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Pramipexole …
- Updated 09.05.2021
- Released 12.22.1998
- Expires For CME 09.05.2024
Pramipexole
Introduction
Historical note and terminology
Almost 1.5 centuries after the first description of Parkinson disease in 1817, dopamine was shown to be concentrated in the neostriatum of the brains of Parkinson disease patients (05). Dopaminergic deficits in patients with Parkinson disease were described a few years later (03). It was also demonstrated that replenishment of dopamine through intravenous levodopa briefly improved the symptoms of patients with Parkinson disease (06). The success of levodopa started the search for alternative ways to enhance dopaminergic transmission. One of the earlier dopamine agonists to be investigated was apomorphine. It had been used earlier, in 1951, for the treatment of Parkinson disease (34). Ergot derivatives then entered the dopamine agonist arena for the treatment of Parkinson disease. Bromocriptine is the best known example of this class of drugs.
Pramipexole, a non-ergot dopamine agonist, was synthesized in the United States and first manufactured in 1997 under the brand names of Mirapex and Mirapex ER (39). Initial clinical development of pramipexole was as a treatment for schizophrenia and depression, but this use appears to have been discontinued. The first biochemical and pharmacological studies on pramipexole were published in 1992 (27). Pramipexole was first approved in the United States by the Food and Drug Administration in 1997. It was launched for the treatment of Parkinson disease as monotherapy and as an adjunct to levodopa. It has received approval from the European Medicines Evaluation Agency for the same indication. It was also approved for treatment of restless legs.
Pharmacology
Pramipexole is an amino-benzothiazole–type dopamine agonist.
It binds to presynaptic and postsynaptic dopamine D2 and D3 receptors, but does not have affinity for the dopamine D1 receptor site.
Pharmacodynamics. Pramipexole stimulates presynaptic and postsynaptic dopamine D2 receptors in a dose-dependent manner and reduces extracellular concentrations of dopamine by inhibiting dopamine synthesis and release. Pramipexole is highly specific to D3 and D2 receptors, with affinity to D3 being about 8 times higher than that of D2. Although not proven, the motor benefits of pramipexole in Parkinson disease are likely due to dopamine D2 stimulation, whereas its effects on mood and apathy may be related to its D3 agonist properties. Pramipexole has a relatively high affinity for a2 adrenoreceptors but has little effect on other neurotransmitter systems. In addition to an antiparkinsonian effect, it is considered to have a neuroprotective effect demonstrated by prevention of levodopa-induced toxicity in vitro. The possible mechanisms are as follows:
• Site-directed antioxidant effect on dopamine neurons and receptors, which is an action that it does not share with bromocriptine and pergolide. Pramipexole reduces neuronal damage in gerbil ischemia models and reduces amphetamine-induced neuronal damage. | |
• Like other dopamine agonists, pramipexole reduces dopamine synthesis turnover in mice during repeated injections of amphetamine and, thus, reduces the free radical formation during this process. This is considered to contribute to the neuroprotective effect of pramipexole. | |
• Pramipexole attenuates intracellular processes such as the mitochondrial transition pore opening that is associated with programmed cell death. | |
• It stimulates a mesencephalic-derived neurotrophic activity. | |
• Pramipexole has biological regulatory effects on dopaminergic neuron-associated genes, which may explain both the slower decline of imaged dopamine transporter and the neuroprotective effect. | |
• Pramipexole has a neuroprotective effect and protects dopaminergic neurons from glutamate neurotoxicity by the reduction of intracellular dopamine content, independently of dopamine D(2)-like receptor activation. | |
• In vitro and in vivo studies of pramipexole in Parkinson disease models show that it decreases the phosphorylation of α-synuclein, which may contribute to its neuroprotective properties (09). | |
• Analysis of immune parameters in a 2-year prospective study on Parkinson disease patients comparing the effect of levodopa alone and a levodopa/pramipexole combo therapy suggest that levodopa alone may promote a proinflammatory response, but when combined with pramipexole, it promotes a clinically beneficial immunoregulatory environment (11). | |
• Neuroinflammation is important in the progression of Parkinson disease. In a rat model of Parkinson disease induced by 6-hydroxydopamine, pramipexole has been shown to improve the motor behavior by mediating the inflammatory response and regulating the nuclear receptor subfamily 4 group A member 2 and nuclear factor kappa B signaling pathways (13). |
A review of various studies shows that neuroprotection requires treatment prior to neurologic insult and high concentrations of pramipexole are required
Pharmacokinetics. Pramipexole exhibits linear pharmacokinetics over the dose range of 0.125 to 1.5 mg administered every 8 hours in healthy volunteers. Plasma concentrations of pramipexole are proportional to dose. The plasma elimination half-life is approximately 7 to 9 hours, sufficiently long to make it a practical drug for oral administration in Parkinson disease patients with short-duration levodopa responses. Pramipexole is excreted by the renal organic transport system and renal clearance accounts for about 80% of the total clearance of an oral dose.
Therapeutic drug monitoring. A simple and validated ultra-high-pressure liquid chromatography–tandem mass spectrometry method was developed for the simultaneous determination of the dopaminergic agents pramipexole and ropinirole in the plasma of patients with Parkinson disease (28). This method was successfully applied to measure plasma concentrations of pramipexole and ropinirole in a series of patients with Parkinson disease on chronic treatment.
Formulations. An extended-release formulation of pramipexole is available for use as a once-daily oral treatment for Parkinson disease, and the effects are equal to that of 3-times-daily immediate release pramipexole. Potential benefits of prolonged release of pramipexole include improved compliance and a potential for better symptomatic control, particularly in patients with early disease who can be managed with monotherapy. Introduction of extended-release pramipexole in Taiwan resulted in higher levodopa equivalent dose per day in prescriptions with pramipexole than those who were prescribed immediate release pramipexole because of better compliance to the medication (08).
Near-infrared light-responsive pramipexole and hollow gold nanospheres-loaded biodegradable poly (D, L-lactide-co-glycolide) microspheres have been fabricated using solid-in-oil-in-water and water-in-oil-in-water emulsion-solvent evaporation techniques to achieve remotely triggerable modulated drug release (22).
Dexpramipexole, the (R)-(+) enantiomer of pramipexole, is a pharmacologically distinct entity regarding dopamine receptor affinity and is in clinical trials as a neuroprotective for the treatment of neurodegenerative diseases. Because dexpramipexole is excreted exclusively by the kidneys, it should not be used in patients with severe renal impairment (15).
Methods of delivery. An experimental study has investigated iontophoretic delivery of pramipexole and determined that therapeutic amounts of the drug could be delivered transdermally (18). A prolonged-release pramipexole transdermal patch is in development. Studies in rats have shown that the patch produces a significantly longer half-life and improved bioavailability compared to oral tablets (32). It has the potential to serve as an alternative to conventional oral tablets and improve patient compliance.
Pharmacogenetics. DRD3 Ser9Gly gene polymorphisms are significantly associated with the therapeutic efficacy of pramipexole in Chinese patients with Parkinson disease (25).
Clinical trials
Efficacy of this drug is indicated by studies shown in Table 1. Although clinical trials started in 1997, only those conducted within the last decade are listed in Table 1.
Table 1. Clinical Trials of Pramipexole in Parkinson Disease
Study | Results |
Multicenter, double-blind, parallel study of patients with early Parkinson disease not receiving levodopa or dopamine agonists, randomly assigned to immediate release (IR) or extended release (ER) pramipexole or placebo. | Pramipexole ER is not inferior to pramipexole IR in patients with early Parkinson disease (30). |
Pramipexole On Underlying Disease (PROUD), a randomized multicenter study, was designed to identify whether early vs. delayed pramipexole initiation has neuroprotective effects as assessed clinically and by neuroimaging in patients with Parkinson disease (33). | There was little difference in 15-month pramipexole usage from that delayed for 6 to 9 months indicating that pramipexole does not have disease-modifying effects. |
A 26-week randomized, double-blind, placebo-controlled study assessed the efficacy of pramipexole for patients with mild to moderate restless legs syndrome (RLS) and pretreatment serum ferritin >30 ng/mL. The primary efficacy endpoint was change in International RLS Study Group Rating Scale. | Pramipexole was effective, safe, and well tolerated. Mild augmentation (aggravation of RLS) was difficult to distinguish from natural RLS fluctuations, at least in a non-iron-deficient population (16). |
A double-blind, randomized, crossover trial compared the effects of pramipexole vs. dual-release levodopa/benserazide for short-term treatment of de novo patients with RLS. | Results showed comparable efficacy (04). |
A 52-week randomized, double-blind trial assessed efficacy and augmentation in patients with RLS who were treated with pregabalin as compared with placebo and pramipexole. | Pregabalin provided significantly improved treatment outcomes as compared with placebo, and augmentation rates were significantly lower with pregabalin than with pramipexole (01). |
Most of the early clinical trials were limited to a period of 31 weeks, but they showed that pramipexole is effective as monotherapy in early Parkinson disease and may delay the need for levodopa. Pramipexole is also effective in patients with advanced Parkinson disease as an adjunctive therapy to levodopa, particularly in those who have experienced undesirable motor effects due to levodopa therapy. Pramipexole reduces the motor fluctuations and enables reduction of levodopa dose. In patients with advanced disease and "on-off" phenomena, pramipexole also reduced the mean number of "off" hours per day from 6 to 4; the number of "off" hours did not change with placebo.
Presently available evidence indicates the following advantages of pramipexole:
• A low side-effect profile compared to that of ergot-derived dopamine agonists. Pramipexole may not cause restrictive valvular heart disease and may, therefore, represent the first choice in patients with valvular lesions under treatment with ergot dopamine agonists. | |
• It has a beneficial effect on all the 3 cardinal motor signs of Parkinson disease: akinesia, rigidity, and tremor. It is especially valuable in the treatment of tremors. | |
• It is also effective against depression, a frequent problem in Parkinson disease patients. | |
• It enables a substantial reduction in levodopa daily dose in patients with advanced Parkinson disease. |
Extended-release (ER) and immediate-release (IR) formulations of pramipexole have been compared in clinical trials, and the results are as follows (12):
• In short-term double-blind studies, pramipexole ER was equal to pramipexole IR and significantly more effective than placebo as monotherapy in patients with early Parkinson disease in terms of improving activities of daily living and motor function (12). | |
• Pramipexole ER is like pramipexole IR and is significantly more effective than placebo as adjunctive therapy to levodopa in patients with advanced Parkinson disease (12). | |
• In long-term extensions of these trials, open-label treatment with pramipexole ER was associated with sustained symptomatic benefit. | |
• In a retrospective clinical trial (NCT00466167) on patients with advanced Parkinson disease on levodopa therapy, both the pramipexole formulations showed improvements in sleep disturbances, but SR formulation had numerical advantage in Parkinson Disease Sleep Scale (PDSS) mean change over IR formulation (40). |
A metaanalysis of randomized clinical trials shows that pramipexole is effective in improving the symptoms of patients with primary moderate-to-severe restless legs syndrome, although the quality of evidence is rather low (24). Further clinical trials should use objective measures for the evaluation of restless legs syndrome and closely observe any augmentation during treatment.
Indications
Pramipexole is approved for the treatment of early Parkinson disease as monotherapy and as an adjunct to levodopa in advanced stages of the disease. It is also approved for the treatment of restless legs syndrome.
Off-label uses
(1) Pramipexole is being explored as an alternative to clonazepam, the first-line treatment for rapid eye movement (REM) sleep behavior disorder, which has side effects that limit its use. However, the evidence from a systematic review of trials of pramipexole for REM sleep behavior disorder is inconclusive (36). | |
(2) A randomized, open-label, crossover study of pramipexole in patients with sleep bruxism did not show its efficacy (07). | |
(3) Cocaine craving. | |
(4) Pramipexole has been safely combined with haloperidol in the treatment of schizophrenia. However, further clinical studies are required to support this combination. | |
(5) High-dose pramipexole is being investigated as a neuroprotectant in amyotrophic lateral sclerosis. | |
(6) Low-dose pramipexole therapy is reported to be safe and clinically effective on long-term follow-up of patients with tetrahydrobiopterin deficiency (31). | |
(7) Sleep-related eating disorder. | |
(8) Chronic cluster headache. | |
(9) Pramipexole improves depressive symptoms in patients with Parkinson disease. A PET study has shown that pramipexole binds to D2/D3 receptors in the prefrontal cortex, amygdala, and medial and lateral thalamus, which are implicated in depression and might be target sites of antidepressive effect of pramipexole (17). A systematic review of randomized clinical trials and observational studies on pramipexole for patients with major depressive episodes found some evidence for an effectiveness of pramipexole (37). | |
(10) A randomized, placebo-controlled, double-blind study showed that pramipexole is effective against subjective tinnitus associated with presbycusis at a dose schedule used for the treatment of Parkinson disease (35). | |
(11) Based on a 24-week study, pramipexole is considered effective for relieving levodopa-induced dyskinesia as its effects on D3 dopamine receptors may balance the D1 dopamine receptor supersensitivity (38). | |
(12) Restless genital syndrome in Parkinson disease (02). | |
(13) Pramipexole has been shown to have a neuroprotective effect on striatal neurons in a mouse genetic model of Huntington disease by promoting the clearance of soluble mutant Huntingtin protein (mHTT) through a D3 receptor-mediated mechanism (26). | |
(14) An older male with posttraumatic stress disorder-related nightmares experienced total elimination of dreams upon introduction of pramipexole for restless legs syndrome and nightmares recurred after discontinuation of pramipexole (10). | |
(15) A case of dramatic response of osmotic demyelination-induced parkinsonism/dystonia to pramipexole has been reported, in which a lack of response to levodopa suggests deficits in the presynaptic nigral as well as non-nigral compensatory structures (14). |
Contraindications
Patients with advanced Parkinson disease who have blood pressure problems should use pramipexole with care. Because elderly patients are likely to be on drugs that affect the nervous system, they are more at risk for developing hallucinations. Pramipexole is excreted through the kidneys and patients with kidney disease may require dosage adjustment.
Goals and duration of treatment
In addition to ameliorating the core symptoms of akinesia and rigidity in Parkinson disease, pramipexole improves tremor and depressive symptoms in routine clinical practice.
Long-term (mean of 8 years) analysis of patients with reported studies of shorter duration shows that efficacy of pramipexole decreases with time, with increase in dose, and with addition of other agents (23). There is some concern that long-term treatment with pramipexole may aggravate restless legs syndrome. The patient’s response and the need for further treatment should be evaluated after 3 months.
Dosing
For Parkinson disease, pramipexole is administered orally 3 times daily and the recommended starting dose is 0.375 mg per day for 1 week. The dose is increased gradually, but not more often than once in 5 to 7 days, until a maximum therapeutic effect is reached. The maximum dose is 4.5 mg per day given in 3 divided doses. The daily maintenance dose is 1.5 mg. It is recommended that levodopa dose be reduced during the pramipexole dose escalation period. If treatment is to be discontinued, pramipexole should be tapered off over a 1-week period.
A 3-times daily immediate-release formulation and a once-daily extended-release formulation of pramipexole are bioequivalent, and most patients can be switched overnight from 1 to the other without the need for dosage adjustment.
For restless legs syndrome, immediate-release tablets of pramipexole should be taken once a day, 2 to 3 hours before going to bed. The recommended starting dose is 0.088 mg of active drug, but this can be increased every 4 to 7 days to reduce symptoms further, to a maximum of 0.54 mg. The prolonged-release tablets are not suitable for restless legs syndrome.
Special considerations
Geriatrics. Elderly patients are more susceptible to the adverse effects of pramipexole-it should only be used when there are motor fluctuations with levodopa-carbidopa therapy. Use of pramipexole enables levodopa-carbidopa dose reduction, thus helping to overcome the “off” periods. Elderly patients with renal disease require dose adjustment. The half-life of the drug is 12 hours in elderly subjects. Compared with healthy elderly persons, patients with Parkinson disease have reduced drug clearance (about 30% lower), presumably because of decreased renal function.
Pregnancy. No information is available about the use of pramipexole in pregnancy. This is unlikely in patients with Parkinson disease but may coexist with off-label indications. Animal studies have shown that pramipexole could be teratogenic at high doses, but the evidence is insufficient. Nevertheless, use of pramipexole should be avoided during pregnancy.
As a dopaminergic agonist, pramipexole is contraindicated in lactating mothers because it suppresses lactation. Concentration in milk is much higher than in plasma, increasing the risk of transmission to the baby.
Anesthesia. There are no special interactions of anesthetics with drugs used for Parkinson disease. Pramipexole should be discontinued for at least 6 hours before anesthesia and can be resumed in the postanesthetic period after the patient has recovered from nausea. These are general precautions with dopamine agonists, as they tend to induce nausea and vomiting as side effects.
Interactions
Inhibitors of cytochrome P450 enzymes do not affect pramipexole elimination because it is not significantly metabolized by these enzymes in vivo or in vitro. Pramipexole does not inhibit CYP enzymes CYP1A2, CYP2C9, CYP2C19, CYP2E1, and CYP3A4.
Because pramipexole is a dopamine agonist, dopamine antagonists such as neuroleptics (eg, phenothiazines) or metoclopramide may diminish its efficacy.
Cimetidine can increase the area under the curve of pramipexole by 50%. Coadministration with other drugs that are eliminated through the cationic transport system (eg, ranitidine, diltiazem, verapamil, and digoxin) can decrease the total clearance of an oral dose by 20%, and pramipexole can decrease their clearance. For a detailed list see Physicians’ Desk Reference.
Adverse effects
All patients enrolled in the advanced-disease trials for pramipexole were treated concurrently with levodopa, and some received amantadine, selegiline, and anticholinergics in various combinations. More than half (53%) of the patients treated had postural hypotension during pramipexole therapy, 47% had dyskinesia, 28% had extrapyramidal syndrome, 27% insomnia, 26% dizziness, and 17% hallucinations. Except for the hallucinations, all these events occurred in a substantial percentage of placebo recipients as well. Age appeared to increase the risk of hallucinations. Adverse events tended to be less frequent in patients with early disease. The most frequently reported events were nausea (28% of patients), dizziness (25%), drowsiness (22%), and insomnia (17%). Antecollis developed during treatment with pramipexole in a patient, and withdrawal of the drugs led to reversal of symptoms (19). For further details see Physicians’ Desk Reference.
Augmentation is the main complication of long-term treatment with pramipexole and is characterized by an overall increase in severity of restless legs syndrome symptoms. Other causes of augmentation such as iron deficiency and use of serotonergic drugs should be considered, and if appropriate measures do not improve the situation, pramipexole may be substituted by another dopaminergic drug. However, all dopaminergic drugs can cause augmentation of restless legs syndrome, and in this case, a nondopaminergic drug such as pregabalin may be used. Drug-induced dystonia and complex regional pain syndrome have been reported following introduction of pramipexole and increasing its dose to alleviate the symptoms of Parkinson disease in patients on chronic L-dopa treatment (29). This is due to overexpression of dopamine-3-like (D3) receptor, as the effect of a high dose of pramipexole and recovery follows discontinuation of the drug. Therefore, caution is required with observation of side effects when starting therapy with pramipexole and increasing the dose.
Patients on pramipexole therapy may have attacks of sleep without warning even while driving. The patients should be warned of this possibility and advised not to drive while on pramipexole therapy. Sleepiness with use of pramipexole may be treated with modafinil. Irresistible daytime sleepiness is a frequent problem in patients with Parkinson disease treated with dopamine agonists and is reported in almost half of patients treated with pramipexole in some series. It is managed by adjusting the amount of drug and dosage schedule or discontinuing the drug if the patient's lifestyle cannot adopt it.
Pramipexole, like other dopamine agonists, has been associated with compulsive behavior, and cases of pramipexole-induced pathological gambling that resolved following discontinuation of the drug have been reported (20). Punding, an impulse control disorder that is characterized by repetitive behavior, has been reported due to treatment with pramipexole, and it improved after discontinuation of the medication (21).
Peripheral edema is associated with pramipexole therapy and appears to be dose dependent but may also be idiosyncratic. No predisposing features have been identified, and edema responds poorly to diuretic therapy.
Media
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Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Author
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K K Jain MD†
Dr. Jain was a consultant in neurology and had no relevant financial relationships to disclose.
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