Continuing Education Activity
Pramipexole is a medication used in the management and treatment of Parkinsonism and restless leg syndrome. It is in the anti-parkinsonian class of drugs. This activity describes the indications, action, and contraindications for pramipexole as a valuable agent in managing Parkinsonism and restless leg syndrome. This activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, relevant interactions) pertinent to the interprofessional team members of patients with Parkinsonism and restless leg syndrome.
- Identify the mechanism of action of pramipexole.
- Describe the potential adverse effects of pramipexole.
- Review the appropriate monitoring for patients receiving therapy with pramipexole.
- Outline some interprofessional team strategies for improving care coordination and communication to advance pramipexole and improve outcomes.
Dopaminergic agonists have been used for the treatment of Parkinsonism. They can categorize into ergot derived and non-ergot derived. The focus of this review is pramipexole, a non-ergot-derived dopaminergic agonist used broadly in the treatment of Parkinson’s disease (PD) and restless leg syndrome (RLS). The FDA approved pramipexole for the treatment of PD in 1997 as monotherapy or add-on drug to other first-line agents. Younger patients are more prone to the motor fluctuations seen in patients treated with levodopa-carbidopa, the most effective agent in treating PD. Hence, treatment with pramipexole should initiate as monotherapy in young patients with PD. On the other hand, 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. Using pramipexole can permit levodopa-carbidopa dose reduction, thus help overcome the “off” periods seen.
Two years later, the first randomized control trial was conducted on pramipexole to explore its efficacy in treating RLS. After several studies in this regard, the FDA approved pramipexole for the treatment of RLS in 2006, shortly after it approved ropinirole in 2005, another drug of the same group. Apart from the FDA-approved indications, studies have shown that pramipexole has been effective in the treatment of bipolar depression and treatment-resistant depression. Besides, a study yielded promising results regarding the efficacy of pramipexole in essential tremors. However, all the studies, though promising, suggested that further trials are necessary to prove the efficacy of pramipexole in the above conditions.
Pramipexole’s role has also been discovered in patients chronically treated with morphine. A very recent study suggested that it can effectively reduce tolerance to morphine and shorten the duration of its withdrawal symptoms. This result led to the conclusion that pramipexole could restore the analgesic effects of morphine in a patient once they weaned off it.
Mechanism of Action
Pramipexole is a selective dopaminergic agonist with a minor agonistic activity at other receptors. According to the dissociation constant (Km in nmol/L), the lower the value, the higher affinity of a drug to a receptor. Pramipexole recorded the lowest Km value with the D3 dopaminergic receptor and a slightly higher value for the D2 receptor. Therefore, pramipexole is highly specific to D3 and D2 receptors, with affinity to D3 being about eight times higher than D2. Affinity to D1 receptors is insignificant, being around 200000 times lower than that to D3. Apart from dopaminergic activity, pramipexole exhibits a small affinity to some serotonergic and adrenergic receptors.
Pramipexole’s efficacy in PD is attributed to its D3 selectivity. It binds to presynaptic dopamine autoreceptors exerting negative feedback on endogenous dopamine synthesis. This process leads to a decrease in oxidative stress, which mitigates the damage to the nigrostriatal pathways.
Although the exact pathophysiology of RLS has remained undiscovered, studies strongly suggest a dopaminergic involvement. Unlike in PD, where the nigrostriatal pathways are affected, a set of neurons in the midbrain appears to be the target in RLS. These neurons project into the dorsal horn of the spinal cord, modulating nociception. Pramipexole, given to RLS patients, restores optimal neurotransmission in these pathways.
Pramipexole exerts an anti-depressant effect in PD and cases of major depressive disorder. Studies show that such patients have downregulation of dopaminergic receptors, increasing their suicidal propensity. Pramipexole plays a role in the upregulation of such receptors and their potentiation in the mesolimbic system, an area of the brain responsible for mood regulation.
Pramipexole is administered orally and is available in the form of tablets. As soon as it got approved for the treatment of PD, the immediate release (IR) tablet form became available in doses of 0.125, 0.25, 0.5, 1, and 1.5 mg. In 2010, pramipexole became available in the form of extended-release (ER) in larger doses of 0.375, 0.75, 1.5, 2.25, 3, 3.75, and 4.5 mg, permitting a simplified single daily dosing. Both IR and ER have an identical mechanism of action and efficacy. For instance, 4.5 mg ER administered once daily is clinically equivalent to 1.5 mg IR administered three times daily.
In PD, pramipexole is initiated at a dose of 0.125 mg thrice daily and gradually increased every week to a maximum dose of 1.5 mg thrice daily, depending on the clinical response. This slow titration is to minimize the adverse effects of the drug. In patients with renal insufficiency, pramipexole has to be titrated according to the degree of the insufficiency, as it is almost entirely excreted unchanged through the kidneys. In patients with creatinine clearance (CrCL) of 35 to 59 ml/min, the initial dose administered should be 0.125 mg twice daily and increased gradually over a longer period of two weeks compared to a week in patients with normal renal function. For severe renal impairment (CrCL of 15-34 ml/min), the initial dose should be 0.125 once daily.
Pramipexole is given as a single dose 2 to 3 hours before bedtime for the treatment of RLS. The dose can be increased every 4 to 7 days to attain maximum symptom relief. Usually, most patients are free of symptoms in the dose range of 0.125 and 0.75 mg. Hence, IR tablets are most suitable in RLS, given the small dose required for symptoms to abate.
No dose adjustments should be made in cases of hepatic insufficiency since pramipexole undergoes minimal hepatic metabolism.
The adverse effects of pramipexole are attributed to both peripheral and central dopaminergic stimulation. These include, in decreasing order of frequency, dyskinesia, postural dizziness, nausea, orthostatic hypotension, and visual hallucinations. Other infrequent ones include fatigue, headache, and constipation.
A severe adverse effect is the sudden onset of sleep, which can lead to road traffic accidents. Consequently, manufacturers issued a warning concerning the use of pramipexole in patients involved in driving or activities demanding vigilance.
Compulsive behaviors like punding and impulse control disorders like gambling, excessive shopping, and hypersexuality are known serious adverse effects of treatment with pramipexole.
Renal impairment is not a contraindication to pramipexole use. In geriatric patients with declining renal function and younger ones with renal insufficiency, the dose requires titration at a much slower rate. Hepatic insufficiency is not a contraindication as well.
Pregnancy may be a contraindication to pramipexole use. Studies conducted on rats showed that pramipexole could affect fetal development at higher doses. The evidence of teratogenicity remains insufficient. Hence, the advice is to avoid pramipexole in pregnancy. Being a dopaminergic agonist, it is contraindicated in lactating mothers since it suppresses lactation. Moreover, it is around six times more concentrated in milk than in plasma - the risk of transmission to the nursing baby increases.
As mentioned earlier, pramipexole causes sudden sleep attacks in individuals. Hence, drivers or people who have jobs requiring alertness are advised against the use of the drug.
The therapeutic plasma concentration of pramipexole is around 0.2 to 7 ng/ml. According to a study, most PD patients in remission had a plasma concentration of 2.47 +/- 3.27 ng/mL. This concentration should be cautiously monitored in patients with renal impairment to prevent pramipexole toxicity. The elimination half-life of 8 to 12 hours in individuals with normal renal function increases to 36 hours in patients with moderate to severe renal function.
There has been little evidence of pramipexole toxicity due to overdose. A case report has been published in the literature describing attempted suicide with a variety of medications. However, the overdose manifestations were more suggestive of pramipexole toxicity more than that of other drugs. A 59-year-old male was brought to the hospital 5 hours after ingesting 3 mg pramipexole, 2250 mg venlafaxine SR, and 360 mg mirtazapine.
His vitals were stable, and his neurological examination, including muscle tone and power, was normal. He was mildly agitated and had visual hallucinations. Nine hours later, he developed severe myoclonus to the extent he feared falling from bed. He consistently reported spiders crawling in the room and an alien man sitting on a chair next to him. He had some degree of urinary retention and was jittery and hypervigilant, and could not move due to postural dizziness. His routine blood reports were normal, with mild elevation in lactate. The serum concentration of pramipexole was significantly elevated at 34.2 ng/ml, around five times the upper limit of the therapeutic range. It decreased progressively, and the patient was then discharged after his symptoms subsided.
The combination of the above symptoms was very suggestive of pramipexole toxicity. The patient did not meet the Hunter Serotonin Toxicity Criteria, which rules out venlafaxine toxicity. Moreover, mirtazapine overdose is known to cause hypersomnolence.
The patient received no specific antidote. Only 5 mg diazepam was given to control his agitation.
Enhancing Healthcare Team Outcomes
To improve treatment outcomes in PD patients, the role of transdermal administration of dopamine agonists (DA) has been under investigation. In many patients, switching from oral DA such as pramipexole to transdermal DA such as rotigotine proved beneficial. These include ones with swallowing difficulties and gastrointestinal symptoms. Gastroparesis significantly reduces the absorption of oral PD, minimizing its therapeutic benefit. Transdermal rotigotine bypasses GI reducing the incidence of nausea and vomiting and obviating the problem of absorption due to gastroparesis. Transdermal patches are an effective alternative in patients on pramipexole undergoing surgery. Many patients had switched to rotigotine before surgery and restarted pramipexole post-operatively. Neurologists and anesthesiologists agree that the transdermal route can be as effective as oral DA in controlling PD symptoms preoperatively.
In patients with renal impairment, transdermal rotigotine can be used instead of pramipexole and other renally excreted oral DA.
Evidence suggests that the route of administration and formulation of the DA influences the occurrence of impulse control disorder (ICD). Studies show that the incidence of ICD in patients treated with transdermal rotigotine is lower than in patients treated with oral PD agents like pramipexole. ICDs are attributed to the D3 selectivity of oral DA. Rotigotine being less selective to D3 poses a smaller risk of ICD.
Pramipexole is well known to improve depressive symptoms in patients with PD through direct dopaminergic stimulation. Its efficacy has recently had investigative activity in cases of bipolar depression and treatment-resistant depression (TRD). A case report from France suggested that a combination of selegiline and pramipexole was effective in the treatment of TRD. One study indicated that pramipexole could be effective in treating depression resistant to electroconvulsive therapy. More studies are necessary in this regard. However, such promising results can offer a few more options for healthcare professionals to treat depression resistant to first-line agents.
Given the evolving information regarding therapy with pramipexole, therapy requires the efforts of an interprofessional team that includes clinicians, specialists, mid-level practitioners, nurses, and pharmacists, each contributing from their areas of expertise and working collaboratively with other disciplines. All members need to remain current on the latest information and studies for this drug as they come to light, so they can contribute to optimized therapeutic outcomes and minimize adverse events. [Level 5]