Drug tolerance is defined as a diminution in the response to a drug after prolonged exposure requiring an increased dose to produce the previous response. Tolerance to DAs is thought to be an early stage of augmentation (discussed below) and has been documented in the medical literature [52] and is seen often clinically. It usually develops after several months or years of drug usage.

Once all the above triggers that might worsen RLS have been ruled out, tolerance may be difficult to differentiate from progression of disease and augmentation (which is discussed below). Since tolerance is reversible, stopping the drug for a short time (typically a few weeks or more) will reestablish the effectiveness of the drug which does not occur with disease progression.

There are several actions available when tolerance to DAs occurs. If the DA dose is relatively low, its dose may be increased to the upper limits defined above. If further tolerance develops, care should be taken with further increases of the drug to avoid the emergence of augmentation. Another DA may be substituted but it is quite likely that cross-tolerance may develop. If that occurs, then treatment with α2δ drug and/or opioids as discussed above may be instituted. For patients who prefer the DAs to those other treatments, rotation drug therapy may be helpful. The α2δ drug and/or opioid can be taken for a few weeks then the DA resumed for weeks or months until significant tolerance develops again.

After Akpinar described the use of levodopa for treating RLS in 1982 [1], this drug was widely prescribed and dramatically helped many RLS sufferers. However, after an initial period of relief, most patients developed very increased RLS symptoms that required higher and higher doses to obtain a therapeutic response, symptoms started occurring earlier in the day and expanded to the arms and other body parts. This phenomenon was quite puzzling until the term augmentation was first described in 1996 [2]. Augmentation was further defined with the development of criteria for its diagnosis by an NIH workshop in 2003 [55] (Fig. 13.1) [56] and subsequently by a consensus conference at the Max Planck Institute (called the MPI criteria) in 2007 [57] (Table 13.1). When it became apparent that the majority of patients taking levodopa for RLS were developing augmentation [2], physicians switched the treatment to a dopamine agonist. Pergolide was one of the first DAs used to treat RLS. It worked quite well to treat the RLS symptoms of those augmented patients but its use was often limited by its side effects. Therefore, most physicians treating RLS with or without augmentation switched to ropinirole and pramipexole when they became available in 1997 for Parkinson’s disease and especially after they were FDA approved for RLS in 2005 and 2006 respectively. The majority of these patients seemed to do very well with short-acting DA treatment and there appeared to be only minor concerns about augmentation. However, more recent studies using the more current NIH or MPI criteria for diagnosing RLS have found much higher rates of augmentation; up to 8% per year in a community sample study [55] and 5–7% per year in 10-year long retrospective study [33]. Augmentation symptoms from DAs tends to be severe often resulting in discontinuation of the DA [57]. Since the augmentation problem may develop at any time during 10 or more years of treatment, it is not often identified as such by most primary care physicians or even many specialists who are the local consultants for difficult RLS cases. These patients are thought to have gradual progression of their disease and are most often treated with escalating doses of DAs, frequently even into the high Parkinson’s disease ranges. This has resulted in patients with augmentation making up the majority of RLS referrals to doctors, who have greater expertise with RLS such as movement disorder specialists [58].

As discussed above, one of the most important aspects of treating the augmentation caused by short-acting DAs is the recognition of the problem. Although the diagnostic criteria for augmentation are well defined [54, 56], there is considerable overlap of its features with other conditions that may confuse the diagnosis. The most common misdiagnosis of augmentation is the natural progression of the disease. This misunderstanding may have been further propagated by earlier studies, which found that augmentation occurred no later than 4 months [59] or 2.5 years [60] after the initiation of short-acting DA therapy. It is now clear that augmentation can occur for up to 10 years [57] or longer. When the augmentation symptoms onset within a few months of treatment, the diagnosis is much more obvious (patients will typically complain about the relative sudden worsening after the short period of symptom relief). However, as discussed above, when augmentation arises after several years of treatment, most physicians will assume it is due to progression of the disease. The only definite way to differentiate between these two issues is to stop the short-acting DA. Patients with augmentation will show improvement of their symptoms within a few weeks or months (after an initial period of marked worsening) while those with natural progression of the disease will not. However, since the cessation of treatment in augmentation cases causes a temporary dramatic increase of RLS symptoms resulting in significant suffering, this is usually not a very practical approach. Therefore, physicians should be very suspicious of augmentation whenever the dose of a short-acting DA must be increased. With augmentation, there will be further dose increases after shorter and shorter intervals while natural progression requires dose increases over prolonged intervals (personal observation).

Before augmentation is diagnosed, triggers that may impact RLS should be ruled out [56]. As discussed above, a thorough review of the patient’s medications, lifestyle, and iron status should be performed. Removing the trigger may improve the RLS and obviate the need for additional RLS medication or concerns of augmentation. Rebound should not be confused with augmentation. Since rebound is an end of the dose effect of a short-acting DA, symptoms will occur as the drug’s action is waning which typically occurs about 6–8 h after the medication is taken. Therefore, the clinical presentation of rebound is a worsening of RLS symptoms several hours after taking the DA rather than a few hours prior to taking the DA as with augmentation. Tolerance to the DAs also shares features of augmentation and may even be an early stage or subtype of augmentation [52]. However, despite tolerance producing a decreased effectiveness of a given DA dose with time that requires higher doses of that DA, it does not cause an earlier onset of symptoms or expansion of symptoms to other body parts.