double blind placebo controlled trial – American ME and CFS Society

Transcranial direct current stimulation for post-COVID fatigue: a randomized, double-blind, controlled pilot study

Abstract:

Fatigue is one of the most frequent and disabling symptoms of the post-COVID syndrome. In this study, we aimed to assess the effects of transcranial direct current stimulation on fatigue severity in a group of patients with post-COVID syndrome and chronic fatigue.

We conducted a double-blind, parallel-group, sham-controlled study to evaluate the short-term effects of anodal transcranial direct current stimulation (2 mA, 20 min/day) on the left dorsolateral prefrontal cortex. The modified fatigue impact scale score was used as the primary endpoint. Secondary endpoints included cognition (Stroop test), depressive symptoms (Beck depression inventory) and quality of life (EuroQol-5D).

Patients received eight sessions of transcranial direct current stimulation and were evaluated at baseline, immediately after the last session, and one month later. Forty-seven patients were enrolled (23 in the active treatment group and 24 in the sham treatment group); the mean age was 45.66 ± 9.49 years, and 37 (78.72%) were women. The mean progression time since the acute infection was 20.68 ± 6.34 months.

Active transcranial direct current stimulation was associated with a statistically significant improvement in physical fatigue at the end of treatment and 1 month as compared with sham stimulation. No significant effect was detected for cognitive fatigue.

In terms of secondary outcomes, active transcranial direct current stimulation was associated with an improvement in depressive symptoms at the end of treatment. The treatment had no effects on the quality of life. All the adverse events reported were mild and transient, with no differences between the active stimulation and sham stimulation groups.

In conclusion, our results suggest that transcranial direct current stimulation on the dorsolateral prefrontal cortex may improve physical fatigue. Further studies are needed to confirm these findings and optimize stimulation protocols.

Source: Oliver-Mas S, Delgado-Alonso C, Delgado-Álvarez A, Díez-Cirarda M, Cuevas C, Fernández-Romero L, Matias-Guiu A, Valles-Salgado M, Gil-Martínez L, Gil-Moreno MJ, Yus M, Matias-Guiu J, Matias-Guiu JA. Transcranial direct current stimulation for post-COVID fatigue: a randomized, double-blind, controlled pilot study. Brain Commun. 2023 Apr 10;5(2):fcad117. doi: 10.1093/braincomms/fcad117. PMID: 37091591; PMCID: PMC10116605. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10116605/ (Full text)

Muscle injections with lidocaine improve resting fatigue and pain in patients with chronic fatigue syndrome

Abstract:

OBJECTIVE: Patients with chronic fatigue syndrome (CFS) complain of long-lasting fatigue and pain which are not relieved by rest and worsened by physical exertion. Previous research has implicated metaboreceptors of muscles to play an important role for chronic fatigue and pain. Therefore, we hypothesized that blocking impulse input from deep tissues with intramuscular lidocaine injections would improve not only the pain but also fatigue of CFS patients.

METHODS: In a double-blind, placebo-controlled study, 58 CFS patients received 20 mL of 1% lidocaine (200 mg) or normal saline once into both trapezius and gluteal muscles. Study outcomes included clinical fatigue and pain, depression, and anxiety. In addition, mechanical and heat hyperalgesia were assessed and serum levels of lidocaine were obtained after the injections.

RESULTS: Fatigue ratings of CFS patients decreased significantly more after lidocaine compared to saline injections (p = 0.03). In contrast, muscle injections reduced pain, depression, and anxiety (p < 0.001), but these changes were not statistically different between lidocaine and saline (p > 0.05). Lidocaine injections increased mechanical pain thresholds of CFS patients (p= 0.04) but did not affect their heat hyperalgesia. Importantly, mood changes or lidocaine serum levels did not significantly predict fatigue reductions.

CONCLUSION: These results demonstrate that lidocaine injections reduce clinical fatigue of CFS patients significantly more than placebo, suggesting an important role of peripheral tissues for chronic fatigue. Future investigations will be necessary to evaluate the clinical benefits of such interventions.

Source: Staud R, Kizer T, Robinson ME. Muscle injections with lidocaine improve resting fatigue and pain in patients with chronic fatigue syndrome. J Pain Res. 2017 Jun 26;10:1477-1486. doi: 10.2147/JPR.S139466. ECollection 2017. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5499959/ (Full article)

Use of lisdexamfetamine dimesylate in treatment of executive functioning deficits and chronic fatigue syndrome: a double blind, placebo-controlled study

Abstract:

The purpose of this study was to assess the efficacy of lisdexamfetamine dimesylate (LDX) for the treatment of executive functioning deficits in adults (ages 18-60) with chronic fatigue syndrome (CFS). The study’s primary outcome measure was the Behavior Rating Inventory of Executive Function-Adult (BRIEF-A). Secondary outcome measures were standardized assessments of fatigue, pain and global functioning.

Twenty-six adults who met criteria for CFS and had clinically significant executive functioning deficits were randomly assigned to a flexible morning dose (30, 50, 70 mg/day) of either placebo or LDX for a 6-week trial. The data were analyzed with standard analysis of variance (ANOVA) procedures. Participants in the LDX group showed significantly more positive change in BRIEF-A scores (Mchange=21.38, SD=15.85) than those in the placebo group (Mchange=3.36, SD=7.26).

Participants in the active group also reported significantly less fatigue and generalized pain relative to the placebo group. Although future studies with LDX should examine whether these benefits generalize to larger, more diverse samples of patients, these results suggest that LDX could be a safe and efficacious treatment for the executive functioning deficits often associated with CFS. The possibility that dopaminergic medications could play an important role addressing the symptoms of CFS is also discussed.

Source: Young JL. Use of lisdexamfetamine dimesylate in treatment of executive functioning deficits and chronic fatigue syndrome: a double blind, placebo-controlled study. Psychiatry Res. 2013 May 15;207(1-2):127-33. doi: 10.1016/j.psychres.2012.09.007. Epub 2012 Oct 9. https://www.ncbi.nlm.nih.gov/pubmed/23062791

Nicotinamide adenine dinucleotide (NADH) in patients with chronic fatigue syndrome

Abstract:

BACKGROUND: Nicotinamide adenine dinucleotide (NADH) may be depleted in chronic fatigue syndrome (SFC). The purpose of the study was to evaluate the efficacy of supplementation with NADH in these patients.

MATERIAL AND METHODS: A double blind, placebo controlled, 3 month long clinical trial was conducted. The patients were randomized to oral NADH oral 20mg or placebo during the first two months. The intensity of the fatigue, functional performance, mood state, functional impact of the fatigue, quality of life, sleep quality, exercise capacity and functional reserve as well as the investigator’s and patient’s opinion on the efficacy of the intervention prior to and at 30, 60 and 90 days of the onset of the treatment were evaluated. A stress test was performed in the baseline visit and at 60 days (last day of the double blind treatment).

RESULTS: A total of 86 patients, 77 of whom completed the study (mean age, 47 years, 72 women) were enrolled. No significant differences were found in most of the variable studied at the end of the study. Administration of NADH was associated to a decrease in anxiety condition of -1.0 points (p<0.05) and of -0.2 points (p=NS) in the placebo assigned group. Maximum heart rate after the stress test decreased a mean of -8.1l/min (p<0.05) in the NADH group and increased by +1.7l/min in the placebo group (p=0.73). No differences were found in the perception of efficacy with NADH and placebo, by the investigator and patients.

CONCLUSIONS: Administration of oral NADH was associated to a decrease in anxiety and maximum heart rate, after a stress test in patients with CFS. On the contrary, this treatment did not modify other clinical variables and the global functional performance.

Source: Alegre J, Rosés JM, Javierre C, Ruiz-Baqués A, Segundo MJ, de Sevilla TF. Nicotinamide adenine dinucleotide (NADH) in patients with chronic fatigue syndrome. Rev Clin Esp. 2010 Jun;210(6):284-8. doi: 10.1016/j.rce.2009.09.015. Epub 2010 May 5. [Article in Spanish] https://www.ncbi.nlm.nih.gov/pubmed/20447621

A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome

Abstract:

OBJECTIVE: To provide a preliminary assessment of the efficacy and safety of fludrocortisone acetate treatment of chronic fatigue syndrome.

DESIGN: A placebo-controlled, double-blind, random-allocation crossover trial of 6 weeks of fludrocortisone.

SETTING: An outpatient clinical trials unit.

PATIENTS: Twenty-five participants with chronic fatigue syndrome (mean age, 40 years; 19 [76%] women; mean duration of illness, 7.0 years) were recruited from a research and clinic registry. Five patients withdrew from the trial.

INTERVENTIONS: All participants were scheduled to receive fludrocortisone acetate (0.1-0.2 mg) or a placebo for 6 weeks in each treatment.

MAIN OUTCOME MEASURES: Self-administered questionnaires were completed at the beginning and end of each treatment arm that asked patients to rate the severity of their symptoms on a visual analogue scale. The Medical Outcomes Study 36-Item Short-Form Health Survey, a reaction time test, and a treadmill exercise test were used to assess functional status. Blood pressure, heart rate, and plasma norepinephrine levels were obtained at baseline. Blood pressure and heart rate were recorded at the end of the exercise test and monitored at all subsequent visits.

RESULTS: At baseline, the study participants reported symptom severity greater than 5 for most symptoms, and all had evidence of marked functional impairments. No improvement was observed in the severity of any symptom or in any test of function for the 20 participants who completed both arms of the trial. Blood pressure and heart rate readings were unaffected by treatment, and plasma norepinephrine levels did not differ from those of a healthy control group. The incidence of adverse experiences was similar in the fludrocortisone and placebo arms of the trial.

CONCLUSION: Low-dose fludrocortisone does not provide sufficient benefit to be evident in a preliminary blinded trial of unselected patients with chronic fatigue syndrome.

Comment in: Treatment for chronic fatigue syndrome. [Arch Intern Med. 1998]

Source: Peterson PK, Pheley A, Schroeppel J, Schenck C, Marshall P, Kind A, Haugland JM, Lambrecht LJ, Swan S, Goldsmith S. A preliminary placebo-controlled crossover trial of fludrocortisone for chronic fatigue syndrome. Arch Intern Med. 1998 Apr 27;158(8):908-14. http://www.ncbi.nlm.nih.gov/pubmed/9570178

Double-blind randomized controlled trial to assess the efficacy of intravenous gammaglobulin for the management of chronic fatigue syndrome in adolescents

Abstract:

A double blind randomized controlled trial was conducted in 71 adolescents aged 11-18 years. Inclusion in the trial required fulfilment of the diagnostic criteria, (Fukuda et al., 1994).

Three infusions of 1 gm/kg (max 1 litre of 6 gm/100 ml in 10% w/v maltose solution) were given one month apart. The dummy solution was a 10% w/v maltose solution with 1% albumin of equivalent volume for weight. Efficacy was assessed by difference in a mean functional score including school attendance, school work, social activity and physical activity, between baseline, three months and six months after the final infusion.

There was a significant mean functional improvement at the six month follow-up of 70 adolescents with Chronic Fatigue Syndrome of average duration 18 months. There was also a significant improvement for both groups from the beginning of the trial to the six month post infusion follow-up. Adverse effects were common with both solutions but not predictive of response. Neither solution could be identified by recipients.

Source: Rowe KS. Double-blind randomized controlled trial to assess the efficacy of intravenous gammaglobulin for the management of chronic fatigue syndrome in adolescents. J Psychiatr Res. 1997 Jan-Feb;31(1):133-47. http://www.ncbi.nlm.nih.gov/pubmed/9201655

Double-blind placebo-controlled study of the efficacy of oral terfenadine in the treatment of chronic fatigue syndrome

Abstract:

BACKGROUND: There is no established treatment for chronic fatigue syndrome (CFS), an illness characterized by disabling fatigue exacerbated by physical activity. A variety of immunologic abnormalities have been reported, including a high incidence of atopy and hypoergy or anergy.

OBJECTIVE: Because of anecdotal reports and uncontrolled trials showing antihistamine efficacy in CFS, we evaluated the clinical efficacy of the antihistamine terfenadine (60 mg twice daily) in a placebo-controlled study.

METHODS: Thirty patients with CFS were enrolled in a 2-month, double-blind, placebo-controlled trial of terfenadine. Participants underwent a battery of both immediate- and delayed-type hypersensitivity skin tests and completed a self-assessment questionnaire used to measure severity of symptoms, physical and social functioning, health perceptions, and mental health before each of six biweekly visits.

RESULTS: Twenty-eight patients completed the trial. History of atopy and positive immediate skin test results were prevalent, 73% and 53%, respectively. No evidence for hypoergy or anergy after delayed-type hypersensitivity skin testing was found. No therapeutic benefit from terfenadine could be detected in terms of symptom amelioration, improved physical or social functioning, health perceptions, or mental health. A high incidence of atopy in patients with CFS was confirmed.

CONCLUSION: Although this trial involved a small number of patients, the results suggest that terfenadine is unlikely to be of clinical benefit in treating CFS symptoms.

Source: Steinberg P, McNutt BE, Marshall P, Schenck C, Lurie N, Pheley A, Peterson PK. Double-blind placebo-controlled study of the efficacy of oral terfenadine in the treatment of chronic fatigue syndrome. J Allergy Clin Immunol. 1996 Jan;97(1 Pt 1):119-26. http://www.ncbi.nlm.nih.gov/pubmed/8568124

Immunological and psychological dysfunction in patients receiving immunotherapy for chronic fatigue syndrome

Abstract:

Associations between immunological and psychological dysfunction in 33 patients with Chronic Fatigue Syndrome (CFS) were examined before and in response to treatment in a double blind, placebo-controlled trial of high dose intravenous immunoglobulin. Only those patients who received active immunotherapy demonstrated a consistent pattern of correlations between improvement in depressive symptoms and markers of cell-mediated immunity (CMI).

This finding lends some support to the hypothesis that depressive symptoms in patients with CFS occur secondary to, or share a common pathophysiology with, immunological dysfunction. This pattern and the lack of strong associations between depression and immunological disturbance prior to treatment are less supportive of the view that CFS is primarily a form of depressive disorder or that immunological dysfunction in patients with CFS is secondary to concurrent depression.

Source: Hickie I, Lloyd A, Wakefield D. Immunological and psychological dysfunction in patients receiving immunotherapy for chronic fatigue syndrome. Aust N Z J Psychiatry. 1992 Jun;26(2):249-56. http://www.ncbi.nlm.nih.gov/pubmed/1642616