Need back up articles on Mirapex for Rheumatologist

Discussion in 'Fibromyalgia Main Forum' started by neeter1, Dec 13, 2005.

  1. neeter1

    neeter1 New Member

    I am very interested in Mirapex...my Rheumy has NEVER heard of Mirapex for Fibro...I told him I would bring to him articles (basically clinical trials). I found the one by Dr. Andrew Holman in Renton, Wa...can any of you recommend any other reading for him? He says there has been no clinical trials, etc...I need to show him that YES, people ARE being prescibed Mirapex.


    THANK YOU SO MUCH!
    Neeter
  2. 1sweetie

    1sweetie New Member

    I am prescribed Mirapex for RLS. I have to take a very low dose. I tried to increase the medicine as prescribed but started having lots of problems. My arms and legs would move uncontrollably as I started to rest. They would jump several inches. It was scaring both me and my dog. I also had problems with depression. I wish I didn't have to take it at all but it does help the RLS at the low dosage if I combine it with the Klopnin & pain meds.
    [This Message was Edited on 12/14/2005]
  3. Chilepepper

    Chilepepper New Member

    I am taking Mirapex, I saw it on the news first! Then I saw the info on this site, called my Doc she had no problem. I am on a low dose and I notice a big difference especially with a shoulder spasm (which never went away) and am getting relief! I take it 3 times a day and I also notice that the overall pain is much relieved. But doesn't last very long but, this is my first rx with this but so far it is great. I went on Yahoo clicked on medical went to drug info (or something simular) and checked out the info on it. Check it out if you want. Hope this helped. (we are all so different). Who knows!
  4. JPach007

    JPach007 New Member

    Hi Neeter,
    Try this...Do a search "Mirapex Trials" on Google. You will get some good info. There is even one specifically about reducing Fibro pain.
    I take Mirapex (for about 4 months now) with 1 Ambien and 1 Elavil each night. I have Fibro and Restless Leg Syndrome. The Mirapex has been the best thing that has helped me in over 10 years.
    If I can do anything else to help you, let me know. I hope you can try it.
    JPach
  5. 1sweetie

    1sweetie New Member

    What milligrams are you guys using????

    Susan
  6. darude

    darude New Member

    Go to search as I posted articles on this
  7. neeter1

    neeter1 New Member

    I am doing the investigative work on it because Rheumy doesn't believe me and I want hard evidence for him. I live in Vermont and no one up here has heard of using Mirapex for Fibro. I even call the makers of Mirapex and they couldn't give me any other clinical trials besides Dr. Holman in Renton, Washington. I WILL do as you suggest and again, Thank you.
  8. neeter1

    neeter1 New Member

    Thank you also for replying..I appreciate each and every one of you!!!
  9. neeter1

    neeter1 New Member

    I did talk with Dr. Andrew Holman's office in Renton, Wa. He is the one who did the clinical trial on Mirapex..very nice people. They suggested anyone who wants info can call them and they will talk with you or have Dr. Holman talk with you. I gave my doc's office his number and am having them call him. I hope this will help others that want info on it. I am not too sure if I can leave his number on here but information has it.

    Many Thanks
  10. dunnlb

    dunnlb New Member

    Type "mirapex for fibromyalgia" in your search bar and you should come up with a lot of stuff. One of the things I found:

    Search
    Arthritis

    Mirapex (pramipexole): Fibromyalgia pain relieved by Parkinson's disease drug


    July 29, 2005
    Mirapex (pramipexole): Fibromyalgia pain relieved by Parkinson's disease drug
    A study of 60 fibromyalgia patients who randomly received gradually increasing doses of Mirapex (pramipexole), a commonly prescribed medication for Parkinson's disease, or placebo showed promising results. According to the report in the August issue of Arthritis & Rheumatism:

    42 percent of patients taking Mirapex had a 50 percent or more decrease in pain vs. 14 percent of the placebo group.
    82 percent of patients taking Mirapex had "some improvement" in pain vs. 57 percent of the placebo group.
    Study participants who recevied Mirapex (pramipexole) also showed improvement in fatigue and function. Mirapex (pramipexole) is classified as a dopamine receptor agonist and has also been studied as a treatment for Restless Legs Syndrome.
  11. Musica

    Musica New Member

    Dr. Holman is my rheumatologist. From what I've heard, he would be very happy to talk to your rheumy about Mirapex (pramipexole). His telephone number is 425-235-9500. Here is his article that was in the August issue of Arthritis & Rheumatism.

    ************

    Arthritis & Rheumatism
    Volume 52, Issue 8, Pages 2495-2505
    Published Online: 28 Jul 2005


    Research Article

    A randomized, double-blind, placebo-controlled trial of pramipexole, a dopamine agonist, in patients with fibromyalgia receiving concomitant medications

    Andrew J. Holman *, Robin R. Myers
    Pacific Rheumatology Associates, Renton, Washington
    *Correspondence to Andrew J. Holman, Pacific Rheumatology Associates, 4300 Talbot Road South, Suite 101, Renton, Washington 98055

    Objective
    To assess the efficacy and safety of pramipexole, a dopamine 3 receptor agonist, in patients with fibromyalgia.

    Methods
    In this 14-week, single-center, double-blind, placebo-controlled, parallel-group, escalating-dose trial, 60 patients with fibromyalgia were randomized 2:1 (pramipexole:placebo) to receive 4.5 mg of pramipexole or placebo orally every evening. The primary outcome was improvement in the pain score (10-cm visual analog scale [VAS]) at 14 weeks. Secondary outcome measures were the Fibromyalgia Impact Questionnaire (FIQ), the Multidimensional Health Assessment Questionnaire (MDHAQ), the pain improvement scale, the tender point score, the 17-question Hamilton Depression Inventory (HAM-d), and the Beck Anxiety Index (BAI). Patients with comorbidities and disability were not excluded. Stable dosages of concomitant medications, including analgesics, were allowed.

    Results
    Compared with the placebo group, patients receiving pramipexole experienced gradual and more significant improvement in measures of pain, fatigue, function, and global status. At 14 weeks, the VAS pain score decreased 36% in the pramipexole arm and 9% in the placebo arm (treatment difference -1.77 cm). Forty-two percent of patients receiving pramipexole and 14% of those receiving placebo achieved 50% decrease in pain. Secondary outcomes favoring pramipexole over placebo included the total FIQ score (treatment difference -9.57) and the percentages of improvement in function (22% versus 0%), fatigue (29% versus 7%), and global (38% versus 3%) scores on the MDHAQ. Compared with baseline, some outcomes showed a better trend for pramipexole treatment than for placebo, but failed to reach statistical significance, including improvement in the tender point score (51% versus 36%) and decreases in the MDHAQ psychiatric score (37% versus 28%), the BAI score (39% versus 27%), and the HAM-d score (29% versus 9%). No end points showed a better trend for the placebo arm. The most common adverse events associated with pramipexole were transient anxiety and weight loss. No patient withdrew from the study because of inefficacy or an adverse event related to pramipexole.

    Conclusion
    In a subset of patients with fibromyalgia, 50% of whom required narcotic analgesia and/or were disabled, treatment with pramipexole improved scores on assessments of pain, fatigue, function, and global status, and was safe and well-tolerated.
    ________________________________________
    Received: 20 December 2004; Accepted: 19 April 2005


    ARTICLE TEXT

    Abnormal autonomic arousal ([1-4]), altered sleep stage architecture ([5]), chronic pain, and fatigue characterize fibromyalgia syndrome. The pathogenesis of fibromyalgia is a matter of debate, but centrally mediated abnormalities of sensory processing play an important role ([6]). Clinicians have tried various pharmacotherapies, including such agents as antidepressants, antiepileptics, muscle relaxants, antiinflammatories, sedative hypnotics, analgesics, and nutriceuticals ([7]). As a central neurotransmitter, dopamine influences human behavior, autonomic arousal, and sleep ([8]). Discovery of dopamine receptor subtypes (D1-5) and their dopamine concentration-dependent presynaptic and postsynaptic effects has made analyses of these vital regulatory pathways more complex. These related receptors fulfill different roles in disparate locations, including D3 receptors predominantly found in the mesolimbus ([9][10]).
    Adrenergic arousal arising from the locus ceruleus fragments normal sleep. Theoretically, this brainstem stimulation may be negated, or at least modulated, by adaptive neurotransmission influenced by dopamine through D3 receptors in the mesolimbus. Dopaminergic neurotransmission reduces the expression of arousal from central sympathetic stimulation in the locus ceruleus. Consequently, a D3 receptor agonist able to augment mesolimbic control of excessive adrenergic arousal could provide a new direction for the pharmacotherapy of fibromyalgia.
    Pramipexole (Mirapex; Boehringer Ingelheim, Ridgefield, CT) is a second-generation dopamine agonist that was developed for the treatment of Parkinson's disease. It is metabolized in the renal system and does not have significant effects on the cytochrome P450 system. Thus, interactions with other medications would not be expected. However, in Parkinson's disease, 14% of patients treated with pramipexole experience hallucinations when it is used in combination with carbidopa, presumably due to enhanced D2 neurotransmission. It has 7-10 times greater affinity for the D3 receptor compared with the D2 receptor and 17 times greater affinity compared with the D4 receptor ([10]). It has no affinity for other dopamine receptors (D1 or D5) or for serotonin, acetylcholine, histamine, muscarinic, opioid, 1-adrenergic, or -adrenergic receptors. It has mild affinity for the 2-adrenoreceptor, a target of clonidine and tizanidine.
    Blinded, placebo-controlled studies have demonstrated its efficacy in the treatment of Parkinson's disease and restless legs syndrome ([11]). The cause of restless legs syndrome is unknown, but this arousal is more commonly found in patients with fibromyalgia than in healthy controls ([12]). Based on these observations and the encouraging results of preliminary open-label studies of pramipexole treatment of fibromyalgia ([13][14]), we undertook the present study to evaluate pramipexole more rigorously in a randomized, placebo-controlled trial.
    PATIENTS AND METHODS

    Entry criteria
    Patients who were eligible for this 14-week, single-center, randomized, double-blind, placebo-controlled, parallel-group, escalating-dose trial were ages 22-67 years and fulfilled the American College of Rheumatology (ACR) 1990 criteria for the diagnosis of fibromyalgia ([15]). Inclusion criteria included patient-reported visual analog scale (VAS; 10-cm) scores for pain of 5 cm and tender point scores >10 (defined below). Exclusion criteria included uncontrolled thyroid disease, alcohol/substance abuse, pregnancy, lactation, untreated but documented sleep apnea, an Epworth Sleepiness Scale score >12, previous use of dopamine agonists, severe cervical pain on extension or known cervical myelopathy, and uncontrolled bipolar disorder, panic disorder, or psychosis as determined by the patient's psychiatrist.
    To mimic a real-world setting, no specific medications were excluded, and a washout period was not required. Patients receiving antiepileptic, antiinflammatory, antidepressant, hypnotic, and analgesic medications, including narcotics, were eligible for enrollment if the dosages had been stable for at least 6 weeks prior to study entry and were strictly maintained throughout the duration of the study. Nonpharmacologic therapies, such as injection of trigger points, acupuncture, and massage, were allowed.
    Study design
    The protocol, telephone screening, and consent forms were approved by the Western Institutional Review Board (WIRB; Olympia, WA), and all patients provided written informed consent at study entry. Patients were recruited by local advertisements and preliminary telephone screenings. Purchased pramipexole tablets were processed by Olympic Pharmacy (Gig Harbor, WA) and were supplied as capsules containing 0.25 mg, 0.50 mg, 0.75 mg, and 1.0 mg; calcium carbonate placebo capsules were identical. Using computer-generated codes, Olympic Pharmacy randomly assigned packets to the placebo and active-treatment groups and maintained the security of the blind. Biweekly pill counts were performed at each study visit to monitor compliance.
    Between August 2003 and February 2004, 60 patients were randomized in a 2:1 ratio of patients receiving active drug to patients receiving placebo for 14 weeks. The study medication was taken daily at bedtime and was increased weekly, as follows: 0.25 mg at week 1, 0.5 mg at week 2, 0.75 mg at week 3, 1.0 mg at week 4, 1.25 mg at week 5, 1.5 mg at week 6, 1.75 mg at week 7, 2.0 mg at week 8, 2.5 mg at week 9, 3.0 mg at week 10, 3.75 mg at week 11, and 4.5 mg at weeks 12, 13, and 14. The dosage was then tapered to 0 mg during week 15. Evaluations were conducted every 2 weeks up to week 14, and the final evaluation was performed at week 15. At the discretion of the investigator, an additional 2 weeks could be allowed to slow the dosage escalation.
    Safety assessments consisted of monitoring for adverse events at each study visit and by telephone. At each study visit, orthostatic supine and standing heart rate and blood pressure (after 30 seconds to increase sensitivity to orthostasis) as well as specific gravity of the urine were assessed. Serious adverse events were reported to the WIRB, Boehringer Ingelheim, and the Food and Drug Administration. Laboratory monitoring, including levels of thyroid-stimulating hormone, aspartate aminotransferase, alanine aminotransferase, and creatinine, a complete blood cell count, and an erythrocyte sedimentation rate, were obtained at study entry and visit 8 (when patients were taking 4.5 mg every evening). Dosages of all other medications were to remain stable, but if nausea occurred, addition of a proton-pump inhibitor was allowed. All subjects were given lansoprazole, pantoprazole, esomeprazole, and rabeprazole, and then continued their preferred proton-pump inhibitor at their discretion. This strategy has been previously reported to improve pramipexole tolerability in patients with fibromyalgia ([13][14]).
    Clinical assessments at each visit included the Fibromyalgia Impact Questionnaire (FIQ) ([16]), the Beck Anxiety Index (BAI) ([17]), the 17-point Hamilton Depression Inventory (HAM-d) ([18]), the pain improvement scale, the tender point score, and the Multidimensional Health Assessment Questionnaire (MDHAQ) ([19]). Assessments for restless legs syndrome activity were not performed. The pain improvement scale was a self-assessment instrument to determine pain relief, and patients selected one of the following responses: none, a little, moderate, a lot, and complete relief of pain. The tender point score was defined as the sum of scores for the 18 fibromyalgia syndrome tender points, as defined by the ACR. Each tender point was scored on a scale of 0-3, where 0 = painless, 0.5 = trace tenderness, 1 = classic tenderness ( 4 kg of pressure), 2 = severe tenderness with grimacing, and 3 = exquisite tenderness and sudden withdrawal (range 0-54). Both investigators standardized this tender point scoring technique to 10% variability prior to the beginning of the study, but the same assessor did not necessarily evaluate the same subject throughout the study.
    Given the availability of pramipexole and the lack of industry and grant support for an open-label extension, patients were independently unblinded by Olympic Pharmacy after they completed the study in order to facilitate their appropriate medical care with their other physicians. To limit bias, the entry criteria, protocol, and study design remained strictly rigid. The investigators interacting with the patients as well as all patients still enrolled in the study remained blinded until the conclusion of the entire study.
    Statistical analysis
    An intent-to-treat analysis was used for all outcome measures for patients who received at least 1 dose of study drug and had at least 1 followup evaluation. The primary end point was defined as improvement in the VAS pain score on the MDHAQ from study entry to week 14 for pramipexole (dosage of 4.5 mg) compared with placebo. Secondary end points included improvements in scores on the FIQ, BAI, HAM-d, tender point assessment, pain improvement scale, and the function, psychiatric, VAS for fatigue, and VAS for global status subscales of the MDHAQ.
    All computations were performed using SPSS version 10.1 software (SPSS, Chicago, IL). Data sets were initially evaluated for normality using the Kolmogorov-Smirnov test. All statistical tests were 2-sided, and P values less than 0.05 were considered significant. Normal data were evaluated by Student's t-test, with statistical significance determined after evaluation by Levene's test for equality of variances. Non-normally distributed data were evaluated by the Mann-Whitney U test. Categorical data were compared using the chi-square test, and safety data were evaluated by Fisher's exact test. Correlations were assessed by Pearson's correlation coefficient, if parametric, or by Kendall's tau, if nonparametric due to small data sets. In a secondary analysis, the influence of demographic data on outcome was analyzed using analysis of covariance (ANCOVA).
    RESULTS

    Characteristics of the study patients. In response to newspaper advertisements, 204 patients contacted the investigators to inquire about the study and were screened by telephone. Sixty-eight of these patients were evaluated in the clinic, and 60 of them were entered into the study. Reasons for lack of participation were as follows: patient's decision (33%), Epworth Sleepiness Scale score >12 (23%), cervical spine myelopathy symptoms (17%), VAS score for pain <5 cm (11%), previous use of dopamine agonists (10%), excessive travel distance (9%), age (6%), uncontrolled psychiatric disease (2%), lack of fibromyalgia diagnosis (2%), heavy alcohol use (1%), and uncontrolled thyroid disease (1%) (Figure 1).
    Figure 1. Flow chart showing the distribution of study patients from initial contact to completion of the study. The numbers of patients who failed the telephone screen total more than 136 because
    some patients had more than one of the conditions listed. VAS = visual analog scale; FMS = fibromyalgia syndrome.

    Baseline characteristics of the study patients are summarized (Table 1). Three men and 57 women were enrolled into the study. Their mean age was 49 years (range 22-67 years), their self-reported mean duration of fibromyalgia syndrome was 8.6 years (range 1-50 years), and they had taken a mean of 9.6 medications for fibromyalgia syndrome (range 1-40), which were prescribed by a mean of 5.8 medical professionals (range 1-30). Preexisting renal disease and orthostasis were not exclusion criteria, but none of the subjects had either disorder at study entry. A greater percentage of patients in the placebo arm used narcotic analgesics, but the treatment groups were well matched overall, and there were no statistically significant differences between the 2 groups. A summary of concomitant medications taken by the study patients is shown in Table 2.
    Table 1. Baseline characteristics of the study patients*
    ________________________________________
    Placebo group (n = 21) Pramipexole group (n = 39) P
    ________________________________________
    Age, mean ± SD years 46 ± 9.5 51 ± 10.1 0.10
    % female 95 94 0.95
    % white 95 100 0.17
    Body mass index, mean ± SD 32 ± 6.6 31 ± 8.3 0.42
    Duration of FMS, mean ± SD years 7.9 ± 6.8 8.9 ± 9.2 0.66
    No. of previous FMS medications, mean ± SD 9.5 ± 9.1 9.7 ± 8.5 0.94
    No. of previous FMS caregivers, mean ± SD 5.6 ± 4.3 5.9 ± 6.0 0.84
    Education, % 0.45
    <13 years 24 20 -
    13-16 years 67 57 -
    >16 years 9 23 -
    Marital status, % 0.10
    Single 19 33 -
    Married 48 53 -
    Divorced 28 6 -
    Widowed 5 8 -
    Work status, % 0.19
    Working 43 55 -
    Homemaker 19 14 -
    Student 9 0 -
    Retired 5 0 -
    Disabled 24 31 -
    Concomitant medications, %
    Narcotics 67 44 0.09
    Antiepileptics 29 18 0.34
    NSAIDs 38 36 0.87
    Antidepressants 33 44 0.44
    SSRIs 52 39 0.30
    RLS medications 9 5 0.57
    Anxiolytics 24 18 0.59
    Muscle relaxants 29 18 0.34
    Hypnotics 24 15 0.43
    CPAP, % 0 8 0.19

    ________________________________________
    * P values were determined by Student's t-test or chi-square test for categorical data. FMS = fibromyalgia syndrome; NSAIDs = nonsteroidal antiinflammatory drugs; SSRIs = selective serotonin-reuptake inhibitors; RLS = restless legs syndrome; CPAP = continuous positive airway pressure.
    Included are generally sedating antidepressants that are taken at bedtime.

    Table 2. Summary of concomitant medications*
    ________________________________________
    Patient Narcotic Antiepileptic NSAID Antidepressant SSRI RLS Anxiolytic Muscle relaxant Hypnotic
    ________________________________________
    1P No Gabapentin 300 No No No No No No No
    2A No No Ibuprofen 200 No No Lorazepam 1 No No No
    3A Tramadol 100 No No No Venlafaxine 75 No No Cyclobenzaprine 10 No
    4A No No No Trazodone 100 No No No No No
    5P§ Codeine 15 No No No No No No No No
    6A Hydrocodone 5 No No Trazodone 25 Venlafaxine 150 No No No Zaleplon 10
    7A§ No No No Bupropion 300 Citalopram 40 No No No Zolpidem 10
    8P No No No Trazodone 50 Venlafaxine 75 No No No No
    9A§ No No Ibuprofen 400 No No No No No No
    10P Methadone 15 Gabapentin 900 No Bupropion 300 No No No Methocarbamol 500 No
    11A§ No No Naproxen 500 Amitriptyline 10 No No No Methocarbamol 1,500 No
    12A§ No No No Trazodone 200 No No No No No
    13A Methadone 70 No No Trazodone 150 No No No No No
    14P No No No No Sertraline 150 No No No No
    15A Tramadol No No No No No Diazepam 5 No No
    16A§ Propoxyphene 100 No Valdecoxib 20 Trazodone 50 Citalopram 20 Clonazepam 2 No No No
    17P Hydrocodone 15 No No No Paroxetine 20 No Diazepam 5 No No
    18A Hydrocodone 10 No No No No No No No No
    19A No No No No Sertraline 50 No No No No
    20A No No No No No No No No No
    21P Hydromorphone 8 Gabapentin 200 Celecoxib 200 No No Lorazepam 2 No Carisoprodol 700 Zolpidem 10
    22A No No Naproxen 500 Trazodone 125 No No No Cyclobenzaprine 10 No
    23A§ No Gabapentin 300 No No Fluoxetine 20 No No No No
    24P§ Hydrocodone 20 No Piroxicam 20 No Citalopram 40 No Temazepam 15 No Zolpidem 10
    25A§ Oxycodone 20 Topiramate 100 Celecoxib 400 No No No Lorazepam 2 No No
    26P No No No No No No No No No
    27P§ No No No No No No No No No
    28A§ No Gabapentin 900 Celecoxib 200 No Citalopram 40 No No Carisoprodol 1,050 No
    29A Oxycodone 80 No Ibuprofen 800 No No No No Cyclobenzaprine 10 Zolpidem 10
    30A No No No Trazodone 150 Venlafaxine 150 No Alprazolam 1 No No
    31P Hydrocodone 5 No No No Paroxetine 20 No No Tizanidine 4 No
    32A No No No No No No No No No
    33P Morphine pump No Rofecoxib 50 No No No No No No
    34A No Depakote 125 No No No No No No No
    35A Oxycodone 10 No Rofecoxib 50 No No No Buspirone 60 Cyclobenzaprine 30 No
    36P Oxycodone 40 No No No No No No Cyclobenzaprine 10 Zolpidem 10
    37P Oxycodone 90 No No Doxepin 60 Fluoxetine 40 No Lorazepam 2 No No
    38A Oxycodone 20 No Aspirin 1,000 Trazodone 150 Venlafaxine 50 No No No No
    39A No No No Nortriptyline 100 No No No No Zolpidem 10
    40P Hydrocodone 15 No Diclofenac 150 Trazodone 100 Fluoxetine 20 No No Cyclobenzaprine 10 No
    41A No Gabapentin 600 No No Fluoxetine 20 No No No No
    42A§ No No Rofecoxib 25 Trazodone 100 No No No No No
    43A§ No No No No No No No No No
    44A No No Celecoxib 200 No Fluoxetine 20 No No No No
    45P Codeine 20 Gabapentin 1,200 Aspirin 1,000 Trazodone 50 No No No No No
    46A§ No No No Mirtazapine 15 No No No No No
    47A No No No No Sertraline 50 No No No No
    48P Hydrocodone 10 No Diclofenac 150 Trazodone 450 Fluoxetine 40 No Lorazepam 1 No No
    49P Hydrocodone 5 Gabapentin 2,700 Celecoxib 400 No Paroxetine 20 No Alprazolam 4 Carisoprodol 700 Zolpidem 10
    50A§ Tramadol 200 No Ibuprofen 400 Nefazodone 100 Venlafaxine 75 No No No No
    51A§ Codeine 10 No Naproxen 1,000 No No No No No No
    52P Oxycodone 20 No No No Citalopram 20 Lorazepam 2 No No Zalepion 10
    53A Codeine 10 Gabapentin 100 No Doxepin 10 No No No Tizanidine 8 Zolpidem 10
    54A§ Hydrocodone 5 No No Nefazodone 100 Paroxetine 20 No No No No
    55A No Gabapentin 600 No No No No No No No
    56A Oxycodone 240 No No No No No Alprazolam 1 No No
    57P No No No No No No No No No
    58A§ Hydrocodone 10 No No No No No Clonazepam 1 No No
    59A§ Morphine 150 No No Trazodone 100 Citalopram 20 No Clonazepam 3 No Zolpidem 10
    60P No Gabapentin 300 Naproxen 500 Amitriptyline 10 Citalopram 20 No No No No

    ________________________________________
    * Dosages of medications represent milligrams in 24 hours. Patient numbers are followed by the randomization abbreviation (A = active-treatment arm; P = placebo arm).
    Non-narcotic analgesics such as tramadol were included in this category.
    Medications considered for this category included those used for restless legs syndrome (RLS) that are taken exclusively at bedtime (clonazepam, lorazepam, and carbidopa).
    § Patient experienced a 50% decrease in pain score (by visual analog scale) measured at study end.

    Of the 39 patients randomized to receive pramipexole, 33 (85%) completed the study. One withdrew immediately after the entry visit because of lack of interest and an impending job transfer. Of the 21 patients randomized to receive placebo, 16 (76%) completed the study. One withdrew at week 3 for the new occurrence of reactive arthritis, 1 moved to Central America at week 10, and 1 died at week 10 of unrelated medical issues. Protocol violations for initiating a new medication occurred in 2 patients in the placebo arm and 5 in the active arm; medications begun were citalopram (week 3; pramipexole), tramadol (week 5; pramipexole), methadone (week 5; pramipexole), gabapentin (week 7; placebo), valproate (week 7; pramipexole), diazepam (week 9; pramipexole), and zalepion (week 12; placebo).
    Given the potentially beneficial effects of these new medications, efficacy assessments were made using only data obtained prior to the violation, but the patients continued in the study to monitor safety. No one withdrew because of inefficacy or a pramipexole-related adverse event.
    Efficacy. The pramipexole group noted significantly decreased pain compared with the placebo group at study end (week 14; 4.5 mg), as determined by scores on the VAS (Figure 2). The mean ± SEM decrease in the VAS score for pain from baseline to the study end point was -2.48 ± 0.38 cm (36%) in the pramipexole group and -0.71 ± 0.54 cm (9.4%) in the placebo group, with a between-group difference of -1.77 cm (95% confidence interval [95% CI] -3.07, -0.47) (P = 0.008) (Table 3). Significant improvement was also noted at week 12 (dosage of 4.5 mg) (P = 0.03) and at week 15 following the 1-week taper, with a difference of -2.36 cm (95% CI -3.79, -0.86) (P = 0.003). Except at week 3, all other VAS assessments for pain trended better for the pramipexole arm without achieving statistical significance. Post hoc analysis of VAS scores for pain demonstrated that 82% of the patients taking pramipexole noted some improvement compared with 57% of those taking placebo (P = 0.04). A 50% decrease in pain was achieved by 42% of those taking pramipexole compared with 14% of those taking placebo (P = 0.03)
    Figure 2. Change in pain scores (10-cm visual analog scale [VAS]) and Fibromyalgia Impact Questionnaire (FIQ) scores in the pramipexole and the placebo groups over 14 weeks. = P < 0.05; = P < 0.01 for the relative difference between pramipexole and placebo, by 2-tailed t-test.

    Table 3. Results of the MDHAQ, FIQ, HAM-d, BAI, and tender point score outcome measures at study end*
    ________________________________________
    Placebo group
    ________________________________________ Pramipexole group
    ________________________________________ Between-group difference at end point (95% CI) P
    No. of patients Change, mean ± SEM No. of patients Change, mean ± SEM
    ________________________________________
    MDHAQ subscale scores, range 0-10
    Pain 21 -0.71 ± 0.54 38 -2.48 ± 0.38 -1.77 (-3.07, -0.47) 0.008
    Fatigue 21 -0.55 ± 0.46 38 -2.11 ± 0.48 -1.56 (-2.88, -0.24) 0.021
    Global status 21 -0.16 ± 0.61 38 -2.52 ± 0.43 -2.35 (-3.82, -0.89) 0.002
    Function 21 0.01 ± 0.39 38 -0.83 ± 0.21 -0.84 (-1.64, -0.04) 0.041
    Psychiatric 21 -1.47 ± 0.46 38 -1.92 ± 0.43 -0.51 (-1.85, 0.82) 0.44
    FIQ total score, range 0-80 21 -3.73 ± 2.79 38 -13.30 ± 2.75 -9.57 (-18.01, -1.05) 0.028
    HAM-d total score, range 0-52 21 -1.33 ± 2.14 38 -4.84 ± 1.69 -3.51 (-9.07, 2.05) 0.24
    BAI total score, range 0-63 21 -4.38 ± 1.68 38 -7.00 ± 1.67 -2.62 (-7.77, 2.53) 0.31
    Tender point score, range 0-54 21 -9.55 ± 1.92 38 -14.58 ± 2.16 -5.03 (-11.52, 1.46) 0.13

    ________________________________________
    * MDHAQ = Multidimensional Health Assessment Questionnaire; FIQ = Fibromyalgia Impact Questionnaire; HAM-d = Hamilton Depression Inventory; BAI = Beck Anxiety Index.
    Secondary measures of efficacy favoring pramipexole over placebo included the FIQ score (Figure 2), pain improvement scale (Figure 3), and the MDHAQ function, VAS fatigue, and VAS global scores (Table 3). At week 14 (dosage of 4.5 mg), the total FIQ score decreased by a mean ± SEM of -13.30 ± 2.75 (24%) in the pramipexole group and -3.73 ± 2.79 (7%) in the placebo group, with a between group difference of -9.57 (95% CI -18.01, -1.05) (P = 0.028). Following the taper at week 15, the between-group difference was -14.1 (95% CI -23.0, -5.17) (P = 0.003). The FIQ scores also improved significantly at week 8 (dosage of 2.0 mg; P = 0.047) and week 12 (dosage of 4.5 mg; P = 0.047). Positive trends for the HAM-d total score, the BAI total score, the tender point score, and the MDHAQ psychiatric score were evident, but they did not reach statistical significance. Subjects with abnormal HAM-d and BAI scores at study entry did not demonstrate a more substantial trend toward improvement with pramipexole.
    Figure 3. Patients' assessments of improvement in pain from baseline to study end (week 14), by treatment group. Significantly more patients in the pramipexole group experienced moderate or better improvement compared with those in the placebo group, by chi-square test.

    ANCOVA revealed that all demographic variables and concomitant medication categories, including narcotic use (F = 0.002, P = 0.96), education level (F = 0.094, P = 0.76), or disability status (F = 0.32, P = 0.57), did not significantly influence the VAS pain score outcome or the occurrence of adverse events.
    Safety. Of the 59 patients who had at least 1 dose of study medication, 100% of them experienced at least 1 adverse event (Table 4). Most statistically significant adverse events included weight loss (mean -3.3 lbs; range of changes in weight -24 to +15 lbs) and increased anxiety in the pramipexole group and weight gain (mean 4.7 lbs; range of changes in weight -7 to +19) in the placebo group. Pramipexole was well tolerated, although nausea was very common in both treatment groups. Response to the voluntary addition of proton-pump inhibitors to treat the nausea was similar for both groups (62% in the placebo group versus 71% in the pramipexole group), and the proton-pump inhibitor response and patient preference were not predictable, as previously described ([14]). Patient preferences in the placebo group versus the pramipexole group for lansoprazole 30-90 mg (15% versus 20%), pantoprazole 40-120 mg (39% versus 23%), esomeprazole 40-120 mg (31% versus 31%), and rabeprazole 20-60 mg (15% versus 26%), respectively, were not statistically significantly different. For 1 patient in the study, the dosage escalation was delayed for 1 week because of nausea (pramipexole group). In contrast to the treatment of Parkinson's disease with pramipexole, hallucinations and sleep attacks were noticeably absent in our study patients. Infections were common, but were equally distributed between the 2 study groups.

    Table 4. Adverse events observed in at least 5% of patients*
    ________________________________________
    Adverse event Placebo group (n = 21) Pramipexole group (n = 38) P
    ________________________________________
    Nausea 71 79 0.83
    Weight loss (>5 lbs) 10 40 0.01
    Infection 24 37 0.23
    Weight gain (>5 lbs) 57 21 0.01
    Increased anxiety 0 18 0.04
    Diarrhea 0 17 0.06
    Morning somnolence 0 16 0.06
    Dizziness 19 13 0.84
    Vomiting 0 13 0.10
    Constipation 10 13 0.56
    Headache 19 13 0.84
    Increased insomnia 19 11 0.90
    Diaphoresis 5 11 0.41
    Tachycardia 0 8 0.26
    Decreased memory 5 8 0.55
    Bloating 0 5 0.41
    Injury 5 3 0.88
    Muscle spasm 5 3 0.88
    Urinary frequency 10 3 0.29
    Urticaria 5 3 0.88
    Edema 10 3 0.29
    Hiccough 5 0 0.36
    Tinnitus 5 0 0.36
    Chest pain 5 0 0.36

    ________________________________________
    * Values are percentages of patients. P values were calculated by Fisher's exact test.
    Results of tests for hematopoietic, hepatic, renal, and thyroid function and inflammation were uniformly normal at study entry and at the final evaluation. Orthostatic hypotension, defined as a decrease in systolic blood pressure of 10 mm Hg combined with an increase in heart rate of 20 beats per minute, as assessed in both the supine and the standing positions, was not found at any visit.
    The incidence of serious adverse events was 2.6% in the pramipexole group and 4.7% in the placebo group. One patient died during the study; the cause of death was unclear but was thought to be unrelated to participation in the placebo arm of the study. One serious adverse event occurred in the pramipexole group. A patient was hospitalized because of transient global amnesia that lasted <24 hours. Despite a detailed evaluation, the cause remained obscure and did not recur. Investigators were informed of these events 1 week after the adverse event had resolved, and the patient elected to continue study participation. The study drug was continued (double-blinded), and the patient successfully completed the study 6 weeks later.
    DISCUSSION

    In this randomized, double-blind trial, pramipexole demonstrated greater efficacy compared with placebo on measures of pain, function, fatigue, and global status after a 14-week, fixed escalation of the dosage to 4.5 mg taken at bedtime. This is the first trial of pramipexole and only the second trial for a D3 receptor agonist in the treatment of fibromyalgia ([20]).
    Pramipexole was generally well tolerated. These patients did not have the sleep attacks or hallucinations commonly described by patients taking pramipexole at a dosage of up to 1.5 mg orally 3 times a day for the treatment of Parkinson's disease. Orthostatic hypotension was not seen at any treatment visits. About 40% of patients in the pramipexole arm lost 1-24 pounds over 14 weeks. During the study, weight loss was unpredictable and random among the subjects, with wide variability. Consequently, significant weight fluctuations were not noticed by the investigators or typically noted by the patients. A mean loss of 3.3 lbs of weight in the pramipexole group over 14 weeks was interesting, but was too small to affect the double-blinded study design. Mild weight gain was more common in the placebo arm.
    Patients did not appear to lose weight because fibromyalgia symptoms improved. Weight loss in our study patients did not correlate with pain response or improvement in fatigue, function, or HAM-d scores. The impact of D2 receptor inhibition on weight gain in patients taking antipsychotic medications has suggested a role for a dopaminergic influence on the metabolic rate ([21]), but the role of D3 is unknown.
    In both arms of the study, reports of nausea were remarkably common. An emphasis of the language in the consent form on the potential for nausea and discussions of proton-pump inhibitor dosing to control the nausea may have influenced the incidence of this adverse event. It is possible that some subjects may have erroneously suspected that they were receiving the active drug if they developed nausea. While nausea and medication intolerance are common for patients with fibromyalgia, it is unclear whether this may have affected the placebo response during the study.
    Increased anxiety was noted by 18 of 38 subjects who took pramipexole and by none who took placebo (P = 0.04). In contrast, the change in BAI scores from baseline reflected only a modest improvement in the pramipexole group as compared with the placebo group (P = 0.31) (between group difference -2.62 [95% CI -7.73, 2.53]). This may be explained by the fact that cumulative adverse event reporting describes transient episodes of anxiety that are possibly related to a paradoxical stimulatory event rather than chronic anxiety. Interestingly, anxiety was usually reported early in the pramipexole dosage titration (<2.0 mg every evening), as has previously been described ([13]).
    Most trials do not report outcome measures after discontinuation of an investigational medication. We chose to report these data to further explore safety and to measure rebound symptoms of fibromyalgia. The VAS scores for pain and the FIQ scores decreased further at the conclusion of the 7-day taper period. Scores in the placebo group did not change. This study was not designed to address this finding or record additional data, but the finding raises interesting questions about a mechanism of action of pramipexole in patients with fibromyalgia.
    Dopaminergic neurons in the mesolimbus decrease tonic pain in animal models ([22]). Dopamine and D2 agonists can decrease N-methyl-D-aspartate (NMDA)-mediated pain through activation of a receptor tyrosine kinase ([23]). Yunus ([24]) has proposed that dopamine agonists act as analgesics, but they may also play a more complex role, possibly a central autonomic regulatory role. Its relatively short serum half-life (8 hours) and efficacy when taken at bedtime would not favor a purely analgesic explanation for the effects of pramipexole. A dynamic neuroregulatory role deserves further study.
    Although the pathogenesis of fibromyalgia is unclear, Wood ([25]) has suggested a central role for dopamine and the hippocampus, which mitigates memory, learning, stress modulation, and nociception. The hippocampus also inhibits adrenergic arousal arising from the locus ceruleus ([26]). Chronic pain states alter hypothalamic-pituitary-adrenal axis activity and induce hippocampal atrophy ([27]). Consequently, modulation of adrenergic arousal could be impaired.
    Inappropriate arousal of the sympathetic nervous system has also been demonstrated in fibromyalgia syndrome ([28]). But, autonomic tone depends on homeostatic balance. Inhibitory dopaminergic neurotransmission in the hippocampus counteracts stimulatory arousal from the locus ceruleus. Excessive arousal or inadequate mesolimbic attenuation of adrenergic arousal, or both, could fragment sleep stage architecture in patients with fibromyalgia. The specificity of pramipexole for the D3 receptor favors a hippocampal effect, because D3 receptors are found in the mesolimbic hippocampus and not in the locus ceruleus ([29]).
    Dopamine-mediated D3 effects in the mesolimbus are concentration-dependent, and a 4.5-mg dose of pramipexole every evening would be considered high compared with the lower doses typically used to treat restless legs syndrome or Parkinson's disease. High concentrations of pramipexole favor postsynaptic neurotransmission ([10]). Lower concentrations favor a presynaptic effect that inhibits dopaminergic neurotransmission in the hippocampus. Increased anxiety noted in patients taking pramipexole tended to occur very early in the dosage escalation. We hypothesize that lower pramipexole doses induced anxiety (adrenergic arousal) by initially enhancing presynaptic neurotransmission in the hippocampus. This action would favor an initial decrease in hippocampal activity and reduce its normal attenuation of adrenergic arousal. Gradually increasing the pramipexole dosage sufficiently enhances its postsynaptic effect. Consequently, this increasing postsynaptic dopaminergic neurotransmission would promote and augment hippocampal control of excessive adrenergic arousal. Future studies could quantify these proposed autonomic effects and their impact on sleep stage architecture with different dosages of pramipexole.
    While autonomic dysregulation has been demonstrated in fibromyalgia, the role of autonomic imbalance in the pathogenesis of fibromyalgia remains unclear. Moldofsky and colleagues ([5]) induced fibromyalgia symptoms in normal subjects by using an auditory arousal to disrupt deep, non-rapid eye movement, stage 3/4 sleep for 4 consecutive nights. In a study of middle-aged women conducted in 1999, Lentz and colleagues ([30]) reproduced Moldofsky's findings; however, in a 1998 study, Older and colleagues ([31]) did not produce fibromyalgia symptoms despite effective reduction of stage 3/4 sleep. However, Older et al used a different arousal technique for fragmenting deep sleep stages. Their choice of music rather than a startling, computer-generated sound may indicate that the nature of the arousal matters as much as the actual disruption of sleep. Polysomnographic studies of pramipexole taken at bedtime in the dosages we used to treat fibromyalgia syndrome are needed to document whether its therapeutic effect occurs by abrogating the aberrant sympathetic arousal that fragments deep sleep.
    These observations have led to the hypothesis that dysautonomic regulation drives the symptoms of many disorders commonly seen in patients with fibromyalgia ([32]), including irritable bowel syndrome, gastric hyperacidity, irritable bladder, anxiety disorders, palpitations, and temperature dysregulation. Fragmented sleep and loss of normal deep-sleep stages may simply be another consequence of prolonged dysautonomic arousal. It will require further study to determine whether fibromyalgia is the predictable sequela of abnormal sleep or the resultant complex of inadequate stage 4 sleep combined with its dysautonomic protagonist.
    This study has a variety of limitations and unorthodox design features. First, most fibromyalgia clinical trials do not allow concomitant medications. While data from previous trials may be more readily interpretable, patients who are willing to participate in such trials may not represent the norm. Although no medication has yet been approved specifically for the treatment of fibromyalgia, most patients have found some medications to be partially beneficial. Many are unwilling to discontinue their medications to participate in a typical clinical trial including these subjects. In clinical practice, caregivers often assess new medications as an augmentation strategy similar to this study design.
    Our inclusion of patients taking stable dosages of other medications for fibromyalgia also increased the risk of Type II error. Monitoring patient commitment to stable dosages of medications was critical to assessing the treatment response. Initiating any potentially beneficial medication during the study could artificially affect the results of response analysis. Consequently, for protocol violations, the response at the final, untainted, pramipexole dosage was used as the final response. This approach reduced this confounding variable, but it also decreased the final treatment response over baseline as compared with placebo.
    This protocol may be more applicable to a subset of patients with partially treated or possibly more severe fibromyalgia. But, the study design limits the interpretation of why or how pramipexole may improve pain, fatigue, and function scores. Also, while ANCOVA did not demonstrate a significant influence of demographic variables on treatment outcome, the study was not sufficiently powered to predict which combination of concomitant medications might yield a positive response to this adjunctive use of pramipexole. Longer trials are required to confirm these results, particularly in subjects who have discontinued concomitant medications.
    The optimal rate of dosage escalation and the impact of other dosing schemes were not addressed in this study. However, the gradual increase in pramipexole dosage over many weeks appears central to the success of the protocol. Other limitations include the 14-week duration of the study. These efficacy and safety results may not be generalizable to a longer duration of treatment. Since pharmacokinetic data are not available for treatment of humans with 4.5 mg of pramipexole each evening, accurate dopamine receptor dynamics and other potential pramipexole-related effects are unknown.
    Finally, it should be noted that some exclusion criteria in this study were particularly important. Both positional cervical myelopathy ([33]) and untreated obstructive sleep apnea ([34]) are potent adrenergic arousals that commonly contribute to autonomic dysregulation. Both conditions limit the efficacy and tolerability of a D3 agonist ([13]) when used to treat fibromyalgia. Given the significant prevalence of cervical pain and obstructive sleep apnea in patients with fibromyalgia, many may not respond to treatment with pramipexole. Although cervical pain on extension may result from a variety of causes, it was thought to be a reasonable query with which to exclude positional cervical myelopathy. Future studies may clarify why and how these two complex arousals influence sleep stage fragmentation, pain, fibromyalgia, and treatment response to a dopamine agonist.
    In summary, a new treatment approach using a D3 receptor agonist offers hope to patients with fibromyalgia. This 14-week study of pramipexole in patients with fibromyalgia demonstrated improvement in measures of pain, fatigue, function, and global status, with a reassuring adverse event profile. Further investigation of this pramipexole treatment paradigm is warranted to determine its mechanism of action in patients with fibromyalgia, its long-term risks and benefits, and to confirm these findings in patients not taking concomitant medications.
    Endnotes
    1 Dr. Holman holds patents for the use of dopamine 2/dopamine 3 receptor agonists in the treatment of fibromyalgia (patents US 6.277.875.B1 and US 6.300.365.B1).


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  12. neeter1

    neeter1 New Member

    This is exactly what I needed. I appreciate it very much...and thank you to ALL of you!!
  13. Beba

    Beba New Member

    has any seen Dr. Holman in 2006, if so, your thoughts would be appreciated.
    thanks!