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Clinical Characteristics of Pramipexole-Induced Peripheral Edema

Clinical Characteristics of Pramipexole-Induced Peripheral Edema

ORIGINAL CONTRIBUTION Clinical Characteristics of -Induced Peripheral

Eng-King Tan, MD; William Ondo, MD

Background: Pramipexole, a new , ef- (range, 0.25-11 months). The mean (±SD) dose at onset fectively treats early and advanced Parkinson disease and of PE was 1.7 ± 1.0 mg/d (dose range, 0.75-3 mg/d) and . the mean (±SD) dose when PE was at its maximum was 2.6 ± 0.7 mg/d (dose range, 1.5-3 mg/d). In all cases, the Objectives: To report the clinical features of and to in- PE rapidly abated with discontinuation of therapy, and vestigate the predisposing factors and eventual out- in all cases that we rechallenged, it rapidly returned. The comes in patients who developed (PE) condition seemed to be dose dependent but also idio- following treatment with pramipexole. syncratic, as we could not identify any predisposing fea- tures. It resulted in extensive medical evaluation in some Design: Retrospective case series in a tertiary referral patients and was only minimally responsive to diuretic center. therapy.

Results: Of the 300 patients who were receiving pra- Conclusion: Peripheral edema should be included mipexole therapy, 17 patients had mild to severe PE, among the potential adverse events associated with pra- which was attributable to the medication. Fifteen pa- mipexole therapy. tients had Parkinson disease and 2 patients had restless legs syndrome. The mean (±SD) time of onset of PE af- ter pramipexole therapy was started was 2.6 ± 3.6 months Arch Neurol. 2000;57:729-732

RAMIPEXOLE, a new dopamine REPORT OF CASES agonist, has been shown to be an effective treatment of early CASE 1 and advanced Parkinson dis- ease (PD)1-7 and restless legs A 66-year-old woman (patient 6) had 8,9 syndrome.P It is a potent agonist at the D2 symptoms of for 4 years. She dopamine- group, with highest af- was initially started on a combined regi- 7,8,10,11 finity to D3 dopamine-receptors. Pra- men of levodopa/ and amanta- mipexole is usually well tolerated. Com- dine hydrochloride. Pramipexole therapy monly reported include , was added 1 year ago. She noticed some , and visual .1-7 Re- ankle PE within 1 week of adding prami- cently, sleep attacks have also been re- pexole therapy. Nevertheless, she fol- ported.12 Peripheral edema (PE) as a side ef- lowed the dosing schedule and subse- fect of dopamine , has been rarely quently increased to a maintenance dose reported with mesylate,13-16 of 3 mg/d. Pramipexole therapy im- hydrochloride,17 and cabergo- proved PD, but the PE extended up to both line.16 However, this adverse effect is not of her knees resulting in discomfort and demonstrated in other studies.18-20 difficulty wearing her shoes. To our knowledge, PE has not been The results of an extensive evalua- shown to be significantly associated with tion including a 2-dimensional echocar- 1-6 From the Parkinson’s Disease pramipexole therapy. We describe the diogram, Doppler ultrasound of her lower Center and Movement clinical features and investigate possible extremities, and hepatic and func- Disorders Clinic, Department predisposing factors and eventual out- tion tests were unremarkable. The PE im- of Neurology, Baylor College comes in patients who developed PE af- proved only mildly with leg elevation and of Medicine, Houston, Tex. ter starting pramipexole therapy. furosemide therapy. therapy

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 therapy of levodopa and hydrochloride. Bilat- eral ankle swelling was noticed about 3 weeks after ini- PATIENTS AND METHODS tiating pramipexole therapy, while taking 1.5 mg/d. He titrated up to 3 mg/d. The PE at the ankles increased in Of the 300 patients who were receiving pramipex- severity and progressed above both of his knees to the ole therapy and evaluated at our outpatient clinic, 17 midthigh. The severity of the PE limited his mobility and satisfied the following inclusion criteria and were en- caused significant distress. Treatment with diuretics gave rolled in this study: (1) taking pramipexole therapy only mild improvement in his condition. His liver and for parkinsonism or restless legs syndrome, (2) no renal function test results were within normal limits. He history of PE prior to initiation of pramipexole also underwent a series of cardiac studies the results of therapy, (3) development of PE while receiving pra- which were unremarkable. mipexole therapy and resolution or marked improve- After 1 year of receiving 3 mg/d pramipexole therapy ment of PE shortly after stopping the medication, and with persistent PE, he was instructed to taper the dos- (4) no clinical and biochemical evidence of renal, car- age and then discontinue taking the medication. Three diac, and hepatic failure. The following information was documented for days after discontinuing the drug, the PE completely re- patients who were enrolled in the study: (1) demo- solved. Because pramipexole therapy significantly im- graphics, (2) duration of disease, (3) total duration proved his PD symptoms, he restarted the drug. At 1.5 of pramipexole therapy, (4) duration of pramipex- mg/d, he noticed a gradual return of the PE at his ankles. ole therapy until the onset of PE, (5) dose of prami- The dose has not been increased, and the PE remains re- pexole per day when PE was at its worst, (6) sever- stricted to his ankles. ity of PE (ie, at the level of ankle, midshin, knee, thigh, or generalized), (7) functional disability, as mea- RESULTS sured by difficulty wearing shoes, walking, or exer- tional dyspnea, (8) outcome (either still receiving Seventeen patients (8 males) were studied, with a mean therapy or no longer receiving therapy), (9) history of other medication usage, (10) effects of rechal- (±SD) age of 63.8 ± 10.6 years (age range, 44-82 years). The lenge with pramipexole, and (11) potential dose re- mean (±SD) duration of PD was 7.3 ± 5.0 years (range, 2-28 sponse. years). Fifteen patients were treated for PD, 13 in Hoehn All study patients were asked to taper and then and Yahr stage II while receiving pramipexole therapy, and completely stop pramipexole therapy. Those pa- 2 in stage III. Two patients had restless legs syndrome. tients who found the drug to be effective for their dis- The mean (±SD) time of onset of PE after prami- ease symptoms, were given the choice to restart the pexole therapy was started was 2.6 ± 3.6 months (range, medication, after the PE had subsided. 0.25-11 months) (Table). The mean (±SD) dose at on- set of PE was 1.7 ± 1.0 mg/d (dose range, 0.75-3 mg/d) and the mean(±SD) dose when PE was maximum was 2.6 ± 0.7 mg/d (dose range, 1.5-3 mg/d)(Table). Seven was discontinued, as her internist thought this may be patients (41.2%) had PE restricted to the ankles, 5 (29.4%) culpable; however, there was no improvement in the PE. at the calves, and 5 (29.4%) at or above the knees. Six- At the time of our physical examination, she had teen patients (94.1%) reported difficulty wearing their moderate bradykinesia and rigidity in her extremities. Pit- shoes, and 13 (76.5%) had difficulty walking. No pa- ting PE of both her lower extremities were present up to tient had concurrent reticularis or erythromyal- her knees, with thickening of overlying skin, indicating gia. All except 1 patient reported complete resolution of chronicity of the PE. There was no or PE after the medication was stopped for a few days. The erythromylagia. She had no evidence of renal, hepatic, remaining patient had an 80% reduction of her PE. or cardiac failure. We instructed her to taper off the dos- Eleven patients (64.7%) decided to restart pramipexole age of pramipexole over a course of 1 week without ad- therapy, but at a lower dosage. Ten reported return of justing her levodopa dosage. One week after she was no the PE within 1 week, but to lesser severity, and 2 longer receiving pramipexole therapy, she reported at least patients discontinued use of the drug. an 80% improvement of her PE, and she was able to wear Other possible concurrent causes of PE included 2 pa- her usual shoes. As pramipexole therapy improved her tients with quiescent malignancy of the prostate and uterus, PD, and was otherwise well tolerated, she elected to re- and 1 patient with hypothyroidism. Three were receiving start pramipexole therapy, but at a lower dose of 0.75 amantadine therapy, and 2 were receiving a calcium an- mg/d. Within 2 weeks, she had noticed an increase of her tagonist. None of these patients had a history of PE. PE at her ankles, but to a lesser degree than before. She continued usage of pramipexole therapy at this dosage. COMMENT CASE 2 We report mild to severe PE in patients that is attribut- able to pramipexole therapy. In all cases, the PE rapidly A 60-year-old man (patient 11) has a 3-year history of abated within 1 week after discontinuation of the drug, PD, presently complicated by levodopa-induced dipha- and in all cases that we rechallenged with pramipexole sic dyskinesias and motor fluctuations. Pramipexole therapy, PE rapidly returned. The condition seemed to therapy, at an initial dose of 0.375 mg/d, was started be dose dependent but also idiosyncratic, as we could not 1 year ago. At that time, he was receiving a combined identify any predisposing features. It resulted in exten-

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©2000 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 10/02/2021 Characteristics of Pramipexole-Induced Peripheral Edema (PE) in 17 Patients With Parkinson Disease and Restless Legs Syndrome

Duration of Effect of Dose Patient No./ Duration of Treatment Until Dose at PE Dose at PE Functional Reduction of Sex/Age, y Disease, y PE Onset, mo Onset, mg/d Maximal PE, mg/d Severity Disability* Pramipexole Therapy 1/M/63 4 0.38 0.75 3 Ankles Yes † 2/F/82 2 0.5 1.5 2.25 Ankles No . . . 3/M/66 7 11 2 3 Ankles Yes . . . 4/F/69 1.5 11 3 3 Ankles No † 5/M/71 8 0.5 0.75 3 Calves Yes . . . 6/F/66 5 0.25 0.75 3 Knees Yes † 7/M/67 4 0.25 0.75 3 Calves Yes † 8/M/69 13 6 2.25 2.25 Ankles Yes † 9/F/44 3 1 3 3 Knees Yes . . . 10/F/66 6 0.38 1.5 1.5 Knees Yes . . . 11/M/60 4 0.75 1.5 3 Thighs Yes † 12/M/65 14 6 1.5 1.5 Calves Yes † 13/F/53 1.5 0.25 0.75 1.5 Ankles Yes † 14/F/47 28 0.25 0.5 1.5 Ankles Yes ‡ 15/M/76 6 6 3 3 Calves Yes . . . 16/F/74 15 2 3 3 Thighs Yes † 17/F/47 17 2 3 3 Calves Yes † Mean 63.8 8.2 2.6 1.7 2.6 ...... SD 10.6 7.1 3.6 1.0 0.7 ......

*Includes patients who had difficulty wearing shoes and/or who had difficulty with gait. Ellipses indicate not applicable. †Peripheral edema was less severe after rechallenging with pramipexole therapy at a lower dose. ‡Peripheral edema improved with reduction of the initial dose of pramipexole therapy.

sive medical evaluation in some patients and was only to its ergot effects, ␣1-adrenoreceptors, or minimally responsive to diuretic therapy. In some cases, affinity is unknown. Some have suggested that because of gait and balance difficulties caused by the PE were in- its rarity, this may represent an idiosyncratic reaction.13 terpreted as worsening PD. The mechanism by which pramipexole induces PE is Because many patients initially seen by us already unknown. It is not an ergot and has high affinity for were receiving pramipexole therapy and others fol- the D3-receptor subtype, moderate affinity for ␣2- low-up elsewhere after being prescribed pramipexole by adrenoreceptor, and, unlike ergots, low affinity for 10 us, we were unable to accurately determine the exact ␣1-adrenoreceptor. It may have different propensity to prevalence of PE in our practice, but we estimate it to be induce PE compared with other dopamine agonists. as high as 5% to 7%. We cannot ascertain whether aman- tadine, or calcium antagonists, both recognized causes CONCLUSIONS of PE,21,22 may increase the risk or severity of PE when pramipexole is added to the regimen. Of the 5 patients This study draws attention to our clinical observation that who had severe PE (up to the knee), 1 was was receiv- pramipexole therapy can induce PE and that this may be ing amantadine therapy, and 1 was receiving a calcium severe in some patients with PD and restless legs syn- antagonist. Our small sample size precludes any mean- drome. The PE seems to be dose related, poorly respon- ingful analysis of their contribution. sive to diuretics, and easily reversed by stopping the medi- Shannon et al1 reported PE to be present in 7.9% of cation. Recognition of this adverse effect can avoid the patients receiving pramipexole compared with 3.3% unnecessary investigations and morbidity. The decision in the placebo group. However, the difference was not whether to continue treatment with the drug in patients statistically significant. None of the patients in the pra- with mild to moderate PE should be individualized. We mipexole-treated group discontinued the drug therapy do not think our experience is unique, and this compli- because of PE and no further information was provided. cation may be unrecognized and underreported. As more Other large studies of pramipexole therapy have not re- centers acquire experience with pramipexole, the true ported any PE.2-6 Reports of PE as a of other magnitude of this potential problem may become clearer. dopamine-agonist therapy have been inconsistent. Con- flicting reports regarding this complication indicate that Accepted for publication September 22, 1999. it is likely to be uncommon. We thank Joseph Jankovic, MD, Parkinsons’s Disease Ergot dopaminergic-agonists, such as bromcriptine and Center and Movement Disorders Clinic, Baylor College of mesylate have actually been used to treat pa- Medicine, Houston, Tex. tients with cyclical PE.23-25 Their effectiveness could be a Corresponding author: William Ondo, MD, Parkin- result of dopamine-mediated inhibition of mineralocorti- son’s Disease Center and Movement Disorders Clinic, De- coid activity. However, others have also reported severe gen- partment of Neurology, Baylor College of Medicine, 6550 eralized PE with bromocriptine therapy.14,15 Whether the Fannin, Smith 1801, Houston, TX 77030-3408 (e-mail: PE caused by bromocriptine therapy in such cases is due [email protected]).

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