The rationale for this study was that the daily use of pyridostigmine and regular exercise would stimulate the hypothalamic–pituitary–IGF-1 axis in FM patients and the resulting increase in IGF-1 levels would result in improvement in FM symptoms. As we have previously reported (22
), the combination of PYD and regular exercise failed to increase IGF-1 levels, which were low for their age in 58% of the study population. As might have been predicted from this negative response, we found that the primary outcome measures of FIQ pain VAS score, tender point count, and total myalgic score did not improve in the present study. Furthermore, there was no improvement in the following secondary outcome measures: total FIQ score, FIQ fatigue VAS score, FIQ stiffness VAS score, FIQ depression VAS score, QOL, BMI, or percentage of body fat. However, there was a significant improvement in both FIQ restorative sleep VAS score and FIQ anxiety VAS score in the 2 PYD-treated groups, whereas the 2 exercise groups experienced improvements in fatigue VAS score, flexibility, balance, lower body strength/endurance,
max, and time on the treadmill.
The improvements in anxiety levels and sleep quality (“awoke well rested”) in subjects taking PYD are intriguing. This is unlikely to be a spurious statistical finding resulting from multiple comparisons, since the predetermined significant P
value was set at 0.01 rather than 0.05. We speculate that these improvements may be related to an augmentation of parasympathetic tone as a consequence of the daily use of PYD (28
) and regular exercise (29
). There is now persuasive evidence that FM patients have dysautonomia, as evidenced by results of heart rate variability studies, tilt-table testing (30
), and sympathetic skin responses (31
). Two common clinical manifestations of dysautonomia are neurally mediated hypotension and postural orthostatic tachycardia syndrome (35
). Both of these dysautonomia syndromes have shown improvement with regular use of PYD (36
). The observed improvement in restorative sleep was unexpected and may be related to recent observations that vagal stimulation can improve alertness and reduce daytime sleepiness (37
). On the other hand, GH is known to stimulate slow-wave sleep (24
), and a transient surge in GH levels related to the nighttime dose of PYD is another possibility. The observed improvement in anxiety is consistent with many reports of reduced heart rate variability in anxiety disorders (39
) and the ability of PYD to improve heart rate variability (28
). There is some preliminary evidence that increasing heart rate variability through biofeedback benefits some clinical features of FM (42
This study is the first to attempt to combine training exercise and a medication in an effort to manipulate the GH–IGF-1 axis in patients with FM and to measure changes in symptoms. It is only the second study to combine a drug and exercise in a randomized controlled trial in FM patients. In an abstract published in 1992, Isomeri et al (43
) reported improvement in the pain VAS score with amitriptyline and exercise in FM patients. One other exercise study reported on IGF-1 levels in a randomized controlled strength training intervention conducted for 21 weeks (44
). Despite improvements in muscle mass, lower body strength/endurance, and neural recruitment, there was no improvement in IGF-1 levels.
In a previous article using data from this study group (22
), we reported that strenuous exercise plus PYD promoted an acute surge in GH levels during testing, but did not increase IGF-1 levels. However, the exercise level achieved during the tri-weekly classes did have beneficial effects in terms of fatigue, flexibility, balance, lower body strength/endurance,
max, and time on the treadmill. Presumably, these benefits of exercise, which have been described in many previous studies, are not a result of changes in the hypothalamic–GH–IGF-1 axis. In our previously published review of 46 other published trials of exercise in FM patients (4
), fitness and physical function were most often improved as a result of aerobic or mixed-type training programs. Pain, however, was not consistently improved in these trials. At higher exercise intensity, frequency, and duration (exercise dose), there was often a worsening of pain, whereas a lower exercise dose often resulted in clinical improvements. Some of these trials had attrition rates between 30% and 87%, limiting the interpretation of the results and highlighting the difficulty in maintaining compliance in exercise trials in FM. The exercise portion of this study confirms that group-based, mixed-type exercise training in FM is possible and that the attrition rates are low (9%).
The study had several limitations. First, we may not have selected the most sensitive measurement of pain. At the time this study was funded, pain was commonly measured with a single VAS score, a total myalgic score, and a count of tender points. Newer recommendations suggest that the brief pain index and the patient's global assessment of change be used in FM intervention studies (45
). Furthermore, there is increasing evidence that the number of tender points is not particularly sensitive to change in the average FM patient. Another possible limitation of the study is that the dose of PYD may not have been adequate or the duration of the trial sufficiently long. To our knowledge, there has never been a PYD dosage-escalation study or placebo comparison in FM patients. We chose the dosage of PYD based on our previous experience with a single-dose protocol and the clinical experience of other FM patient healthcare providers (23
A future trial with PYD could use an unblinded investigator who adjusts the dosage until the IGF-1 level is normalized, along with a similar adjustment in the dosing of the placebo medication. In the previous study of injectable recombinant GH, there was normalization of the serum IGF-1 level within 4 weeks, but symptom improvements began at 4 months and were still continuing at 9 months (12
). This lag time for improvement in symptoms is consistent with the known kinetics of muscle anabolism in patients taking GH (46
). In general, 6 months of PYD at a dosage of 60 mg 3 times a day plus FM-tailored group exercise for 60 minutes 3 times a week was safe and well-tolerated. The side effects of the drug, including loosening of stool and increased tearing and salivation, were common, but were well-tolerated by the study subjects. The side effect of abdominal pain was somewhat problematic and was cited by 2 patients as the reason for discontinuing the study.
Overall, our study provides additional objective evidence of abnormalities in the GH–IGF-1 axis in patients with FM, but the combination of PYD and exercise at the dosage and duration tested was not able to increase IGF-1 levels or to improve most FM symptoms, except for anxiety and sleep quality. Future trials aimed toward manipulating the GH–IGF-1 axis in FM patients may include exercise and somatostatin-blocking agents, such as PYD, in combination with GH-releasing hormone secretagogues. Based on the results of this study, it would be reasonable to prospectively study the effects of long-term PYD therapy on heart rate variability and possible interactions with sleep and anxiety levels.