Effective Treatment of Chronic Fatigue Syndrome and Fibromyalgia
A Randomized, Double-Blind, Placebo- Controlled, Intent to Treat Study
Hypothalamic dysfunction has been suggested in Fibromyalgia (FMS) and Chronic Fatigue Syndrome (CFS). This dysfunction may result in disordered sleep, subclinical hormonal deficiencies, and immunologic changes. Our previously published open trial showed that patients usually improve by using a protocol which treats all the above processes simultaneously. The current study examines this protocol using a randomized, double-blind design with an intent-to-treat analysis.
72 FMS patients (38 active: 34 placebo; 69 also met CFS criteria) received all active or all placebo therapies as a unified intervention. Patients were treated, as indicated by symptoms and/or lab testing, for: (1) subclinical thyroid, gonadal, and/or adrenal insufficiency, (2) disordered sleep, (3) suspected NMH, (4) opportunistic infections, and (5) suspected nutritional deficiencies.
At the final visit, 16 active patients were "much better," 14 "better," 2 "same," 0 "worse," and 1 "much worse" versus 3, 9, 11, 6, and 4, respectively, in the placebo group (p < .0001, Cochran-Mantel-Haenszel trend test). Significant improvement in the FMS Impact Questionnaire (FIQ) scores (decreasing from 54.8 to 33.2 versus 51.4 to 47.7) and Analog scores (improving from 176.1 to 310.3 versus 177.1 to 211.9) (both with p < .0001 by random effects regression), and Tender Point Index (TPI) (31.7 to 15.5 versus 35.0 to 32.3, p < .0001 by baseline adjusted linear model) were seen. Long-term follow- up (mean 1.9 years) of the active group showed continuing and increasing improvement over time, despite patients being able to wean off most treatments.
Significantly greater benefits were seen in the active group than in the placebo group for all primary outcomes. Using an integrated treatment approach, effective treatment is now available for FMS/CFS.
Fibromyalgia (FMS), which currently affects an estimated 3 to 6 million Americans, and Chronic Fatigue Syndrome (CFS) are two illnesses which often coexist. Severe persistent fatigue, diffuse migratory pain, cognitive dysfunction, and disordered sleep are common symptoms that patients often report in these overlapping syndromes. Current research suggests that many triggers can initiate a cascade of events, causing hypothalamic-target gland axis dysfunction and associated loss of normal circadian cycling of cortisol secretion. Hypothalamic dysfunction may result in some of the
changes reported in FMS and/or CFS. These include:
- Disordered sleep with associated pain. Disordered sleep (as well as hormonal and other changes) may cause immune dysfunction-e.g., Natural Killer Cell dysfunction, decreased proliferative responses and opportunistic infections.
- Hormonal deficiencies and hypothalamic-pituitary-target gland axis dysfunction. These can also contribute to the neurotransmitter changes seen in FMS. And,
- Autonomic dysfunction-including Neurally Mediated Hypotension (NMH).
Macro and micro nutrient deficiencies have also been shown by some authors. In our initial pilot study, simultaneously treating the above problems. We found that simultaneously treating these resulted in significant clinical improvement. Which mix of treatments were needed, however, varied from patient to patient.
Although a concept that is sometimes uncomfortable and foreign to traditional styles of thinking, the need for multiple interventions can occur when an illness affects a critical control center (such as the hypothalamus) which impacts the multiple systems noted above. Unfortunately, we have not yet found a single treatment that reverses hypothalamic dysfunction directly. Thus, this situation is different from illnesses that affect a single target organ and which can be treated with a single intervention. For example, pituitary dysfunction itself often requires treatment with several hormones. This effect is multiplied in hypothalamic dysfunction, which affects several critical systems in addition to the pituitary gland. We therefore hypothesized that an integrated treatment approach based on simultaneously treating the above problems (even if a modest degree of suspicion that would usually not be treated is present) will be clinically beneficial in CFS and FMS. Subgroup analysis was done to assess the effect of antidepressant therapy. Our current study tests the efficacy of this therapeutic approach and the above hypothesis using a randomized, double-blind, placebo-controlled protocol with an intent-to-treat analysis in an outpatient setting.
Materials and Methods
Seventy-two patients with FMS who met entry criteria were entered into the study between November 1995 and November 1997. All but three (all in the active group) also met the 1994 Center For Disease Control (CDC) criteria for CFS. Patients were recruited by word of mouth, patient support groups, and media reports regarding our research center. All patients were required to meet 1990 American College of Rheumatology (ACR) criteria for FMS.
major intercurrent illnesses (e.g., active cancer, multiple sclerosis, poorly controlled Diabetes, Emphysema, or Lupus) were present that could cause their symptoms. In addition, patients were excluded if: they were overtly hypothyroid (i.e., low T4 and elevated Thyroid Stimulating Hormone [TSH]) or hyperthyroid (i.e., high T4 and low TSH). Creatinine >1.9 mg/dL (168 umoL/L), AST >60 u/L (1.00 ukat/L), glucose > 200 mg/dL (11.1 mmol/L), Hematocrit (HCT) < .34 or Erythrocyte Sedimentation Rate (ESR) >45 mm/h were present. Patients were not excluded for depression, anxiety or sleep disorders.
Patients discontinued any previous treatments when able (except thyroid hormones, estrogen and progesterone) that were part of the study protocol. Patients were allowed to continue or begin active treatment upon completing the study and to participate in any other interventions on their own that were not part of the study protocol. Patients received a thorough history, physical exam and lab testing including a Complete Blood Count (CBC), Chem 18, serum magnesium, ESR, Urinalysis with micro, B12, Folate, Total T3, Free T4 or Free T7 index, TSH, HgbA1C, Cortrosyn (25 unit) Stimulation test, DHEA- Sulphate, IgE and stool O & P's. Follicle Stimulating Hormone (FSH), Luteinizing Hormone (LH) and estradiol levels were checked in females. Free Testosterone levels and stool tests for Clostridium difficile toxin were checked in a subset of the patients. Detailed informed consent was obtained from each patient.
Patient demographics at study entry are described in Table 1. Mean age at entry was 44.6 years (std. dev. 8.1, range 23-61). Sixty-six of 72 patients (92%) were female, and mean reported duration of CFS was 8.3 years (std. dev. 6.5, range 0.5-34 years). Average number of physicians consulted before coming to this clinic was 7.7 (range 0-100). Placebo patients were four years older, on average, than active-treatment patients (p = 0.037 by t-test), but there were no other significant demographic differences. The two treatment groups had no significant, or nearly significant, differences in mean entry values of the outcome measures, including the individual components of the Analog Total. With a possible range of 0-500, entry visit mean Analog Total was 176.5 (std. dev. 64.1, range 20-355) and, with a possible range of 0-80, the entry visit mean Fibromyalgia Impact Questionnaire score was 53.2 (std. dev. 9.6, range 30.4-74.6). Seventy-two patients met entry criteria and began treatment. Thirty-eight patients were randomized to the active intervention and 34 to the placebo intervention. The treatment protocol described below was completed by 32 patients in each group. The remaining 8 (6 active, 2 placebo) dropped out between visits 1 and 3. For some outcomes and visits, missing data yield sample sizes below 72 but, unless indicated, reported results concern the intention-to-treat sample. Participants gave written informed consent at the time of the initial examination and were informed of the double-blind, placebo-controlled nature of the study. The protocol is consistent with the principles of the Declaration of Helsinki.
Randomization and Blinding
Treatment was assigned in randomized blocks of six (B.B.). Patients then chose a date convenient for them to begin the study. Midway through the study, our statistician (L.M.), using the random number facility in SAS, generated the remaining code to maintain an equal number of active and placebo patients. Codes were kept away from the clinic in areas not accessible to patients or to the treating physician. Decisions as to whether the patients met entry criteria and their treatment prescriptions were made by the treating physician (J.E.T.), who was blinded to the patients' assignment and allocation sequence.
When possible, medications and identically appearing placebos were obtained from the companies making them. When not available, placebos were made by the pharmacist to approximate the medications' appearance. The treating physician did not have access to the medications. Containers of medications were labeled with various codes, with the code sheet accessible only to the pharmacist and the person responsible for dispensing medication (B.B.).
Four outcome measures were used. The primary outcome measures were the initial versus the final visit scores:
- Overall response—At the final visit the patients were asked whether they felt much worse, worse, same, better or much better after completing the protocol.
- Visual Analog (well-being) Scale (VAS) of 0-100 for 5 questions (obtained at each visit):
a. How is your energy? 0 (near dead)-100 (excellent)
b. How is your sleep? 0 (poor sleep)-100 (excellent, uninterrupted sleep)
c. How is your mental clarity? 0 (severe "brain fog")-100 (normal healthy)
d. How bad is your achiness? 0 (very severe, painful)-100 (no problem)
e. How is your overall sense of well being? 0 (horrible)-100 (great)
- FIQ or Fibromyalgia Impact Questionnaire (disability index)-described previously (obtained at each visit).
- Tender Point Index (TPI)—This value is calculated by multiplying the number of positive tender points (TP—out of 18) by their degree of tenderness (1= TP painful, 2= grimaces, withdrawal or involuntary jerk on TP palpation, 3= markedly withdraws on palpation, 4= patient refuses to allow a TP to be examined because of the severity of the pain) (maximum score of 72). Five patients had their TPI checked 3 times (each 1 hour apart) at the initial visit, with TPI scores showing good intra-visit consistency. The TPI was assessed at the initial and final visits.
After the study was completed, overall response, Analog and FIQ scores were checked on all available patients (who opted to stay on treatment) to assess for tachyphylaxis and/or continuing improvement and the patient's ability to maintain their improvement after tapering off most of the treatments.