Trazodone for restless legs

Treating the Difficult RLS Patient

Diagnosing and treating difficult cases of restless legs syndrome (RLS) can be a complicated task, but identifying and managing the disorder can be less daunting when putting the “six Ds” into practice:

  1. diagnosis incorrect (consider primary versus secondary etiology);
  2. drug side effects;
  3. drug is ineffective;
  4. dosage is too low;
  5. dyssomnia from other sources
    1. depression
    2. anxiety;
  6. dopaminergic augmentation.

Cases of RLS can take unexpected twists, potentially leading patients to a knotted state of mismanagement. Proper use of the six Ds can help practitioners untangle difficult RLS cases and facilitate proper care. Mr D, the subject of this case report, required shifts in strategic management for his RLS and became a testimony to the positive outcomes when the six Ds are put into practice.


RLS is a neurosensorimotor disorder. Refractory RLS causes significant discomfort/pain, insomnia, and impairment in social function. The US incidence of RLS was reported in 2005 as 9.7% (11% of women and 8% of men).1 A Canadian survey estimated the prevalence of RLS symptoms at 17% for women and 13% for men,2 while in Singapore a study yielded much lower prevalence, 0.6% in an older and 0.1% in a younger cohort.3

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Although etiology for RLS remains unknown, hypotheses include dysfunctional iron regulation4 or dopamine deficit in the central nervous system.5 In studies of potential candidate genes, links to familial RLS have been found on chromosome 12q6 and periodic limb movements of sleep (PMLS) with and without restless legs syndrome on chromosome 6p21.2.7

Ropinirole and pramipexole are approved treatments of RLS, although off-label therapies are common—clonazepam, gabapentin, pregabalin, levodopa, and opiates. Initial response to drug therapy is seen in about 70% to 80% of patients, but successful long-term management of moderate to severe RLS frequently requires pharmacologic adjustment and combination therapy.8 The Medical Advisory Board of the Restless Legs Syndrome Foundation (RLSF) has proposed the RLSF algorithm based on frequency of symptoms to assist clinicians in the management of patients with RLS.9


Mr D, age 64, presented with a 24-year history of severe sleep onset insomnia. He denied daytime sleepiness. The insomnia coincided with the development of bilateral discomfort deep in each of his calves beginning with watching evening TV. The leg discomfort was “kind of painful.” He was in and out of bed three or four times to walk. He was in good health with mild snoring, hypertension controlled by beta blocker, and a stable weight with BMI of 27. Neurologic examination was normal. Chemistries, including serum ferritin at 68 ng/ml, were normal. A clinical diagnosis of moderate-severe restless leg syndrome was made. He was started on pramipexole at 0.125 mg at 17:00 and 0.25 mg at 21:00 for a 23:30 bedtime.

For 3 years, he reported sleeping well for 7 or more hours. RLS symptoms then presented earlier at 13:00. Over 1 year, pramipexole was adjusted, eventually reaching 0.25 mg at 12:00, 0.25 mg at 17:00, and 0.5 mg at 21:00. RLS symptoms then presented as early as 11:00 with infrequent involvement of the arms. Recheck of ferritin was 62 ng/ml. Mr D met criteria for augmentation of RLS. A taper and discontinuation of pramipexole occurred over 2 weeks. Concurrently, the high-potency, longer-acting opiate levorphanol tartrate was increased to 2 mg one half tablet at 17:00 and one tablet at 22:00, and he reported excellent relief of RLS and normal sleep.

Four years into levorphanol therapy, he developed daytime sleepiness. Snoring had worsened. Polysomnography demonstrated 19 obstructive apnea/hypopneas per hour and minimal central events. Nasal CPAP to 8 CWP was titrated, but adherence was poor. A change to an oral appliance was accepted, but sleepiness did not improve (Epworth sleepiness score of 14). Modafinil, taken as needed, improved sleepiness with no change in RLS symptoms while continuing levorphanol.


The RLSF algorithm defines refractory patients as having nearly daily RLS symptoms with ineffective therapeutic response, intolerable side effects, and/or augmentation. We propose assessment of these difficult RLS patients using the six Ds to enhance case management.


Ask whether the diagnosis is correct. Early in their course, refractory patients should have met the four essential clinical criteria to diagnose RLS. The first author has proposed the acronym “URGE” to assist assessment:

  1. Urge to move is the core symptom of RLS that is uniquely described by the patient. More than 25% of patients use the term “painful.”
  2. Rest, eg, sitting or lying still, increases symptom presentation. RLS symptoms manifest when the individual is in a resting position. They are not positional discomfort from the temporary compression of a nerve or vessel (“leg is asleep”).
  3. Gyration or Going relieves or reduces the symptoms. However, if the person stops moving, the symptoms may return.
  4. Evening/night worsening represents circadian influences on RLS presentation.

RLS mimics should be excluded and include leg cramps, noted in up to 50% of seniors15 from muscle fatigue, vascular disease, or metabolic disturbance; primary akathisia; and secondary akathisia from treatment with neuroleptics and metoclopramide (Reglan).

Do not confuse RLS with PLMS. Approximately 80% of patients with RLS have PLMS, and 30% of patients with PLMS have RLS symptoms. To lessen confusion, consider the following:

RLS PLMS Comparisons

PSG = polysomnography, EDS = Excessive daytime sleepiness

Neurological examination is usually normal in idiopathic cases. Iron deficiency has been defined as a ferritin level <18 ng/ml or a transferrin saturation <16%. Ferritin levels <50 ng/ml in RLS patients should result in treatment with oral iron supplementation (ferrous sulfate 325 mg with vitamin C 100 mg up to tid on an empty stomach for better iron absorption).

Polysomnography is not needed for the diagnosis of RLS, unless other sleep disorders are suspected.


Side effects to therapy may limit dosing or complicate therapy. The FDA-approved dopaminergic agents for RLS cause nausea, vomiting, dizziness, excessive sedation, worsening of insomnia, and peripheral edema. Although less frequent in RLS patients than in patients with Parkinson’s disease, any use of dopaminergic medications should be closely observed for pathological sleepiness, compulsive gambling, and hypersexuality.


Responsiveness to therapies may be reduced in iron-deficient patients. Supplemental iron should be considered in these patients. Approximately 25% of patients receiving ropinirole16 or pramipexole17 responded inadequately in large clinical trials. Addition or change to another therapeutic agent is needed.

RLS Medication and Dosage


In cases of insufficient response, dose increase should be considered. Unless limited by side effects, treatment should be adjusted until reaching “trigger” dosage, highest dose, or intolerable side effects.


Literature review by Picchietti and Winkelman18 indicated that symptoms of depression are common in adults with RLS. The relationship appears complex with overlap between RLS and depressive symptoms. In another study, Saletu et al reported RLS patients have more symptoms of depression and anxiety (on the Zung Self-Rating Depression and Anxiety Scales) and lower quality of life than healthy controls.19

In refractory RLS patients, clinicians should review all medications that are taken by the patient. Most antidepressants and lithium have been reported to exacerbate RLS. Most SSRI reduce CNS dopamine transmission (exception high dose venlafaxine) and may worsen RLS and PLMS.20 Bupropion21 and trazodone may reduce PLMS and are considered to be the preferred agents for depression in RLS.

Another confound is the similarity of clinical symptoms or consequences of RLS and mood disorders.


Augmentation is defined as RLS symptoms that develop 4 hours earlier than pretreatment symptoms. Additionally, augmentation can be diagnosed if symptom onset presents 2 hours earlier plus at least two of the following:

  • spread to other body areas;
  • rapid increases in severity;
  • worsening with increased dose;
  • improvement with decreasing dose;
  • shorter periods of relief from a dose.22

Augmentation occurs in 70% of patients treated with levodopa,23 as compared to 20% to 35% of patients who are on dopamine agonists like pramipexole.24,25 The risk of augmentation is apparently reduced when levodopa is used less than three times per week.

The RLSF algorithm outlines four options of pharmacologic management of augmentation.9

  1. Change timing of dosing or to a different dopamine agonist;
  2. Change to gabapentin;
  3. Add a second agent such as benzodiazepine or a low-potency opioid to reduce dose of dopamine agonist;
  4. Change to high-potency opioid.

In summary, treatment strategies should be based on symptom frequency and severity. All patients should limit caffeine consumption past noon, obtain exercise in midday, and avoid use of decongestants and antihistamines. For intermittent RLS, the risk of augmentation from treatment is lower with prn dosing, so ropinirole, levodopa-carbidopa 25/100, or sedative-hypnotics can be offered as needed up to three times per week. For near daily RLS, the dopamine agonists, particularly pramipexole or ropinirole, would be the drugs of choice. Alternative therapies include gabapentin, pregabalin, codeine, propoxyphene, and tramadol, particularly if the patient’s RLS includes other painful conditions. The most severe patients benefit from high-potency, long-acting opiates such as methadone, levorphanol, and fentanyl patch. Treatment of RLS should be individualized with consideration of age, concomitant medications, other diseases, and history of augmentation or rebound. Future medication options will likely include the Neupro patch (rotigotine) and gabapentin enacarbil.

Philip M. Becker, MD, is clinical professor, and Muhammad Sattar, MD, is a sleep medicine fellow at the Sleep Medicine Fellowship Program, Department of Psychiatry, University of Texas Southwestern Medical Center at Dallas. The authors can be reached at [email protected]

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Medications for Restless Legs Syndrome

Daily medication is usually recommended only for people who have symptoms of restless legs syndrome at least three nights a week, or as determined by your doctor. Keep in mind that drugs used to treat primary RLS do not cure the condition, but only relieve symptoms. People whose RLS symptoms occur sporadically may be prescribed medication to take only when they have symptoms.

The following medications are the most widely prescribed to treat RLS. They may be given alone or, in certain cases, in combination. Your doctor will prescribe the best treatment plan for you.

  • Dopamine agonists: These are most often the first medicines used to treat RLS. These drugs, including pramipexole (Mirapex), rotigotine (Neupro), and ropinirole (Requip), act like the neurotransmitter dopamine in the brain. Side effects include daytime sleepiness, nausea, and lightheadedness.
  • Dopaminergic agents: These drugs, including Sinemet — a combination of levodopa and carbidopa — increase the level of dopamine in the brain and may improve leg sensations in RLS. However, they may cause a worsening of symptoms for some people after daily use. Side effects can also include nausea, vomiting, hallucinations, and involuntary movements (dyskinesias).
  • Benzodiazepines: Benzodiazepines, such as alprazolam (Xanax), clonazepam (Klonopin), and temazepam (Restoril), are sedatives. They do not so much relieve symptoms as help you sleep through the symptoms.
  • Opiates: These drugs are most often used to treat pain, but they can also relieve RLS symptoms. Because opiates are very addictive, they are usually used only when other drugs don’t work. Hydrocodone (Vicodin, Norco) is one example.
  • Anticonvulsants: These agents, such as gabapentin (Neurontin) and gabapentin enacarbil (Horizant), may help relieve the symptoms of RLS as well as any chronic pain or nerve pain.
  • Alpha2 agonists: These agents stimulate alpha2 receptors in the brain stem. This activates nerve cells (neurons) that “turn down” the part of the nervous system that controls muscle involuntary movements and sensations. The drug clonidine (Catapres) is an example.


Year : 2017 | Volume : 20 | Issue : 2 | Page : 166-167

Bupropion and iron for restless leg syndrome: Do they have efficacy similar to ropinirole?
Samir Kumar Praharaj
Department of Psychiatry, Kasturba Medical College, Manipal, Karnataka, India

Date of Web Publication 8-May-2017

Correspondence Address:
Samir Kumar Praharaj
Department of Psychiatry, Kasturba Medical College, Manipal – 576 104, Karnataka

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0972-2327.205775

How to cite this article:
Praharaj SK. Bupropion and iron for restless leg syndrome: Do they have efficacy similar to ropinirole?. Ann Indian Acad Neurol 2017;20:166-7

I read with interest the study on efficacy and tolerability of ropinirole, bupropion, and iron for the treatment of restless leg syndrome (RLS) reported by Vishwakarma et al. in October-December issue of 2016. The authors have rightly pointed out that the dopamine agonist, ropinirole is considered as the standard treatment of idiopathic RLS (beside pramipexole and rotigotine), at a dose ranging from 1.5 to 4.6 mg in the systematic review and meta-analysis by Aurora et al. Similar conclusions were reached in the meta-analysis by Scholz et al. There is only one randomized, placebo-controlled trial that found bupropion to be efficacious than placebo in RLS at 3 weeks but not at 6 weeks. Although iron therapy has been evaluated in six randomized-controlled trials, the meta-analysis by Trotti et al. found that the evidence is not sufficient to conclude that it is beneficial in RLS. In the current study, the authors have compared fixed-dose bupropion and combination of iron with folic acid, with ropinirole, which is the standard treatment available and acts as an active control. However, the authors have not specified whether this is a superiority or a noninferiority trial; the latter can be conducted with smaller sample sizes.

The authors have recruited 103 patients but presented the data for 90 patients. It is not clear whether the 13 dropouts received treatment and did not complete 6-week follow-up and at which stage they were lost. A CONSORT diagram depicting the flow of participants in the study is desirable, which improves the understanding of the results. Furthermore, in addition to completer analysis, an intention-to-treat analysis including all randomized patients would reduce the bias in reporting results. Furthermore, from the description, it is not clear about the process of randomization and the allocation concealment.
For the primary outcome, i.e., International Restless Legs Scale (IRLS) score, there were significant effect of time, which suggests improvement in all the three groups, and significant group × time interaction, suggesting differences in efficacy between the treatment groups. Post hoc comparison suggested ropinirole be more effective than bupropion and iron and folate combination as shown in of Vishwakarma et al. However, in the absence of control group, it was assumed that both bupropion and iron and folate combination were effective treatment in RLS. In reality, both treatment groups were neither superior nor equivalent to ropinirole, which is considered as standard treatment. In such situations, it is better to report the effect sizes of the differences with 95% confidence intervals and discuss the practical significance of the finding, i.e., reduction in IRLS scores. Furthermore, it was interesting to observe that ropinirole was effective at a dose of 0.5 mg/day, which is much lower than the recommended dose of 1.5–4.6 mg/day.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.

1. Vishwakarma K, Kalra J, Gupta R, Sharma M, Sharma T. A double-blind, randomized, controlled trial to compare the efficacy and tolerability of fixed doses of ropinirole, bupropion, and iron in treatment of restless legs syndrome (Willis-Ekbom disease). Ann Indian Acad Neurol 2016;19:472-7.
2. Aurora RN, Kristo DA, Bista SR, Rowley JA, Zak RS, Casey KR, et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults – An update for 2012: Practice parameters with an evidence-based systematic review and meta-analyses: An American Academy of Sleep Medicine Clinical Practice Guideline. Sleep 2012;35:1039-62.
3. Scholz H, Trenkwalder C, Kohnen R, Riemann D, Kriston L, Hornyak M. Dopamine agonists for restless legs syndrome. Cochrane Database Syst Rev 2011;3:CD006009.
4. Bayard M, Bailey B, Acharya D, Ambreen F, Duggal S, Kaur T, et al. Bupropion and restless legs syndrome: A randomized controlled trial. J Am Board Fam Med 2011;24:422-8.
5. Trotti LM, Bhadriraju S, Becker LA. Iron for restless legs syndrome. Cochrane Database Syst Rev 2012;5:CD007834.
6. Vieta E, Cruz N. Head to head comparisons as an alternative to placebo-controlled trials. Eur Neuropsychopharmacol 2012;22:800-3.
7. Andrade C. Examination of participant flow in the CONSORT diagram can improve the understanding of the generalizability of study results. J Clin Psychiatry 2015;76:e1469-71.
8. Ranganathan P, Pramesh CS, Aggarwal R. Common pitfalls in statistical analysis: Intention-to-treat versus per-protocol analysis. Perspect Clin Res 2016;7:144-6.
9. Clark L, Schmidt U, Tharmanathan P, Adamson J, Hewitt C, Torgerson D. Poor reporting quality of key randomization and allocation concealment details is still prevalent among published RCTs in 2011: A review. J Eval Clin Pract 2013;19:703-7.

Restless Legs Syndrome: Clinical Implications for Psychiatrists: Page 4 of 5

Long-term use of dopaminergic treatments carries the risk of augmentation, an iatrogenic worsening of RLS symptoms. Augmentation may be challenging to separate from normal disease progression and loss of treatment efficacy over time caused by medication tolerance. Worsening of RLS symptoms may occur independently of treatment because of changes in lifestyle (eg, decreased daytime activity; sleep deprivation; alcohol, antihistamine, dopamine antagonist, or serotonergic reuptake blocker intake) and health status (eg, iron deficiency, decreased kidney function, pregnancy), which should be monitored in patients with suspected augmentation. Key considerations for diagnosing augmentation include the appearance of earlier daytime or evening onset of RLS symptoms compared with baseline, decreased latency to symptom onset at rest, increased symptom intensity, and/or spreading of symptoms to previously unaffected parts of the body (eg, arms).

Augmentation can occur in up to 82% of patients with RLS who use the short-acting dopamine precursor carbidopa/levodopa. With pramipexole and ropinirole, augmentation occurs in roughly 30% to 60% of patients, although these rates can continue to rise over many years. With rotigotine, a longer-acting dopamine agonist, augmentation occurs in 10% to 20% of patients. Dopaminergic medications can also produce troubling de novo psychiatric symptoms in some patients, including impulse control disorders (eg, pathological gambling, shopping, hypersexity).

Alpha-2-delta ligands

The α-2-δ calcium channel ligands gabapentin enacarbil and pregabalin provide RLS symptom relief (Table 2). Given the minimal risk of augmentation with these agents and the chronicity of RLS treatment, recent consensus guidelines have suggested initiating treatment of de novo mild to moderate RLS with an α-2-δ ligand instead of a dopamine agonist.9 Anxiolytic properties of α-2-δ ligands may also make medications like pregabalin, which has efficacy for generalized anxiety disorder, well suited for patients with comorbid anxiety disorders. Moreover, α-2-δ ligands do not appear to increase—and in fact may decrease—impulse control disorders such as pathological gambling. However, the use of anticonvulsants is associated with an increased risk of suicidality, and suicidal ideation has been reported in RLS patients treated with pregabalin.10,11 Patients should be informed of this risk and monitored for emerging suicidal thoughts or behaviors.


μ-Receptor opioid agonists, such as prolonged-release oxycodone/naloxone and methadone, while not currently FDA approved for RLS (see Table 2), can be tried when first-line RLS treatments fail, RLS symptoms are severe, or as an alternative if patients experience severe augmentation. However, opioid therapy for RLS is generally contraindicated in patients with a history of substance use disorders, and prescribing physicians should monitor patients for possible signs of misuse or diversion. Of note is the emergence, or worsening, of RLS with discontinuation of opioid medications used recreationally or for pain relief.

Oral and intravenous iron

Iron deficiency has a direct physiological link to RLS, and conditions that produce iron deficiency, such as renal disease and pregnancy, increase the risk of worsening symptoms of RLS. For these reasons, it is recommended that all patients with RLS have full, fasting iron panels (ferritin, iron, and total iron-binding capacity) conducted at initial presentation and regularly thereafter. Treatment with oral or intravenous iron (see Table 2) should be considered for patients with serum ferritin levels lower than 50 to 75 ng/mL or transferrin saturation less than 20%.

Medication considerations


While effective for treating symptoms of depression and anxiety, patients who take serotonergic antidepressants, such as SSRIs or SNRIs, are at increased risk for new-onset or worsening RLS. In one prospective study, 2% to 10% of patients treated with SSRIs (citalopram, escitalopram, sertraline, paroxetine, and fluoxetine) and SNRIs (duloxetine and venlafaxine) experienced treatment-emergent RLS.1 It has been proposed that the deleterious effects of SSRIs and SNRIs on RLS symptoms may result from serotonergically mediated dopamine inhibition.12

It is important to note that RLS has not been found to be a treatment-emergent adverse effect of non-serotonergic antidepressants, such as the selective norepinephrine-reuptake inhibitor reboxetine and the norepinephrine-dopamine-reuptake inhibitor bupropion, that may improve RLS symptoms in the short term.13 Therefore, careful consideration of classes of antidepressants—opting for non-serotonergic agents when indicated—is essential to reduce possible iatrogenic adverse effects.

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