose-dependent decreases in PPI after apomorphine, scopolamine, or dizocilpine administration, without significant effects on startle amplitude. SD rats from CR were less sensitive to modulation of PPI and/or more sensitive to modulation of startle amplitude, across the three drugs. CONCLUSIONS: SD rats showed vendor differences in sensitivity to pharmacological modulation of PPI and startle. We encourage researchers to sample rats from separate vendors before experimentation to identify the most suited source of subjects for their specific endpoints.

[Pharmacological Treatment for Restless Legs Syndrome].

Restless legs syndrome (RLS) is a neurological disorder that causes insomnia and daytime functional disability due to an urge to move the legs usually accompanied by uncomfortable sensations. Non-pharmacologic treatment includes regular sleep habits and exercise. Iron supplementation is indicated for patients with low serum ferritin levels. Antidepressants, antihistaminergics, and dopamine antagonists should be reduced or discontinued because they induce RLS symptoms. Dopamine agonists and alpha 2-delta ligands are the first-line pharmacological treatments for RLS.

Quinpirole, but not muscimol, infused into the nucleus accumbens disrupts prepulse inhibition of the acoustic startle in rhesus macaques.

Sensorimotor gating is the ability to suppress motor responses to irrelevant sensory inputs. This response is disrupted in a range of neuropsychiatric disorders. Prepulse inhibition (PPI) of the acoustic startle response (ASR) is a form of sensorimotor gating in which a low-intensity prepulse immediately precedes a startling stimulus, resulting in an attenuation of the startle response. PPI is conserved across species and the underlying circuitry mediating this effect has been widely studied in rodents. However, recent work from our laboratories has shown an unexpected divergence between the circuitry controlling PPI in rodents as compared to macaques. The nucleus accumbens, a component of the basal ganglia, has been identified as a key modulatory node for PPI in rodents. The role of the nucleus accumbens in modulating PPI in primates has yet to be investigated. We measured whole-body PPI of the ASR in six rhesus macaques following (1) pharmacological inhibition of the nucleus accumbens using the GABAA agonist muscimol, and (2) focal application of the dopamine D2/3 agonist quinpirole (at 3 doses). We found that quinpirole, but not muscimol, infused into the nucleus accumbens disrupts prepulse inhibition in monkeys. These results differ from those observed in rodents, where both muscimol and quinpirole disrupt prepulse inhibition.

Hypothalamic-prolactin axis regulation in major depressed patients with suicidal behavior.

BACKGROUND: So far, little is known about the control of hypothalamic-prolactin axis activity by dopamine (DA) and thyrotropin-releasing hormone (TRH) in depressed patients with suicidal behavior disorder (SBD). METHODS: We evaluated prolactin (PRL) responses to apomorphine (APO; a DA direct receptor agonist) and 0800 h and 2300 h protirelin (TRH) tests in 50 medication-free euthyroid DSM-5 major depressed inpatients with SBD (either current [n = 22], or in early remission [n = 28]); and 18 healthy hospitalized controls (HCs). RESULTS: Baseline (BL) PRL levels were comparable across the three diagnostic groups. SBDs in early remission did not differ from HCs regarding PRL suppression to APO (PRLs), PRL stimulation to 0800 h and 2300 h TRH tests (∆PRL), and ∆∆PRL values (difference between 2300 h-∆PRL and 0800 h-∆PRL values). Current SBDs showed lower PRLs and ∆∆PRL values than HCs and SBDs in early remission. Further analyses revealed that current SBDs with a history of violent and high-lethality suicide attempts were more likely to exhibit co-occurrence of low ∆∆PRL and PRLS values. CONCLUSIONS: Our results suggest that regulation of the hypothalamic-PRL axis is impaired in some depressed patients with current SBD, particularly those who have made serious suicide attempts. Considering the limitations of our study, our findings support the hypothesis that decreased pituitary D2 receptor functionality (possibly adaptive to increased tuberoinfundibular DAergic neuronal activity) together with decreased hypothalamic TRH drive might be a biosignature for high-lethality violent suicide attempts.

Dopamine agonists for the treatment of pituitary tumours: From ergot extracts to next generation therapies.

Dopamine agonists are a key tool in the therapeutic arsenal of endocrinologists worldwide. They exert their effects by binding to dopamine-2 (D2) receptors expressed by pituitary tumour cells to modulate hormonal secretion and tumour size. They are the established first-line treatment for prolactinomas which express high levels of D2 receptors. Growing data support their use as an adjuvant treatment option for other pituitary tumours including growth hormone, adrenocorticotrophic hormones, thyroid hormone secreting adenomas and nonfunctional pituitary tumours, all of which have been shown to express D2 receptors as well, albeit to varying extents. For those pituitary tumours inadequately treated by dopamine agonist alone, combined agonism of D2 and somatostatin receptors represent a new frontier in clinical development. Here we review the development and role of dopamine agonist for the treatment of prolactinomas, the literature supporting their adjuvant use for the treatment of all other pituitary tumours, and recent progress in the development of the next generation of chimeric compounds that target D2 and other receptor subtypes highly expressed on pituitary tumour cells.

Pharmacological responsiveness of periodic limb movements in patients with restless legs syndrome: a systematic review and meta-analysis.

STUDY OBJECTIVES: Periodic limb movements during sleep (PLMS) are a frequent finding in restless legs syndrome, but their impact on sleep is still debated, as well the indication for treatment. We systematically reviewed the available literature to describe which drug categories are effective in suppressing PLMS, assessing their efficacy through a meta-analysis, when this was possible. METHODS: The review protocol was preregistered on PROSPERO (CRD42021175848), and the systematic search was conducted on and EMBASE (last searched on March 2020). We included original human studies, which assessed PLMS modification on drug treatment with a full-night polysomnography, through surface electrodes on each tibialis anterior muscle. When at least 4 studies were available on the same drug or drug category, we performed a random-effect model meta-analysis. RESULTS: Dopamine agonists like pramipexole and ropinirole resulted the most effective, followed by l-dopa and other dopamine agonists. Alpha2delta ligands are moderately effective as well opioids, despite available data on these drugs are much more limited than those on dopaminergic agents. Valproate and carbamazepine did not show a significant effect on PLMS. Clonazepam showed contradictory results. Perampanel and dypiridamole showed promising but still insufficient data. The same applies to iron supplementation. CONCLUSIONS: Dopaminergic agents are the most powerful suppressors of PLMS. However, most therapeutic trials in restless legs syndrome do not report objective polysomnographic findings, there is a lack of uniformity in presenting results on PLMS. Longitudinal polysomnographic interventional studies, using well-defined and unanimous scoring criteria and endpoints on PLMS are needed. CITATION: Riccardi S, Ferri R, Garbazza C, Miano S, Manconi M. Pharmacological responsiveness of periodic limb movements in patients with restless legs syndrome: a systematic review and meta-analysis. J Clin Sleep Med. 2023;19(4):811-822.

Exploration of restless legs syndrome under the new concept: A review.

Restless leg syndrome (Restless legs syndrome, RLS) is a common neurological disorder. The pathogenesis of RLS remains unknown, and recent pathophysiological developments have shown the contribution of various genetic markers, neurotransmitter dysfunction, and iron deficiency to the disease, as well as other unidentified contributing mechanisms, particularly chronic renal dysfunction. RLS enhancement syndrome is frequently observed in patients with RLS who have received long-term dopamine agonist therapy, manifesting as a worsening of RLS symptoms, usually associated with an increase in the dose of dopamine agonist. Some patients with RLS can adequately control their symptoms with non-pharmacological measures such as massage and warm baths. First-line treatment options include iron supplementation for those with evidence of reduced iron stores, or gabapentin or pregabalin, as well as dopamine agonists, such as pramipexole. Second-line therapies include opioids such as tramadol. RLS seriously affects the quality of life of patients, and because its pathogenesis is unclear, more biological evidence and treatment methods need to be explored.

Treating Severe Refractory and Augmented Restless Legs Syndrome.

Restless legs syndrome (RLS) is a sensory-motor neurologic disorder present to a clinically significant degree in 2% to 3% of the adult population, more commonly with advancing age and in women, that dramatically affects sleep and quality of life. Addressing factors that worsen RLS (eg, iron deficiency, antidepressant or antihistamine administration, OSA) is an important first step in treatment. RLS can generally be well treated with medications such as the alpha2-delta calcium channel ligands (A2Ds) gabapentin, pregabalin, and gabapentin enacarbil or, if these are poorly tolerated or lack efficacy, the dopamine agonists (DAs) pramipexole, ropinirole, or rotigotine. Oral or IV iron supplementation is often efficacious as initial treatment in patients with low normal serum indexes. However, at least one-third of patients do not achieve acceptable symptom relief from initial treatments. Furthermore, DAs, the most commonly used medications for RLS, commonly produce augmentation, a progressive, long-term, iatrogenic worsening of RLS symptoms characterized by increasing severity as well as temporal and anatomic extension of symptoms. If dopaminergic augmentation of RLS is present, substitution of an A2D or opioid for the DA is the primary goal. However, given the profound rebound RLS and insomnia that occurs with even small dose reductions of DAs, the initial change should be the addition of one of these alternate treatments. Once adequate doses, or symptom relief, are achieved with the second agent, subsequent very slow down-titration and discontinuation of the DA is often possible and can lead to dramatic long-term relief of RLS symptoms and improvement in sleep.

Acupuncture for Parkinson's disease: From theory to practice.

Advances in molecular biology and biochemistry have improved the treatment of Parkinson's disease (PD). There has been extensive evidence on the benefit of standard treatment (e.g., deep brain stimulation, levodopa, and dopamine agonists) and acupuncture for PD. This article aims to distill the similarities and differences in the treatment concepts between Chinese and Western medicine from the perspective of reinforcing the deficiency and purging the excess, summarize the latest evidence on the benefits of acupuncture for PD from theory to practice, and propose prospective treatment options for PD.

Surface-functionalized curcumin-loaded polymeric nanocapsules could block apomorphine-induced behavioral changes in rats.

BACKGROUND: Surface functionalization enhances the properties and characteristics of polymeric nanocapsules (NCs) mainly due to the surface charge, surfactants, and polymer coating type. Curcumin (CUR) is a bioactive compound with several proven pharmacological properties and low bioavailability. This study aimed to develop anionic (poly-ɛ-caprolactone; PCL) and cationic (Eudragit® RS100 (EUD)) NCs prepared with sorbitan monostearate (Span 60®) or sorbitan monooleate (Span 80®), coated with d-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and optimized using 23 factorial analysis. Subsequently, the biological activity was evaluated. METHODS: A two-level, three-factor design (polymer, Span type, and TPGS concentration) was used. The biological effects of CUR-loaded TPGS-coated cationic and anionic NCs were assessed in apomorphine-induced stereotyped behavior in rats. RESULTS: The type of polymer (anionic or cationic) and Span® had a factorial influence on the physical and chemical characteristics of NCs according to the changes in TPGS concentrations. Both cationic and anionic CUR-NCs could block apomorphine-induced behavioral changes. CONCLUSIONS: The CUR-loaded TPGS-coated NCs proved to be a promising brain delivery system.

Parkinsonism-like Disease Induced by Rotenone in Rats: Treatment Role of Curcumin, Dopamine Agonist and Adenosine A2A Receptor Antagonist.

BACKGROUND: Parkinsonism is a neurodegenerative disorder that affects elderly people worldwide. METHODS: Curcumin, adenosine A2AR antagonist (ZM241385) and Sinemet® (L-dopa) were evaluated against Parkinson's disease (PD) induced by rotenone in rats, and the findings were compared to our previous study on mice model. RESULTS: Rats injected with rotenone showed severe alterations in adenosine A2A receptor gene expression, oxidative stress markers, inflammatory mediator, energetic indices, apoptotic marker and DNA fragmentation levels as compared to the control group. Treatments with curcumin, ZM241385, and Sinemet® restored all the selected parameters. The brain histopathological features of cerebellum regions confirmed our results. By comparing our results with the previous results on mice, we noticed that mice respond to rotenone toxicity and treatments more than rats with regards to behavioral observation, A2AR gene expression, neurotransmitter levels, inflammatory mediator and apoptotic markers, while rats showed higher response to treatments regarding oxidative stress and energetic indices. CONCLUSION: Curcumin succeeded in attenuating the severe effects of Parkinson's disease in the rat model and can be considered as a potential dietary supplement. Adenosine A2AR antagonist has almost the same pattern of improvement as Sinemet® and may be considered as a promising therapy against PD. To compare the role of animal species in response to PD symptoms and treatments, our previous report on mice explored the response of mice to rotenone toxicity in comparison with rats, where rats have shown a higher response to treatments. Therefore, no animal model can perfectly recapitulate all the pathologies of PD.

2-Phenylcyclopropylmethylamine Derivatives as Dopamine D2 Receptor Partial Agonists: Design, Synthesis, and Biological Evaluation.

Partial agonist activity at the dopamine D2 receptor (D2R) is the primary pharmacological feature of the third-generation antipsychotics─aripiprazole, brexpiprazole, and cariprazine. However, all these drugs share a common phenyl-piperazine moiety as the primary pharmacophore. In this study, we designed and synthesized a series of novel compounds based on the 2-phenylcyclopropylmethylamine (PCPMA) scaffold and studied their pharmacological activity at the D2R. A number of potent D2R partial agonists were identified through binding affinity screening and functional activity profiling in both G protein and ß-arrestin assays. The structure-functional activity relationship results showed that the spacer group is crucial for fine-tuning the intrinsic activity of these compounds. Compounds (+)-14j and (+)-14l showed good pharmacokinetic properties and an unexpected selectivity against the serotonin 2A (5-HT2A) receptor. Preliminary suppressive effects in a mouse hyperlocomotion model proved that these PCPMA-derived D2R partial agonists are effective as potential novel antipsychotics.

Search for safer and potent natural inhibitors of Parkinson's disease.

After Alzheimer's disease, Parkinson's disease (PD) has taken second place in becoming one of the most commonly occurring neurological diseases being responsible for a number of disabling motor symptoms ranging from bradykinesia, akinesia, tremors to rigidity, that mostly targets the elderly population and severely disrupts their quality of life. The true underlying pathology of PD yet remains a mystery, however, recent advances in the field have pointed towards the production of α-synuclein aggregates, oxidative stress, and an imbalance between levels of acetylcholine and dopamine neurotransmitters in the brain that have been shown to result in loss of coordinated movement. Current treatments of PD include the gold standard dopamine precursor L-dopa, dopamine agonists pergolide and bromocriptine, catechol-o-methyl transferases inhibitors, entacapone and tolcapone and monoamine oxidase inhibitors such as Selegine and Rasagiline amongst several other drugs. While these drugs are successful in treating motor symptoms of the disease, they do so with a plethora of side effects that are especially debilitating to the elderly. In the recent years, a considerable amount of attention has been shifted towards phytocompounds such as flavonoids and green tea catechins due to promising experimental results. In this review, we have compiled phytocompounds that have shown potent activity against some of the most important targets for antiparkinsonian therapy. These compounds have exhibited activities that transcend the limits of simply attenuating mitochondrial oxidative stress and have opened doors to the discovery of novel lead compounds for newer, efficacious antiparkinsonian therapies with wider therapeutic windows.

The dopamine D2 agonist quinpirole impairs frontal mismatch responses to sound frequency deviations in freely moving rats.

AIM: A reduced mismatch negativity (MMN) response is a promising electrophysiological endophenotype of schizophrenia that reflects neurocognitive impairment. Dopamine dysfunction is associated with symptoms of schizophrenia. However, whether the dopamine system is involved in MMN impairment remains controversial. In this study, we investigated the effects of the dopamine D2-like receptor agonist quinpirole on mismatch responses to sound frequency changes in an animal model. METHODS: Event-related potentials were recorded from electrocorticogram electrodes placed on the auditory and frontal cortices of freely moving rats using a frequency oddball paradigm consisting of ascending and equiprobable (ie, many standards) control sequences before and after the subcutaneous administration of quinpirole. To detect mismatch responses, difference waveforms were obtained by subtracting nondeviant control waveforms from deviant waveforms. RESULTS: Here, we show the significant effects of quinpirole on frontal mismatch responses to sound frequency deviations in rats. Quinpirole delayed the frontal N18 and P30 mismatch responses and reduced the frontal N55 MMN-like response, which resulted from the reduction in the N55 amplitude to deviant stimuli. Importantly, the magnitude of the N55 amplitude was negatively correlated with the time of the P30 latency in the difference waveforms. In contrast, quinpirole administration did not clearly affect the temporal mismatch responses recorded from the auditory cortex. CONCLUSION: These results suggest that the disruption of dopamine D2-like receptor signaling by quinpirole reduces frontal MMN to sound frequency deviations and that delays in early mismatch responses are involved in this MMN impairment.

Treatment of subcutaneous nodules after infusion of apomorphine; a biopsy-controlled study comparing 4 frequently used therapies.

This study aimed to provide clinical evidence for existing treatments of subcutaneous nodules after subcutaneous infusion of apomorphine, using a biopsy-controlled prospective crossover design of four treatments. We demonstrated that dilution of apomorphine significantly improved patient satisfaction, while subcutaneous hydrocortisone reduced nodule size, however with no differences in the histopathology.

Computational study on new natural compound agonists of dopamine receptor.

Dopamine receptor, a polypeptide chain composed of 7 hydrophobic transmembrane regions, is a new and vital drug target, especially Dopamine receptor 2(D2). Targeting dopamine receptors, Dopamine receptor agonists are a class of drugs similar in function and structure to dopamine and can directly act on dopamine receptors and activate it. Clinically, Dopamine receptor agonist drugs have achieved significant therapeutic effects on prolactinoma and Parkinson's Disease. In the study, we virtually screened a series of potential effective agonists of Dopamine receptor by computer techniques. Firstly, we used the Molecular Docking (LibDock) step to screen out some molecules that can dock well with the protein. Then, analysis of toxicity prediction and ADME (adsorption, distribution, metabolism and excretion) were carried out. More precise molecular docking (CDOCKER) and 3-Dimensional Quantitative Structure-Activity Relationship Modeling Study(3D-QSAR) pharmacophore generation were implemented to research and explore these compounds' binding mechanism with Dopamine receptor. Last but not least, to assess compound's binding stabilities, we carried out a molecular dynamic analysis. As the results show, two compounds (ZINC000008860530 and ZINC000004096987) from the small molecule database (ZINC database) were potential effective agonists of Dopamine receptor. These two compounds can combine with Dopamine receptor with higher affinity and proved to be no toxic. The cell experiment showed that two compounds could inhibit the proliferation and PRL secretion of MMQ cells (pituitary tumor cells). Thus, this study provided valuable information about Dopamine receptor agonist-based drug discovery. So, this study will benefit patients with prolactinoma and Parkinson's disease a lot.

Challenges in the Treatment of Restless Legs Syndrome: A Case Report.

Treatment resistant restless legs syndrome (RLS) in the setting of psychiatric comorbidities can be difficult to manage. Our patient is a 69-year-old Caucasian gentleman with bipolar disorder type I, unspecified anxiety disorder, obstructive sleep apnea (OSA), and treatment-refractory RLS. At initial presentation, the patient's prescribed medication regimen included fluoxetine 40 mg daily, gabapentin 800 mg in the morning and 3200 mg at bedtime, pramipexole 0.375 mg daily, lamotrigine 200 mg daily, trazodone 200 mg at bedtime, and temazepam 15 to 30 mg as needed for insomnia and RLS. Over the course of nearly 4 years, treatment interventions for this patient's RLS included: cognitive behavioral therapy for insomnia, discontinuation of exacerbating medications, switching dopamine agonists, use of pregabalin and iron supplement. This report demonstrates a challenging case of RLS in the setting of psychiatric comorbidities, development of augmentation, and polypharmacy.

Prepulse inhibition based grouping of rats and assessing differences in response to pharmacological agents.

Schizophrenia modeling by disrupting prepulse inhibition (PPI) is one of the most frequently used psycho-pharmacological methods by administering pharmacological agents to stimulate disruption. However, since PPI is also a biological indicator of schizophrenia, it is possible to classify subjects based on their basal PPI values and group them as "low inhibition" and "high inhibition without taking any pharmacological agent. Therefore this study was conducted to show that rats can be divided into groups in terms of susceptibility to schizophrenia according to basal PPI values. It was also observed that these groups might give different responses to different pharmacological agents (apomorphine, amphetamine, MK-801, scopolamine, nicotine, caffeine). Male Sprague Dawley rats (250-350 g) were used in the study. To examine the effects of different pharmacological agents on the groups, apomorphine (0.5 mg/kg and 1 mg/kg), amphetamine (4 mg/kg), MK-801 (0.05 mg/kg and 0.15 mg/kg), scopolamine (0.4 mg/kg), nicotine (1 mg/kg) and caffeine (10 mg/kg and 30 mg/kg) were used. Amphetamine showed a disruptive effect on PPI in both low and high inhibitory groups, while apomorphine, MK-801, scopolamine, and nicotine showed PPI decrease only in the high inhibitory group. Besides, caffeine decreased PPI levels at two doses in the high inhibitory group; however, 10 mg/kg dose caffeine was increased only in the low inhibitory group. According to the data obtained from this study, rats can be grouped with baseline inhibition values by using PPI, and response differences of pharmacological agents to groups may vary.

Restless Legs Syndrome: Contemporary Diagnosis and Treatment.

Restless legs syndrome (RLS) is characterized by an uncomfortable urge to move the legs while at rest, relief upon movement or getting up to walk, and worsened symptom severity at night. RLS may be primary (idiopathic) or secondary to pregnancy or a variety of systemic disorders, especially iron deficiency, and chronic renal insufficiency. Genetic predisposition with a family history is common. The pathogenesis of RLS remains unclear but is likely to involve central nervous system dopaminergic dysfunction, as well as other, undefined contributing mechanisms. Evaluation begins with a thorough history and examination, and iron measures, including ferritin and transferrin saturation, should be checked at presentation and with worsened symptoms, especially when augmentation develops. Augmentation is characterized by more intense symptom severity, earlier symptom occurrence, and often, symptom spread from the legs to the arms or other body regions. Some people with RLS have adequate symptom control with non-pharmacological measures such as massage or temperate baths. First-line management options include iron-replacement therapy in those with evidence for reduced body-iron stores or, alternatively, with prescribed gabapentin or pregabalin, and dopamine agonists such as pramipexole, ropinirole, and rotigotine. Second-line therapies include intravenous iron infusion in those who are intolerant of oral iron and/or those having augmentation with intense, severe RLS symptoms, and opioids including tramadol, oxycodone, and methadone. RLS significantly impacts patients' quality of life and remains a therapeutic area sorely in need of innovation and a further pipeline of new, biologically informed therapies.