ME/CFS treatments

Many patients do not fully recover from Chronic fatigue syndrome (CFS), even with treatment. Some management strategies are suggested to reduce the consequences of having CFS. Medications, other medical treatments, complementary and alternative medicine are considered. A sytematic review has shown that CFS patients are less susceptible to placebo effects than predicted, and have a low placebo response compared to patients with other diseases. CFS is associated with chemical sensitivity, and some patients often  respond to a fraction of a therapeutic dose that is normal for other conditions.

Antidepressants
Antidepressants are often prescribed to CFS patients. Their purpose can be to treat secondary depression or mood swings, but low dosage tricyclic antidepressants are sometimes prescribed to improve sleep quality and reduce pain. . However, antidepressants often have side effects, some of which can increase CFS symptoms, and baseline metabolism differs between patients. Finding antidepressants, if any, that help the individual patient, is therefore a matter of trial and error.

Overall, studies into the use of antidepressants in CFS have had mixed results. Some studies have shown a reduction in symptoms with antidepressant use, while others have shown no benefit.

Experimental RNA Injections
Nucleic acid (double-stranded RNA) compounds represent a potential new class of pharmaceutical products that are designed to act at the molecular level for treatment of CFS. An NDA (New Drug Application) has been submitted to the US FDA (Food and Drug Administration) by Hemispherx Biopharma, for Ampligen®. Over 40,000 doses of Ampligen® have been administered in FDA approved clinical trials.

Autonomic nervous system stimulants
Drugs such as atomoxetine (Strattera®), which stimulate the autonomic nervous system, appear to have positive effects in some people with CFS symptoms. Amphetamines and amphetamine analogs may help some patients. For example, methylphenidate (Ritalin®) has been found to be significantly better than placebo in relieving fatigue and concentration disturbances in a minority of CFS patients but more research is needed into the long term effects. Modafinil (Provigil®), a medication designed to aid in maintaining wakefulness, has had some positive effect on individuals with CFS, but has not been properly studied. A small study suggested that long-term treatment with modafinil may not be beneficial for CFS patients.

Hormones
Various hormones have been tried from time to time, including specifically steroids (such as cortisol) and thyroid hormones. Studies performed by Dr. Jacob Teitelbaum and by Dr. Kent Holtorf incorporating low-dose cortisol therapy have demonstrated positive results,.

A review published in Endocr Rev. Apr. 2003 By Cleare A J compared two hydrocortisone trials, on CFS patients: the first, a placebo controlled trial carried out by McKenzie et al and published in JAMA Sep 1998, with CDC defined patients many comorbid with psychiatric diagnosis, trialled hydrocortisone at 20 to 30 mg at 0800 plus 5mg at 1400 daily for 3 months. There was a moderate but significant benefit on a global health scale, although not on other more specific measures of fatigue or disability. However, there was significant adrenal suppression (of natural function) in 12 of 33 patients on hydrocortisone. A second study published in Lancet. Feb 1999 by Cleare A J et al in a randomised cross-over trial on CDC patients without comorbid psychiatric conditions, used much lower doses of 5–10 mg, (for 28 days of active treatment), chosen to represent a dose likely to replace the observed reduction of approximately 30% in 24-h UFC seen in previous studies. There was a clinically significant fall in fatigue scores in 34% on active treatment (28% returning to levels of fatigue at or below the population median score), compared with 13% (9%) on placebo. There were large reductions in self-rated disability scores in those whose fatigue improved. Furthermore, on this dose of hydrocortisone, there was no significant adrenal suppression, and there were no serious adverse effects. The review concluded that “however, the second treatment study was short term only, and the positive effects wore off rapidly on the switch to placebo; thus, routine use of this strategy as a treatment is not recommended without further evaluation”.

A subsequent study published in Am J Med. Jun 2003 by Blockmans D et al, performed a 6-month, randomized, placebo-controlled, double-blind, crossover study in 100 patients who fulfilled the 1994 CDC criteria for chronic fatigue syndrome. With a combination therapy (5 mg/d of hydrocortisone and 50 microg/day of 9-alfa-fludrocortisone) for 3 months of active treatment, concluded low-dose combination therapy of hydrocortisone and fludrocortisone was not effective in patients with chronic fatigue syndrome.

A recent review and study published in the Journal of Chronic Fatigue Syndrome in February 2008 by Kent Holtorf, reviewed all previous hydrocortisone trials regarding safety and effectiveness, and concluded that "because treatment with low physiological doses of cortisol (less than 15mg) has been shown to be safe and effective and routine dynamic ACTH testing does not have adequate diagnostic sensitivity, it is reasonable to give a therapeutic trial of physiologic doses of cortisol to the majority of patients with CFS and FM, especially to those who have symptoms that are consistent with adrenal dysfunction, have low blood pressure or have baseline cortisol levels in the low or low-normal range."

Immunoglobulin treatments
The role of intravenous immuno-gammaglobulin (IVIgG) in the management of CFS is said to be unclear following four randomised double blind placebo controlled studies examining immunoglobulin, its short term efficacy, and two follow up studies several years after the trials that showed positive effect.

In 1990 Lloyd et al published in Am J Med. a randomized, double-blind, placebo-controlled trial to determine the effectiveness of high-dose IVIgG. Forty-nine patients (40 with abnormal cell-mediated immunity) participated and showed that 2g/kg/month for 3 months was effective for producing remission and immunological improvement in adult patients with CFS (Australian criteria). When followed up 3 years later Wilson et al found that 66% of the 30 who responded had improved or continued to improve including some who were considered non responders at 3 months.

In 1990 Peterson et al published in Am J Med a double-blind, placebo-controlled trial of IV IgG. Thirty patients with CFS were enrolled but did not observe any significant difference between the two groups (CDC 1988 criteria) treated with 1 g/kg or placebo every 30 days for 6 months. At the end of the study, no significant therapeutic benefit could be detected in terms of symptom amelioration or improvement in functional status, despite restoration of IgG1 levels to a normal range. Major adverse experiences were observed in 20% of both the IV IgG and placebo groups.

In 1997 Rowe KS published in J Psychiatr Res. Results of a double blind randomized controlled trial with 71 young adolescents diagnosed with (CDC 1994 defined) CFS to test the efficacy of IVIgG. In this study 1gm/kg/month or placebo for 3 months was given with follow-up at 3 and 6 months. A significant difference was demonstrated between the baseline functional score and the 6 month follow-up and between the mean functional outcomes at 6 months. Adverse effects were common with both active and placebo solutions, but not predictive of response. A follow-up study at 3 years and 5 years with 75% and 78% response found there was no deteriation in overall function over the time, and young people continued to improve although a significant number were still disabled.

A further study in 1997 by Vollmer - Conna et al was published in Am J Med. Ninety-nine adult patients, who fulfilled diagnostic criteria for CFS (Australian criteria, similar CDC 1988), participated in this double-blind, randomized, and placebo-controlled trial. Patients received intravenous infusions with either a placebo solution or one of three doses of immunoglobulin (0.5, 1, or 2 g/kg) on a monthly basis for 3 months. No dose of intravenous immunoglobulin was associated with a specific therapeutic benefit. Adverse reactions, typically constitutional symptoms, were reported by 70% to 80% of patients, with no relationship to immunoglobulin treatment.

Apart from the different criteria on selection of patient subgroups in the various trials, a review in 1999 commented on the mixed results of the trials as follows; Peterson et al did not observe any difference between the two groups in that trial, however noted only 28 subjects completed the study so the results may be subject to Type II error, due to (small) sample size. Volma-Connor et al with variable dosage did not demonstrate a differtence at 3 months however the 3 month follow-up may have been too short a period, given there was no significant difference at 3 months in the 1997 Rowe adolescent study but at 6 months there was (significant differences).

Immune modulation treatment
Treatment with staphylococcal vaccine in fibromyalgia/chronic fatigue syndrome patients has been shown to increase the serological responses and the results further show that this response is related to improvement of the clinical outcomes. There have been 2 RCT trials conducted that show improvements, although regular injections must be continued to maintain the benefits.

In 1998 Andersson M et al published in the journal Eur J Pain, a small study of 28 CFS patients that compared the effect of vaccination with a staphylococcus toxoid with the injections of sterile water. Clinical global impressions showed significant improvement in the vaccine-treated group. In a follow-up study of 23 patients, the vaccine treatment was continued for 2-6 years. Fifty percent were rehabilitated successfully and resumed half-time or full-time work.

In 2002 Zachrisson O et al published in the journal Eur J Pain, a study on one hundred consecutively referred patients fulfilling the ACR criteria for FM and the 1994 CDC criteria for CFS enrolled in a randomised controlled trial to receive active drug or placebo. Treatment included weekly injections containing 0.1 ml, 0.2 ml, 0.3 ml, 0.4 ml, 0.6 ml, 0.8 ml, 0.9 ml, and 1.0 ml SB staphylococcus toxoid or coloured sterile water, followed by booster doses given 4-weekly for a total of 6 months. The treatment was well tolerated. Intention-to-treat analysis showed 32/49 (65%) responders in the SB group compared to 9/49 (18%) in the placebo group (P<0.001). Sixteen patients (33%) in the SB group reduced their CPRS scores by at least 50% compared to five patients (10%) in the placebo group (P< 0.01). An increase in CPRS symptoms at withdrawal was noted in the SB group. Maintenance of treatment is required to prevent relapse.

Titrated drugs, hormones and supplements
In 2001 Jacob Teitelbaum et al published in the Journal of Chronic Fatigue Syndrome results of randomised double blind placebo controlled intent to treat study. Seventy-two FMS patients (thirty-eight active: thirty-four placebo; sixty-nine also met CFS 1994 CDC 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 neurally mediated hypotension (NMH), (4) opportunistic infections, and (5) suspected nutritional deficiencies.

Each patient received either all active or all placebo treatments as a unified intervention. All patients received; for sleep, Melatonin, Valerium Rest plus mixing on an individual basis of a low dose of several sleep medications instead of a high dose of a single agent adjusted so that the patient got 7-8 hours of uninterrupted sleep without waking or next day sedation. For nutritional support; Multivitamin and Magnesium with malic acid. Additional treatments that were individualized based on test results or clinical history included: Ferrous Fumarate, Vitamin B12, Levothyroxine (Synthroid) or dessicated thyroid, Cortisol (Cortef), DHEA, Testosterone Enanthate (Delatestryl) (in males) or natural Testosterone (in females), Estrogen replacement and if uterus present natural progesterone (in females), Oxytocin, Fludrocortisone (Florinef) and increased dietary salt, water & potassium, Sertraline (Zoloft) or Paroxetine (Paxil) or Fluoxetine (Prozac) or Nefazodone (Serzone), Nystatin plus in more severe cases Itraconazole (Sporanox), Metronidazole (Flagyl) followed by Iodoquinol (Yodoxin), Doxycycline. At some time during the study antidepressants; Serotonin Uptake Inhibitors (SSRI's), Amitriptyline and Cyclobenzaprine were added.

One patient in each group dropped out because of side effects and one in each group dropped out with no reason given. At the final visit, sixteen active patients were "much better," fourteen "better," two "same," zero "worse," and one "much worse" versus three, nine, eleven, six, and four, 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. The analyses of antidepressants showed little impact on the primary comparisons of the active and placebo treatments.

Allergy identification and treatment
In cases where CFS-like symptoms may be caused by allergies, enzyme deficiencies or food intolerance, such as chronic sinusitis , coeliac disease, or irritable bowel syndrome, allergy testing, treatments, or elimination diets may prove beneficial.

Essential fatty acid treatments
A number of studies have been carried out supplementing with oils containing derivative essential fatty acids; with Omega-6, gamma linolenic acid GLA; and with Omega-3, eicosapentaenoic acid EPA and docosahexaenoic acid DHA. The studies below used Efamol marine comprised of evening primrose oil containing GLA together with fishoil concentrate containing EPA and DHA.

In 1990 Behan and Behan reported a randomised double blind placebo controlled study of 70 patients with post viral fatigue syndrome (PVFS) given the supplements morning and evening for 15 weeks, Of those patients 84% on active treatment vs 22% on placebo (of olive oil) reported improvements of the symptoms, exhaustion, aches and pains, muscle weakness, lack of concentration, dizziness, vertigo, depression, and memory loss. Patients on active treatment also recorded fewer episodes of cardiac palpitations and tachycardia. All these symptoms showed statistically significant improvement.

In 1990 Behan and Horribin enrolled sixty-three adults with the diagnosis of PVFS in a randomised double-blind, placebo-controlled study. After 3 months, of the patients, 85% on active treatment given the supplements vs. 17% on placebo (of paraffin oil), reported improved or much improved symptoms of fatigue, aches and pains, muscle weakness, lack of concentration, dizziness, vertigo, depression, and memory loss. All these symptoms showed statistically significant improvement. Upon testing only the supplement group's cellular membrane phospholipids, (both n-6 and n-3 EFA feedstock’s) had returned towards normal.

In 1999 a double blind controlled study by Warren et. al. was reported with fifty patients who fulfilled the Oxford Criteria for CFS, and who had negligible pretreatment differences of red-cell membrane (RBC) lipids compared with controls. The study results showed no significant differences between treated and placebo patients, as opposed to the two previous studies, on a different patient subgroup. “However the question remains whether sunflower oil (as placebo) has therapeutic effects of its own.”

A review of CFS treatments by Reid et al. in 2000, when comparing only the Behan/Horrobin and Warren studies concluded they showed mixed results, and classified dietary supplements as "unknown effectiveness".

Magnesium
In 1991 Cox et al published in the Lancet results of a randomised, double-blind, placebo-controlled trial on magnesium in CFS. In an associated case-control study, 20 patients with CFS had lower red cell magnesium concentrations than did 20 healthy control subjects. In the clinical trial, 32 patients with CFS were randomly allocated either to intramuscular magnesium sulphate every week for 6 weeks (15 patients) or to placebo (17). Patients treated with 100mg of magnesium had improved energy levels, better emotional state, and less pain, as judged by changes in the Nottingham health profile. 12 of the 15 treated patients had benefited from treatment, and in 7 patients energy score improved. By contrast, 3 of the 17 patients on placebo felt better (difference 62%, 95% CI 35 to 90), and 1 placebo patient had a better energy score. Red cell magnesium returned to normal in all patients on magnesium but in only 1 patient on placebo.

A review by Reid et al. in 2000 determined that as 3 subsequent studies had failed to find a deficiency of magnesium in people with chronic fatigue syndrome, that magnesium treatments in dietary supplements have "unknown effectiveness".

Another review by Werbach also in 2000 on nutritional strategies for treating chronic fatigue syndrome compared 9 studies and concluded there was marginal magnesium deficiency in CFS. In commenting on the trial above said, “These findings are consistent with a report that CFS patients who were not magnesium-deficient failed to benefit from an injection of 580 mg magnesium, six times the dosage received by the group of magnesium deficient patients (that benefitted in the above trial).” In conclusion said, “It is likely that marginal deficiencies not only contribute to the clinical manifestations of chronic fatigue syndrome, but also are detrimental to the healing processes. Therefore, when feasible, they should be identified by objective testing and their resolution should be assured by repeat testing following the initiation of treatment. Moreover, because of the rarity of serious adverse reactions and the difficulty in ruling out marginal deficiencies, and because some of the therapeutic benefits of nutritional supplements appear to be due to pharmacological effects, it seems rational to consider supplementing CFS patients with the nutrients.

Carnitine treatments
There have been a number of random controlled trials finding benefit for supplementation with L-carnitine or its esters in CDC defined CFS.

In a 1997 trial of random crossover design comparing L-carnitine and amantadine, 30 CFS patients who met CDC criteria, were given each medicine for 2 months, with a 2-week washout period between. Only with L-carnitine (1g, 3 times daily) were statistically significant clinical improvements found; and in 12 of the 18 studied parameters, after 8 weeks of treatment. None of the clinical parameters showed any deterioration. The greatest improvement took place between 4 and 8 weeks of L-carnitine treatment.

A 2004 randomised controlled trial with 90 CDC defined patients compared acetyl-L-carnitine, propionyl-L-carnitine, and its combination in 3 groups of 30 CFS patients during 24 weeks. Treatment showed considerable improvement in 59% of the patients in the acetylcarnitine group and 63% in the propionylcarnitine group, but less in the combination group (37%). Acetylcarnitine significantly improved mental fatigue and propionylcarnitine improved general fatigue. Attention concentration improved in all groups, whereas pain complaints did not decrease in any group. Two weeks after finishing treatment, worsening of fatigue was experienced by 52%, 50%, and 37% in the groups respectively. In the acetylcarnitine group, but not in the other groups, the changes in plasma carnitine levels correlated with clinical improvement.

In 2007 in a randomised controlled trial on 96 elderly patients who met CDC criteria for CFS without psychiatric disorders, were given placebo or carnitine supplementation. The active group had significantly greater improvements in various measures than the placebo group for the following parameters: muscle pain; prolonged fatigue after exercise: sleep disorders: physical fatigue: mental fatigue: fatigue severity scale: functional status: mini mental state examination (MMSE) improvements.

Complementary and alternative medicine usage
Two studies reported increased utilization of alternative treatments by people with CFS vs. without. In one study designed to assess use of alternative medicines and perceived benefits with 63 paired CFS and non-CFS co-twins, 91% of twins with CFS and 71% without CFS used at last one alternative treatment in their life, and a large proportion of all twins considered them helpful. Future research should ascertain the usefulness of alternative practices in the management of CFS.