| Outcomes | No of Participants (studies*) Follow up | Quality of the evidence (GRADE) | Relative effect (95% CI) | Anticipated absolute effects | |
|---|---|---|---|---|---|
| Risk with Control | Risk difference with Central nervous system stimulants (methylphenidate, modafinil, dexamphetamine, lisdexamphetamine) versus placebo (95% CI) | ||||
|
Quality of Life: SF36 physical total Scale from: 0 to 100. |
140 (2 studies) 4-6 weeks |
⊕⊕⊝⊝ due to indirectness, imprecision |
The mean quality of life: sf36 physical total at 4-6 weeks in the control groups was 51.2 |
The mean quality of life: sf36 physical total at 4-6 weeks in the intervention groups (methylphenidate or dexamphetamine) was 1.63 higher (4.11 lower to 7.37 higher) | |
|
Quality of Life: SF36 mental total Scale from: 0 to 100. |
140 (2 studies) 4-6 weeks |
⊕⊕⊝⊝ due to indirectness, imprecision |
The mean quality of life: sf36 mental total at 4-6 weeks in the control groups was 47.3 |
The mean quality of life: sf36 mental total at 4-6 weeks in the intervention groups (methylphenidate or dexamphetamine) was 3.51 higher (1.67 lower to 8.69 higher) | |
|
Quality of Life: SF36 vitality Scale from: 0 to 100. |
42 (1 study) 20 days |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean quality of life: sf36 vitality at 20 days in the control groups was 26.1 |
The mean quality of life: sf36 vitality at 20 days in the intervention group (modafinil) was 0.6 lower (15.95 lower to 14.75 higher) | |
|
Quality of Life: SF36 physical role limitation Scale from: 0 to 100. |
42 (1 study) 20 days |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean quality of life: sf36 physical role limitation at 20 days in the control groups was 21.4 |
The mean quality of life: sf36 physical role limitation at 20 days in the intervention group (modafinil) was 6.45 lower (26.66 lower to 13.76 higher) | |
|
Quality of Life: SF36 physical function Scale from: 0 to 100. |
42 (1 study) 20 days |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean quality of life: sf36 physical function at 20 days in the control groups was 53.6 |
The mean quality of life: sf36 physical function at 20 days in the intervention group (modafinil) was 1.6 lower (19.6 lower to 16.4 higher) | |
|
Quality of Life: SF36 mental health Scale from: 0 to 100. |
42 (1 study) 20 days |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean quality of life: sf36 mental health at 20 days in the control groups was 74.9 |
The mean quality of life: sf36 mental health at 20 days in the intervention group (modafinil) was 6.3 lower (16.26 lower to 3.66 higher) | |
|
Quality of Life: SF36 emotional role limitation Scale from: 0 to 100. |
42 (1 study) 20 days |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean quality of life: sf36 emotional role limitation at 20 days in the control groups was 95.2 |
The mean quality of life: sf36 emotional role limitation at 20 days in the intervention group (modafinil) was 19.3 lower (35.88 to 2.72 lower) | |
|
Quality of Life: SF36 pain Scale from: 0 to 100. |
42 (1 study) 20 days |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean quality of life: sf36 pain at 20 days in the control groups was 57.2 |
The mean quality of life: sf36 pain at 20 days in the intervention group (modafinil) was 2.45 lower (22.61 lower to 17.71 higher) | |
|
Quality of Life: SF36 social Scale from: 0 to 100. |
42 (1 study) 20 days |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean quality of life: sf36 social in the control groups was 43.7 |
The mean quality of life: sf36 social in the intervention group (modafinil) was 2.4 lower (21.85 lower to 17.05 higher | |
|
Quality of Life: general health Scale from: 0 to 100. |
42 (1 study) 20 days |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean quality of life: sf36 general health in the control groups was 49.2 |
The mean quality of life: sf36 general health in the intervention group (modafinil) was 0.4 lower (14.35 lower to 13.55 higher) | |
|
Fatigue: Checklist Individual Strength (CIS) total score Scale from: 20 to 140. |
248 (2 studies) 4-12 weeks |
⊕⊕⊝⊝ due to indirectness, imprecision |
The mean fatigue: checklist individual strength (cis) total score at 4-12 weeks in the control groups was 112.5 final score (Blockmans) |
The mean fatigue: checklist individual strength (CIS) total score at 4-12 weeks in the intervention groups (methylphenidate) was 7.12 lower (12.07 to 2.16 lower) | |
|
Fatigue: Fatigue Severity Scale Scale from: 9 to 63. |
44 (2 studies) 6 weeks |
⊕⊝⊝⊝ due to risk of bias, inconsistency, indirectness, imprecision |
The mean fatigue: fatigue severity scale at 6 weeks in the control groups was −2.5 |
The mean fatigue: fatigue severity scale at 6 weeks in the intervention groups (dexamphetamine or lisdexamphetamine) was 7.67 lower (21.75 lower to 6.4 higher) | |
|
Fatigue: Chalder Physical Fatigue scale Scale from: 0 to 21. |
42 (1 study) 20 days |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean fatigue: chalder physical fatigue scale at 20 days in the control groups was 13.6 |
The mean fatigue: chalder physical fatigue scale at 20 days in the intervention group (modafinil) was 0.25 lower (4.92 lower to 4.42 higher) | |
| Fatigue: Chalder Mental Fatigue scale S cale from: 0 to 12. |
42 (1 study) 20 days |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean fatigue: chalder mental fatigue scale at 20 days in the control groups was 7.4 |
The mean fatigue: chalder mental fatigue scale at 20 days in the intervention group (modafinil) was 0.4 higher (1.55 lower to 2.35 higher) | |
| Sleep quality: sleep latency (time taken to fall asleep in mins) |
20 (1 study) 6 weeks |
⊕⊝⊝⊝ due to indirectness, imprecision |
The mean sleep quality: sleep latency (time taken to fall asleep in mins) at 6 weeks in the control groups was 11.8 |
The mean sleep quality: sleep latency (time taken to fall asleep in mins) at 6 weeks in the intervention group (dexamphetamine) was 1.2 higher (2.91 lower to 5.31 higher) | |
|
Psychological status: HADS anxiety Scale from: 0 to 21. |
120 (1 study) 4 weeks |
⊕⊕⊕⊝ MODERATE1 due to indirectness |
The mean psychological status: hads anxiety at 4 weeks in the control groups was 7.7 |
The mean psychological status: hads anxiety at 4 weeks in the intervention group (methylphenidate) was 0.4 lower (1.74 lower to 0.94 higher) | |
|
Psychological status: HADS depression Scale from: 0 to 21. |
120 (1 study) 4 weeks |
⊕⊕⊕⊝ MODERATE1 due to indirectness |
The mean psychological status: hads depression at 4 weeks in the control groups was 8.7 |
The mean psychological status: hads depression at 4 weeks in the intervention group (methylphenidate) was 0.4 lower (1.93 lower to 1.13 higher) | |
|
Psychological status: Hamilton Anxiety Scale Scale from: 0 to 56. |
24 (1 study) 6 weeks |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean psychological status: hamilton anxiety scale at 6 weeks in the control groups was 6.18 improvement |
The mean psychological status: hamilton anxiety scale improvement at 6 weeks in the intervention group (lisdexamphetamine) was 5.13 higher (2.08 lower to 12.34 higher) | |
| Adverse events: AEs leading to discontinuation |
154 (2 studies) 6-12 weeks |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision | RR 2.91 (0.9 to 9.43) | 39 per 1000 |
75 more per 1000 (from 4 fewer to 333 more) (with methylphenidate or lisdexamphetamine) |
| Adverse events: Serious AEs (pyelonephritis) |
128 (1 study) 12 weeks |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision | Peto OR 7.63 (0.15 to 384.58) | 0 per 1000 |
20 more per 1000 (from 30 fewer to 60 more) (with methylphenidate) |
| Adverse events: sleepiness |
120 (1 study) 4 weeks |
⊕⊝⊝⊝ due to indirectness, imprecision | RR 0.91 (0.57 to 1.46) | 383 per 1000 |
34 fewer per 1000 (from 165 fewer to 176 more) (with methylphenidate) |
| Adverse events: dry mouth |
146 (2 studies) 4-6 weeks |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision | RR 1.9 (1.22 to 2.96) | 254 per 1000 |
228 more per 1000 (from 56 more to 497 more) (with methylphenidate or lisdexamphetamine) |
| Adverse events: dizziness |
120 (1 study) 4 weeks |
⊕⊕⊝⊝ due to indirectness, imprecision | RR 0.79 (0.57 to 1.08) | 633 per 1000 |
133 fewer per 1000 (from 272 fewer to 51 more) (with methylphenidate) |
| Adverse events: akathisia |
120 (1 study) 4 weeks |
⊕⊕⊝⊝ due to indirectness, imprecision | RR 0.85 (0.61 to 1.2) | 567 per 1000 |
85 fewer per 1000 (from 221 fewer to 113 more) (with methylphenidate) |
| Adverse events: abdominal pain |
120 (1 study) 4 weeks |
⊕⊝⊝⊝ due to indirectness, imprecision | RR 1.22 (0.8 to 1.85) | 383 per 1000 |
84 more per 1000 (from 77 fewer to 326 more) (with methylphenidate) |
| Adverse events: chest pain |
120 (1 study) 4 weeks |
⊕⊕⊝⊝ due to indirectness, imprecision | RR 0.68 (0.41 to 1.12) | 417 per 1000 |
133 fewer per 1000 (from 246 fewer to 50 more) (with methylphenidate) |
| Adverse events: anorexia |
20 (1 study) 6 weeks |
⊕⊕⊝⊝ due to indirectness, imprecision | RR 5 (0.7 to 35.5) | 100 per 1000 |
400 more per 1000 (from 30 fewer to 1000 more) (with dexamphetamine) |
| Adverse events: headache |
26 (1 study) 6 weeks |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision | RR 1.47 (0.15 to 14.21) | 91 per 1000 |
43 more per 1000 (from 77 fewer to 1000 more) (with lisdexamphetamine) |
| Adverse events: insomnia |
26 (1 study) 6 weeks |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision | Peto OR 5.66 (0.11 to 299.01) | 0 per 1000 |
70 more per 1000 (from 120 fewer to 250 more) (with lisdexamphetamine) |
| Adverse events |
42 (1 study) 20 days |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision | RR 1.31 (0.79 to 2.17) | 571 per 1000 |
177 more per 1000 (from 120 fewer to 669 more) (with modafinil) |
|
Cognitive function: Behaviour Rating Inventory of Executive Function (BRIEF), global executive composite Scale from: not reported. |
24 (1 study) 6 weeks |
⊕⊝⊝⊝ due to risk of bias, indirectness |
The mean improvement in cognitive function: behaviour rating inventory of executive function (brief), global executive composite at 6 weeks in the control groups was 3.36 |
The mean improvement in cognitive function: behaviour rating inventory of executive function (brief), global executive composite at 6 weeks in the intervention group (lisdexamphetamine) was 18.02 higher (8.39 to 27.65 higher) | |
|
Pain: McGill pain Questionnaire Scale from: 0 to 78. |
24 (1 study) 6 weeks |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean pain: mcgill pain questionnaire at 6 weeks in the control groups was 2.54 improvement |
The mean pain: mcgill pain questionnaire improvement at 6 weeks in the intervention group (lisdexamphetamine) was 7.84 higher (0.44 to 15.24 higher) | |
|
Symptom scales: Clinical Global Improvement - severity Scale from; 1 to 7. |
24 (1 study) 6 weeks |
⊕⊝⊝⊝ due to risk of bias, indirectness, imprecision |
The mean symptom scales: clinical global improvement - severity, at 6 weeks in the control groups was 0.64 improvement |
The mean symptom scales: clinical global improvement - severity, at 6 weeks in the intervention group (lisdexamphetamine) was 1.28 higher (0.3 to 2.26 higher) | |
The majority of the evidence included an indirect population (downgraded by one increment): downgraded if the ME/CFS diagnostic criteria used did not include PEM as a compulsory feature [original analysis]; percentage of participants with PEM unclear [PEM reanalysis – see Appendix G for additional details]
Downgraded by 1 increment if the confidence interval crossed one MID or by 2 increments if the confidence interval crossed both MIDs
Downgraded by 1 increment if the majority of the evidence was at high risk of bias, and downgraded by 2 increments if the majority of the evidence was at very high risk of bias
Heterogeneity, I2=86%, p=0.05, unexplained by subgroup analysis.
Studies included for CNS stimulants: methylphenidate – Blockmans 2006, Montoya 2018; modafinil – Randall 2005; dexamphetamine – Olson 2003; lis-dexamphetamine – Young 2013
From: Pharmacological interventions
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