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, α1-adrenergic, or β-adrenergic receptors. It has mild affinity for the α2-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.
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- PATIENTS AND METHODS
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.
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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|
|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|
|Work status, %|| || ||0.19|
|Concomitant medications, %|| || || |
| RLS medications||9||5||0.57|
| Muscle relaxants||29||18||0.34|
Table 2. Summary of concomitant medications*
|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|
|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|
|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|
|13A||Methadone 70||No||No||Trazodone 150||No||No||No||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|
|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|
|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|
|33P||Morphine pump||No||Rofecoxib 50||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|
|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|
|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|
|56A||Oxycodone 240||No||No||No||No||No||Alprazolam 1||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|
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.
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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|
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.
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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|
|Weight loss (>5 lbs)||10||40||0.01|
|Weight gain (>5 lbs)||57||21||0.01|
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.
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- PATIENTS AND METHODS
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.