Table 2. Primary and secondary clinical endpoints after two weeks of nVNS and sham treatment.
| Primary clinical endpoints | Pain diary | |||||||
| Variables | Sequence | Treatment period Mean±SD | Within-individual differences for nVNS vs. sham | Treatment effect for nVNS vs. sham (95% CI) | P (effect) | P (carry-over) | ||
| 1 | 2 | |||||||
| Average pain score (VAS) | nVNS/sham | 2.9±1.8 | 2.2±2.1 | 0.34±0.61 | 0.17 (-0.86:1.20) | 0.72 | 0.49 | |
| sham/nVNS | 3.6±2.5 | 3.3±2.4 | -0.17±0.88 | |||||
| Maximal pain score (VAS) | nVNS/sham | 4.1±2.3 | 3.4±2.7 | 0.34±0.77 | 0.20 (-1.14:1.54) | 0.76 | 0.56 | |
| sham/nVNS | 4.6±2.6 | 4.4±2.5 | -0.15±1.15 | |||||
| Secondary clinical endpoints | Brief Pain Inventory questionnaire | |||||||
| BPI Pain | nVNS/sham | 3.1±2.1 | 2.8±2.5 | 0.1±0.4 | 0.19 (-1.11:1.48) | 0.76 | 0.40 | |
| sham/nVNS | 3.9±2.2 | 4.0±2.4 | 0.1±1.2 | |||||
| BPI Interference | nVNS/sham | 2.0±1.2 | 2.1±1.1 | -0.1±0.2 | -0.006 (-1.17:1.15) | 0.99 | 0.13 | |
| sham/nVNS | 3.8±2.1 | 3.9±2.6 | 0.0±1.0 | |||||
| Quality of life | ||||||||
| Global health status | nVNS/sham | 64.6±19.7 | 66.7±22.6 | -1.0±4.0 | -1.04 (-13.1:11.0) | 0.86 | 0.13 | |
| sham/nVNS | 50.7±15.7 | 50.7±20.2 | 0.0±10.8 | |||||
| Physical functioning | nVNS/sham | 86.7±34.9 | 78.3±14.8 | 4.2±17.3 | 4.44 (-7.3:16.2) | 0.43 | 0.04 | |
| sham/nVNS | 59.4±18.1 | 60.0±17.3 | 0.3±5.8 | |||||
| Role functioning | nVNS/sham | 83.3±16.7 | 79.2±16.0 | 0.0±8.3 | 3.5 (-7.2:14.1) | 0.49 | 0.08 | |
| sham/nVNS | 50.0±24.6 | 56.9±28.8 | 3.5±7.5 | |||||
| Emotional functioning | nVNS/sham | 81.3±14.2 | 81.3±14.2 | 0.0±3.4 | -1.7 (-13.5:10.0) | 0.76 | 0.09 | |
| sham/nVNS | 65.3±20.4 | 61.8±21.2 | -1.7±10.6 | |||||
| Cognitive functioning | nVNS/sham | 83.3±19.2 | 87.5±16.0 | -2.1±4.2 | -2.1 (-12.7:8.5) | 0.68 | 0.02 | |
| sham/nVNS | 55.6±25.9 | 55.6±17.9 | 0.0±9.4 | |||||
| Social functioning | nVNS/sham | 83.3±19.2 | 87.5±16.0 | -2.1±4.2 | -4.2 (-16.2:7.9) | 0.47 | 0.15 | |
| sham/nVNS | 66.7±23.6 | 62.5±30.3 | -2.1±10.7 | |||||
| Fatigue | nVNS/sham | 29.6±17.0 | 22.2±18.1 | 7.4±3.2 | 6.5 (-7.5:20.5) | 0.34 | 0.16 | |
| sham/nVNS | 45.4±20.9 | 43.5±30.9 | -0.9±10.8 | |||||
| Nausea and vomiting | nVNS/sham | 0.0±0.0 | 0.0±0.0 | 0.0±0.0 | 1.4 (-8.0:10.8) | 0.76 | 0.19 | |
| sham/nVNS | 5.6±8.2 | 8.3±16.7 | 1.4±8.6 | |||||
| Pain | nVNS/sham | 45.8±25.0 | 33.3±13.6 | 6.2±8.0 | 4.2 (-13.1:21.4) | 0.61 | 0.12 | |
| sham/nVNS | 59.7±21.9 | 55.6±25.9 | -2.1±15.1 | |||||
| Dyspnoea | nVNS/sham | 0.0±0.0 | 16.7±19.2 | -5.6±9.6 | -6.9 (-24.7:10.8) | 0.41 | 0.28 | |
| sham/nVNS | 22.2±25.9 | 19.4±26.4 | -1.4±13.2 | |||||
| Insomnia | nVNS/sham | 11.1±19.2 | 16.7±33.3 | 5.6±9.6 | 6.9 (-25.7:39.5) | 0.65 | 0.06 | |
| sham/nVNS | 38.9±37.2 | 41.7±37.9 | 1.4±25.1 | |||||
| Appetite loss | nVNS/sham | 22.2±19.2 | 8.3±16.7 | 11.1±9.6 | 13.9 (0.5:27.3) | 0.04 | 0.37 | |
| sham/nVNS | 27.8±34.3 | 33.3±37.6 | 2.8±9.6 | |||||
| Constipation | nVNS/sham | 0.0±0.0 | 0.0±0.0 | 0.0±0.0 | 0.0 (-15.6:15.6) | 1.00 | 0.29 | |
| sham/nVNS | 13.9±30.0 | 13.9±26.4 | 0.0±14.2 | |||||
| Diarrhoea | nVNS/sham | 16.7±19.2 | 8.3±16.7 | 4.2±8.3 | -2.8 (-15.9:10.4) | 0.66 | 0.22 | |
| sham/nVNS | 41.7±32.2 | 27.8±37.2 | -6.9±11.1 | |||||
| Financial difficulties | nVNS/sham | 16.7±19.2 | 25.0±16.7 | -4.2±8.3 | 0.0 (-12.3:12.3) | 1.00 | 0.29 | |
| sham/nVNS | 30.6±22.3 | 38.9±27.8 | 4.2±10.4 | |||||
| Secondary experimental endpoints | Cardiac-derived parameters | |||||||
| Cardiac vagal tone (LVS) | nVNS/sham | 6.1±3.8 | 5.3±4.5 | 0.4±0.7 | 0.5 (-0.3:1.2) | 0.18 | 0.48 | |
| sham/nVNS | 4.6±1.9 | 4.7±1.9 | 0.1±0.5 | |||||
| Heart rate (beats/min) | nVNS/sham | 65.5±20.1 | 72.3±20.8 | -3.4±2.8 | -3.66 (-6.7:-0.6) | 0.02 | 0.39 | |
| sham/nVNS | 63.5±8.5 | 62.9±5.3 | -0.3±2.4 | |||||
Note: Comparisons between nVNS and sham treatments for the two treatment periods shown by treatment sequence (nVNS/sham, n = 4 and sham/nVNS, n = 12). The difference in pain intensities between the two treatment sequences were calculated for each patient and compared using a t-test for independent samples. One patient had missing data for role functioning, fatigue, dyspnoea, insomnia and appetite loss and one patient had missing data for cardiac vagal tone.
Abbreviations: VAS = visual analogue scale. SD = standard deviation. CI = confidence interval. nVNS = non-invasive vagal nerve stimulation. LVS = linear vagal scale. N = number of patients.