Rasagiline and selegiline are two drugs used clinically to treat early-stage Parkinson ’s disease PD. They are both monoamine oxidase inhibitors that have shown to be effective at slowing the progression of PD. An exhaustive literature search did not reveal any trials that directly compared the efficacy of rasagiline and selegiline. As such, in this review, the efficacy of both agents was evaluated individually and results were then synthesized to determine if either agent is superior in the initial management of early PD in adults.
Five clinical trials (four RCTs, one non-blinded open label trial) evaluated the neuroprotecive potential of rasagiline by assessing: (1) the drug’s ability to delay the need for additional anti-Parkinsonism therapy, (2) improvements in quality of life (QOL) and (3) declines in Unified Parkinson's Disease Rating Scale (UPDRS) scores (Biglan et al, 2006; Goren et al, 2010; TEMPO Study, 2002; Rascol et al., 2011). The use of rasagiline has been demonstrated to decrease the need for additional anti-PD therapy as compared to placebo, or individuals receiving other forms of treatment, with the added benefit of improving QOL in these populations (Biglan et al, 2006; TEMPO Study, 2002). Four trials strongly advocated for early initiation of rasagiline in early-stage PD to preserve UPDRS score. These studies indicated a smaller 1mg was more beneficial than a larger 2mg dose.
Although all studies consistently support the efficacy of rasagiline across all outcome measures, each study possessed unique limitations that impact the generalizability of findings. Of the five studies, three studies were conducted using the same sample population over time (the TEMPO trial published in 2002, the TEMPO extension trial in 2006 and the open label extension trial in 2008), limiting the ability (power) to generalize findings. Over the course of these three trials, attrition rates increased and by the conclusion of the open label extension trial there were not enough people in the study to generate sufficient statistical power to demonstrate the long-term effectiveness of rasagiline. In addition, these studies were not ethnically diverse with over 90% of trial participants identifying as white and, thus, the study’s ability to assess the effectives of rasagiline in other ethnic populations was hindered.
The clinical use of selegiline was associated with slower disease progression in early PD in one systematic review and three randomized clinical trials (Caslaske et al., 2009, Palhagen et al., 2006; Palhagen et al., 1998, & Zhao et al., 2010). These studies evaluated both early initiation of selegiline as a monotherapy and long-term use in combination with levodopa. In all the four studies, it was observed that the progression of PD symptoms was significantly slower in the selegiline treatment group – with differences that remained statistically significant after the washout period. Also, these studies noted that, overall, selegiline effects are best realized in early-stage PD patients after about 36-months of use. A significant association between selegiline use and a slower PD progression was only observed after 36 months of drug administration (Zhao et al., 2010, Palhagen et al., 2006). As with the rasagiline studies, these studies make it difficult to generalize the effectiveness of selegiline to the population in the United States due to the lack of ethnic diversity of study participants. While Zhao et.al. (2010) sampled from an Asian population (approximate mean age 30-40), the sample characteristics of other studies are not well reported.
Although all studies reviewed supported the efficacy of rasagiline and selegiline as an initial PD treatment in the early stages of PD, there are differences in the safety and tolerability of both drugs. Rasagiline, whether prescribed alone or in combination with other dopaminergic agents, showed no serious adverse effects (Mark et al., 2010; Rascol et al., 2011; Goren et al., 2010, TEMPO Study, 2010; Biglan et al, 2006). Adverse experiences, if present, were generally quite mild especially when rasagiline was prescribed as a monotherapy. Indeed, only a few adverse effects were observed with respect to vital sign changes such as blood pressure, which was only observed with a 2mg dosage administration. The differences in safety and tolerability between the placebo and rasagiline were relatively small with no need for dietary tyramine restriction (Mark et al., 2010, Goren et al., 2010, Biglan et al., 2006). However, the same is not true of selegiline. Two multi-center studies conducted in Sweden reported significantly higher rates of adverse reactions to selegiline compared to placebo together with a higher incidence of gastrointestinal disturbances (Palhagen et al., 2006; Palhagen et al., 1998).
The primary reason for differences in tolerability between rasagiline and selegiline is the way that the two drugs are metabolized once administered. While both drugs are monoamine oxidase inhibitors and counteract the progression of PD in a similar manner, the two drugs are metabilized quite differently. Selegiline is metabolized to desmethylselegiline and l-methamphetamine which further metabolizes to L-amphetamine. Long term selegiline use has been linked to increased plasma levels of amphetamine-like compunds which can greatly increase the PD patient’s wakefullness and decrease sleep quality which in turn, reduces quality of life. More importantly, accumulation of amphetamine-like compounds may influence the onset and intensity of non-motor symptoms in PD (Muller, et al., 2012). On the other hand, rasagiline is metabolized to aminoindan (Chen et al. 2007) which has no amphetamine-like properties and may even contribute to the rasagiline’s efficacy (Bar-Am et al. 2010). Studies in animal models of PD demonstronated that aminoindan itself can to increase dopamine transmission in the striatum, improving motor function independent of monoamine oxidase inhibition. The difference in how these drugs are metabolizes indicate that rasagaline may be a better long term treatment option for early-stage PD. There is recent evidence that switching from selegiline administration to rasagaline is safe and well tolerated by patients (Muller, et al., 2012). Thus, clinicians treating PD patients with selegiline may want to consider switching to rasagaline in order to minimize non motor symptoms such as insomnia or poor sleep. – I have included extra citations at the end of this text. I did not put it into any format because I am not sure what format you are using but I included all the information that you need to cite the work.
In conclusion, both rasagiline and selegiline are effective pharmacological options for PD during its early stages. The two drugs have disease-modifying affects that slow PD progression, improve symptom management and lead to better quality of life when compared to controls. Because the sample population for most of the studies reviewed focused on Caucasian, middle aged (approximately 60 years old) individuals, these results can be most accurately applied to this population. Pharmacological management of PD is often a long-term therapy, hence, despite demonstrating similar efficacy, a clinician should always consider a drug that is both safe and well-tolerated to promote compliance when possible. Rasagiline appears to be superior to selegiline when considering the safety and tolerability based on this review. While none of the studies reviewed in this paper evaluated the cost effectiveness of both rasagiline and selegiline in clinical practice, it is noteworthy that rasagiline is significantly more expensive than selegiline (Rasagiline 1mg, 30 ea; $407 versus selegiline 5mg, 30 ea; $60, (Epocrates, 2011)). Hence, given the similar efficacy of both drugs, selegiline may be an appropriate alternative to rasagiline when cost of treatment is an issue. A clinician must always consider the risk-benefit ratio with the initiation of selegiline, and be vigilant of the potential for increased risk of side effects/adverse reactions.
(Muller, et al., 2012)-
Neurology and Preclinical Neurological Studies - Original Article
Switch from selegiline to rasagiline is beneficial in patients with Parkinson’s disease
Thomas Müller1 , Josef A. Hoffmann2, Walter Dimpfel3 and Christian Oehlwein4
TEVA Pharma GmbH, Moerfelden-Walldorf, Germany
Private Practice, Gera, Germany
Received: 19 September 2012Accepted: 16 November 2012Published online: 30 November 2012
(Chen et al. 2007): Clin Ther. 2007 Sep;29(9):1825-49.
Comprehensive review of rasagiline, a second-generation monoamine oxidase inhibitor, for the treatment of Parkinson's disease.
Chen JJ, Swope DM, Dashtipour K.
(Bar-Am et al. 2010)- J Neurochem. 2010 Mar;112(5):1131-7. doi: 10.1111/j.1471-4159.2009.06542.x. Epub 2009 Dec 10.
The neuroprotective mechanism of 1-(R)-aminoindan, the major metabolite of the anti-parkinsonian drug rasagiline.
Bar-Am O, Weinreb O, Amit T, Youdim MB.
Eve Topf and USA National Parkinson Foundation Centers of Excellence for Neurodegenerative Diseases Research and Department of Pharmacology, Rappaport Family Research Institute, Technion-Faculty of Medicine, Haifa, Israel.