Table 2.
Summary of studies on new antiepileptic drugs (n=39).
| Authors | Type of study (class of evidence) | N | Population | Type of therapy (AED dose) | Dose (per day) | Comparison | Significative PSG results (mean ± SD) |
|
|---|---|---|---|---|---|---|---|---|
| Felbamate | Marciani et al. (1998)58 | Case report (class IV) | 1 | Lennox-Gastaut syndrome | Acute add-on therapy | 1,800mg | NA |
After 4 months: 4/Phase shifts: in FEL (21.4) vs. baseline (41.8) No. of Awakenings: in FEL (17) vs. baseline (43) 4/Stage N1 (%): in FEL (39.9) vs. baseline (54.5) WASO(%): in FEL (16) vs. baseline (18.6) |
| Gabapentin | Rao et al. (1988)62 | Double-blind, placebo- controlled, randomized crossover (class I) | 6 | Healthy adults | Acute monotherapy | 1st day: placebo 2nd day: GBP 300mg 3rd day: GBP 600mg |
Placebo |
Deep sleep latency: in GBP was decreased to 70% vs. controls*
SWS: was increased to 120% in GBP vs. controls* |
| Placidi et al (2000)24 | Prospective, non- randomized (class III) | 18 | Drug resistant epilepsy focal cryptogenic (n=12) Focal symptomatic (n=6) |
Acute add-on therapy | 1,800-2,400mg/day | NA |
4-months vs. baseline: Stage N1: in GBP (9.7±4.2) vs. baseline (14.4±3.2)** * •fSWS(%): in GBP (17.1±6.5) vs. baseline (14.4±5.0)* •fREM(%): in GBP (14.7+5.5) vs. baseline (11.1+3.1)** * No. of awakenings: in GBP (13.9±7.4) vs. baseline (21.6±11.0)** * |
|
| Foldvary- Schaefer et al. (2002)59 | Prospective, non- randomized, open label (class III) | 19 | Healthy adults | Acute monotherapy | 300-1,800mg | Healthy controls (n=9) |
GBP group (n=10): •fSWS(%): in GBP (13.0+0.07) vs. baseline (8.0±0.05)** |
|
| Lo et al. (2010)64 | Open-label (class IV) | 18 | Primary insomnia | Acute monotherapy | Mean dose = 540mg (200 900mg) | NA |
After 4 weeks of GBP treatment: •fSE (%): in GBP (87.17+11.37) vs. baseline (80.00±14.79)* - WASO (min): in GBP (7.84+9.92) vs. placebo (16.45±14.78)* •fSWS (%): in GBP (17.68+9.88) vs. baseline (10.47±9.86)** * |
|
|
Madani et al.
(2012)15 |
Single-blind, randomized clinical trial (class II) | 20 GBP group (n=10) | PSG documented sleep bruxism | Acute monotherapy | 100mg during 3 nights 200mg the next 3 nights 300mg from the 6th week to 2 months | Stabilization splint |
Before treatment: •fstage N3 (%) in GBP (18.1+2.6) vs. splint group (15.7±2.5) at baseline Versus baseline: •fTST (min): in GBP (441.7+45.0) vs. baseline (382±40.9) •NREM Sleep latency (min): in GBP (10.9+9.9) vs. baseline (24.2±14.1) f SWS (%): in GBP (20.9+4.0) vs. baseline (18.1±2.6) f SE (%): in GBP (93.1+3.9) vs. baseline (86.3±4.8) |
|
| Furey et al. (2014)61 | 5-hour sleep advance, randomized, double-blind, placebo-controlled, multicenter (class I) | 237 | Adults with sleep complaints | Acute monotherapy | 250mg | Placebo (n=115) | Gabapentin (n=122) Day 1: •fTST (min): in GBP (347.6±7.5) vs. placebo (283.9±9.8)** *WASO (min): in GBP (107.0±7.3) vs. placebo (149.1±9.6)**Stage N1 (%): in GBP (12.3+0.6) vs. placebo (15.7+1.1)* Day 28: •fTST (min): WASO (min): in GBP (113.6±8.1) vs. placebo (152.3±9.3)** REM (%): in GBP (15.6±0.5) vs. placebo (13.6±0.6)* |
|
| Rosenberg et al. (2014)60 | Randomised, double-blind, multicenter clinical trial (class I) | Placebo (n=124) 250mg (n=124) 500mg (n=125) |
Adults with sleep complaints | Acute monotherapy | 250 or 500mg groups | Placebo |
•fTST (min): in 500mg (378.7±7.3)**
* or 250mg (356.5±7.3)**
* vs. placebo (311.4±8.4) WASO (min): in 500mg (73.2±5.8)**
* or 250mg (100.7±6.6)**
* vs. placebo (135.7±7.0) Stage N1 (min): in 500mg (10.8±0.7)**
* or 250mg (11.8±0.7)**
* vs. placebo (15.1±1.0) •fSWS (%) in 500mg (17.0±1.1)** * or 250mg (15.4±1.0)* vs. placebo (12.6±0.9) |
|
| Piovezan et al. (2017)63 | double-blind, randomized, placebo- controlled crossover pilot study (class II) | 8 | Healthy men (>60 years old) | Acute monotherapy | 300mg | Placebo | No significative changes in objective sleep parameters were found. | |
| Lacosamide | Hudson et al. (2015)67 | Multicenter, interventional, open-label study (class III) | 25 | Healthy adults | Monotherapy | 300mg | NA | No significative changes in objective sleep parameters were found. |
| Foldvary- Schaefer et al. (2017)66 | Phase IV randomized, controlled, double blind, single center trial (class I) | 52 | Focal epilepsy | Acute adjunctive | 400mg | Placebo (n=10) |
Comparison between LAC (n=42) and placebo (n=10) at baseline Arousal Index: in LAC [6.1(4.9-8.4)] vs. placebo [10.3 (7.0-13.7)]*Comparison between LAC (n=35) and baseline at follow-up Arousal Index: in LAC-5.0 [-14.0, 3.0] vs. baseline*
values expressed in median (P25-P75) |
|
| Lamotrigine | Placidi et al. (2000)20 | Prospective, uncontrolled, non-randomized (class III) | 13 | Drug-resistant | Acute adjunctive | 200mg | NA |
REM (%): in LTG (13.3+6.0) vs. baseline (8.5±4.3)**
SWS (%): in LTG (12.4+6.0) vs. baseline (17.8±6.1)* No. of entries in REM: in LTG (36.0±27.0) vs. baseline (16.0±12.0)* No. of phase shifts: in LTG (38.0±11) vs. baseline (32.0±11.0)* |
| Foldvary et al. (2001)68 | Prospective, uncontrolled, non-randomized (class III) | 10 | Focal epilepsy | Acute adjunctive Chronic monotherapy: CBZ (n=7); PHT (n=3) | 400mg | NA |
•fStage N2 (%): in LTG (57.5) vs. baseline (50.9)*
SWS (%): in LTG (13.0) vs. baseline (20.2)* Authors did not present standard deviation. Results in (mean). |
|
| Levetiracetam | Bell et al. (2002)6 | Double-blind, randomized crossover (class I) | N=12 volunteers N=16 patients |
Study 1: healthy volunteers; Study 2: focal epilepsy on carbamazepine monotherapy | Adjunctive | 1,000mg | Placebo | Study 1 (n=12): •fStage N2 (min): on LEV (270.0±34.2) vs. placebo (235.0±45.5) •fREM latency (min): on LEV (121.3±70.0) vs. placebo (69.8±) Study 2 (n=16): •fStage N2 (min): on LEV (231.0+33.6) vs. placebo (174.0+21.9) Stage N4 (min): on LEV (58.0±30.1) vs. placebo (72.0±27.2) |
| Bazil et al. (2005)18 | Randomised prospective (class II) | 12 | Healthy | Monotherapy | 3 days 500mg, 3 days 1,000mg, 3 days 1,500mg and 3 days 2,000mg |
Placebo | No. of awakenings in follow-up LVT (17.00+1.60) vs. placebo (8.00+1.80)* | |
| Cicolin et al. (2006)71 | Double-blind crossover (class I) | 14 | Healthy volunteers | Acute monotherapy | Up to 2,000mg/day | Placebo |
•fTST (min): in LEV (391.44+30.58) vs. placebo (363.72+40.04)**
•fSE (%): in LEV (92.78+1.10) vs. placebo (90.61+1.47)** •fStage N2 (min): in LEV (253.09+23.61) vs. placebo (228.22+30.02)** * •fStage N4 (min): in LEV (23.18+3.58) vs. placebo (16.28+3.91)** * WASO (min): in LEV (12.71+1.44) vs. placebo (18.00+4.76)** •fStage N2 (%): in LEV (64.67+3.66) vs. placebo (62.71+3.83)** * •fStage N4 (%): in LEV (5.92+0.77) vs. placebo (4.47+0.89)** *REM(%): in LEV (14.99+2.59) vs. placebo (17.55+3.59)**WASO (%): in LEV (3.26+0.39) vs. placebo (4.97+1.24)** Stage shifts (No.): in LEV (66.00+4.42) vs. placebo (73.50+7.01)** * MSLT: No significant changes were detected. |
|
| Yilmaz et al. (2007)72 | 22 | Complex focal epilepsy | Chronic monotherapy (n=10); Chronic add-on therapy (n=12) |
2,000mg/day | Control group (n=20) |
Measured by actigraphy and MWT After 3 weeks of LEV monotherapy: xVTotal activity score (no./night): in LEV (7779+7861) vs. baseline (9840+7323)**Daytime napping episodes (no./day): in LEV (3.45+1.80) vs. baseline (2.44+0.42)**“TTotal nap duration (min/day): in LEV (38.00+8.23) vs. baseline (23.00+3.90)** |
||
| Zhou et al. (2012)27 | Prospective, nonrandomized (class III) Observational prospective (class III) |
20 | Focal epilepsy without sleep disorders | Monotherapy (n=4) Adjunctive (n=6) | 1,000mg/day | Healthy volunteer controls (n=10) |
After 3 weeks of LEV as add-on: Total activity score (number/night): in LEV (5980+8200) vs. baseline (9840+7323)*Daytime napping episodes (no./day): in LEV (6.70+1.20) vs. baseline (2.44+0.42)*“TTotal nap duration (min/day): in LEV (59.00+9.32) vs. baseline (23.00+3.90)* 1 week LEV (n=10) vs. controls (n=10): REM latency (min): in LEV (176.94+94.43) vs. controls (98.75+60.97)* 1 week LEV (n=10) vs. Baseline (n=10): REM (min): in LEV (59.55+33.27) vs. baseline (71.45+37.12)* REM (%): in LEV (13.29+6.80) vs. baseline (15.67+7.26)* MSLT: No significant changes were detected. |
|
| Perampanel | Gonzalez- Cuevas et al. (2016)73 | Prospective, non- interventional (class III) | 10 | Focal epilepsy | Adjunctive | 4mg | NA |
MWT (n=10): No statistically significant differences were found in objective sleep parameters. |
| Garcia- Borreguero et al. (2017)74 | 20 | Idiopathic RLS | Monotherapy | 2mg (increased to 4mg in week 4 if necessary) | NA | •fTST (min): in PMP (364.64+44.42) vs. baseline (329.85+39.30)*Sleep latency (min): in PMP (20.68+5.10) vs. baseline (32.60+13.10)*Sleep efficiency(%): in PMP (85.64+5.22) vs. baseline (73.02+7.43)** * | ||
| Prospective, open trial (class III) | Mean: 3.8mg/day |
WASO (min): in PMP (39.99+19.41) vs. baseline (89.25±26.12)**
*
•fArousal Index: in PMP (25.06+6.33) vs. baseline (37.29+12.58)** Stage N1 (min): in PMP (57.59+19.46) vs. baseline (73.10+19.86)* •f Stage N3 (min): in PMP (52.00+10.94) vs. baseline (29.45+18.40)** Stage N1 (%): in PMP (16.13+5.66) vs. baseline (22.40+6.44)** •fStage N3 (%): in PMP (14.40+3.04) vs. baseline (8.90+5.45)** REM latency (min): in PMP (86.55+20.72) vs. baseline (115.20+36.65)** PLM: in PMP (2.53+0.85) vs. baseline (3.03+0.86)* PLM index: in PMP (4.36+2.00) vs. baseline (27.76+6.75)** * |
||||||
| Rocamora et al. (2020)75 | Prospective open- label pilot study (class III) | 17 | Refractory epilepsy | Adjunctive | 2mg/day increased by 2mg after 2 weeks and then monthly until the target dose of 4-8mg/ day. | NA |
In all patients group (n=17) •fTST (min): in PMP (399.8 + 52.2) vs. baseline (362.8 + 47.1 min)* •fSleep efficiency(%): in PMP (91.9 + 7.8) vs. baseline (85.3 + 7.7)** WASO (min): in PMP (39.7 + 36.6) vs. baseline (63.2 + 34.1)** •fStage N3 (%): in PMP vs. baseline. Mean presented in a graphic** In normal sleep parameters at baseline subgroup (n= 8) •fSleep latency (min): in PMP (6.2 + 5.7) vs. baseline (15 + 6.9)* In pathological sleep parameters at baseline subgroup (n= 9) •fSleep maintenance index (%): in PMP (92.6 + 4.7) vs. baseline (84.4+7.5)** |
|
| Hindmarch et al. (2005)76 | Randomized, double-blind, placebo and active-controlled, 3-way crossover (class I) | 24 | Healthy adults | Acute monotheraphy | 450mg | Placebo and alprazolam |
Means of nights 2, 3, 4: SL (min): in PGB (6.83±5.55) vs. placebo (13.95+10.78) •fSE (%): in PGB (96.11+2.13) vs. placebo (90.62+5.07) •fTST (min): in PGB (461.73+10.22) vs. placebo (435.55+24.39) No. of awakenings (<1min): in PGB (7.88+4.43) vs. placebo (17.45+6.38) No of awakenings (>1min): in PGB (1.30+1.50) vs. placebo (3.84+3.34) •fSWS (%) in 1st third: in PGB (66.63+10.35) vs. placebo (46.65+12.97) •fSWS(%) in 2nd third: in PGB (31.11+14.89) vs. placebo (19.64+10.04) •fSWS(%) in 3rd third: in PGB (16.92+10.8) vs. placebo (10.8+8.61) |
|
| Haas et al. (2007)5 | Randomised, double-blind, placebo- controlled (class II) | 15 (PGB n=8) | Focal epilepsy + subjective sleep disturbance | Adjunctive | 300mg | Placebo (n=7) |
After 4 weeks, in-home PSG: 4/No. of awakenings: in PGB (2.8+5.1) vs. placebo (5.4+3.5)* •fSleep efficiency (%): in PGB (87.1+8.9) vs. baseline (80.6+13.6)** WASO (min): in PGB (15.1+29.5) vs. baseline (50.5+41.6)* No. of awakenings: in PGB (2.8+5.1) vs. baseline (6.0+4.6)* |
|
| Romigi et al. (2009)23 | Prospective, single-blind, uncontrolled (class III) | 12 | Focal epilepsy | Adjunctive | Individualized (150-375mg/day) | NA |
After 3-months of PGB: Stage 2 (%): in PGB (54.08 + 12.21) vs. baseline (60.44+7.34) •fREM(%): in PGB (16.57+7.43) vs. baseline (10.58+6.44) |
|
| Pregablin | Garcia- Borreguero et al. (2010)79 | Randomized, double-blind, placebo- controlled (class I) | 58 | Idiopathic RLS | Acute monotheraphy | Mean dose: 337mg/day | Placebo (n=28) |
PGB (n=30) on week 12: •fSE: in PGB (85.67+15.42) vs. baseline (77.71+16.67) vs. placebo (75.76±19.88)** * WASO: in PGB (27.18+24.16) vs. baseline (54.71+36.32) vs. placebo (73.46+63.17)** •fStage N3: in PGB (60.62+55.16) vs. baseline (46.29+35.83) vs. placebo (35.23+27.01)* •fStage N4: in PGB (56.04+49.34) vs. baseline (38.79+35.72) vs. placebo (39.78+35.37)** * |
| Bazil et al. (2012)80 | Prospective, randomised, double-blind, crossover (class II) | 9 | Focal epilepsy + insomnia | Adjunctive | 300mg | Placebo |
SWS increased with PGB 4.1+2.5% vs. Baseline, compared with a drop with placebo of 2.0+1.8% vs. baseline*
\p Stage N1: check figure in reference for details.* |
|
| Roth et al. (2012)78 | Randomized, double-blind, placebo- controlled, 2- treatment, 2- period, crossover (class I) |
102 | Fibromyalgia + sleep disturbance | Acute monotherapy | 300-450mg/day | Placebo |
After 8 weeks PGB: •fTST (min): in PGB (396.2+4.7) vs. placebo (370.6+4.7)**WASO (min): in PGB (51.5+3.8) vs. placebo (70.7+3.8)** *Sleep latency (min): in PGB (34.5+3.7) vs. placebo (41.6+3.7)* •fSE (%): in PGB (82.6+0.98) vs. placebo (77.2+0.97)** * •fSWS (%): in PGB (17.2+1.0) vs. placebo (15.0+1.0)** * |
|
| Garcia- Borreguero et al. (2013)77 | Randomizes, double-blind, 3-way crossover (class II) |
75 | RLS | Acute monotherapy | 300mg | Placebo and pramipexole |
After 4 weeks of PGB: WASO (min): in PGB (51.5+4.2) vs. placebo (78.6+4.2)** * PLMAI, PLMA/hour: in PGB (3.9+0.7) vs. placebo (7.6+0.7)** * |
|
| Tiagabine | Mathias et al. (2001)81 | Double-blind, prospective (class I) | 10 | Healthy adults | Monotherapy | 5mg | Placebo |
•fSWS(%): in TGB (62.9±33.5) vs. placebo (32.8±20.0)*
^Sleep efficiency (%): in TGB (82.2±4.2) vs. placebo (78.1±5.7)* |
| Walsh et al. (2005)83 | Randomized, double-blind, Latin-square design (class I) | 22 | Healthy elderly | Monotherapy | 2, 4 and 8mg | Placebo |
2mg: no statistically significative differences were found vs placebo 4mg: •fTST (min): in TGB (407.7±33.4) vs. placebo (396.0±31.0)* WASO (min): in TGB (64.9+31.8) vs. placebo (77.2+31.9)* •fSWS (min): in TGB (59.7±39.1) vs. placebo (44.5±36.8)* 8mg: Stage N1 (min): in TGB (62.4±31.6) vs. placebo (81.3±34.6)** * •fSWS (min): in TGB (87.0±61.0) vs. placebo (44.5±36.8)** * REM (min): in TGB (58.4±18.1) vs. placebo (68.3±16.6)** SWS latency (min): in TGB (33.1±25.8) vs. placebo (51.0±35.3)** REM latency (min): in TGB (94.2±48.2) vs. placebo (71.8±30.2)** |
|
| Walsh et al. (2006)28 | Double-blind, randomized, parallel-group, dose-response study (class I) | 230 | Primary insomnia | Monotherapy | 4, 6, 8 and 10mg | Placebo (n=47) |
4mg (n=46): 4/Stage N1 (%): in TGB (33.6±19.0) vs. baseline (39.3±22.5)** 6mg (n=45): 4/Stage N1 (%): in TGB (25.6±16.8) vs. baseline (32.7±18.0)** * 8mg (n=45): |
|
|
Stage N1 (%): in TGB (27.2+18.2) vs. baseline (32.7+18.0)**
*
10mg (n=47): Significance is in change from baseline vs. placebo. |
||||||||
| Walsh et al. (2006)84 | Double-blind, randomized, five- period, Latin- square, crossover (class I) | 50 | Primary insomnia | Monotherapy | 4, 8, 12 and 16mg | Placebo |
4 mg (n=50): •fSWS(%): in TGB (10.2+1.3) vs. placebo (5.7+1.3)*REM(%): in TGB (18.5+0.6) vs. placebo (20.2+0.6)*8mg (n=50): Stage N1 (%): in TGB (8.2+0.6) vs. placebo (11.0+0.6)** •fSWS(%): in TGB (13.1+1.3) vs. placebo (5.7+1.3)*REM(%): in TGB (16.8+0.6) vs. placebo (20.2+0.6)** *12mg (n=50): Stage N1 (%): in TGB (7.3+0.6) vs. placebo (11.0+0.6)** * Stage N2 (%): in TGB (58.9+1.1) vs. placebo (63.2+1.1)** •fSWS(%): in TGB (20.0+1.3) vs. placebo (5.7+1.3)** *REM(%): in TGB (13.8+0.6) vs. placebo (20.2+0.6)** *16 mg (n=50): WASO (min): in TGB (55.9+3.9) vs. placebo (66.9+3.9)*Stage N1 (%): in TGB (7.8+0.6) vs. placebo (11.0+0.6)*Stage N2 (%): in TGB (53.6+1.1) vs. placebo (63.2+1.1)** * •fSWS(%): in TGB (27.5+1.3) vs. placebo (5.7+1.3)** * REM(%): in TGB (11.1+0.6) vs. placebo (20.2+0.6)* |
|
| Walsh et al. (2006)82 | Radomized, double-blind, parallel-groups (class I) | 38 | Healthy volunteers | Monotherapy | 8mg | Placebo |
Night 2 versus mean of nights 3-6 SWS: More [29.1 (± 23.8)] minutes of SWS on nights 3 to 6 compared to baseline vs. placebo [5.4 (± 22.1)] fewer minutes compared to baseline. |
|
| Roth et al. (2006)85 | Radomized, double-blind, parallel-groups (class I) | 207 | Elderly with primary insomnia | Monotherapy | 2, 4, 6, 8mg | Placebo (n=38) |
2mg (n=42): no significative changes from baseline vs. placebo 4mg (n=38): Stage N1 (min): in TGB (31.2+2.8) vs. placebo (39.1+3.1)* SWS(min): in TGB (44.2+5.6) vs. placebo (35.2+4.4)* 6mg (n=45): Stage N1 (min): in TGB (29.7+2.6) vs. placebo (39.1+3.1)*SWS(min): in TGB (72.2+7.9) vs. placebo (35.2+4.4)*REM (min): in TGB (50.6+3.0) vs. placebo (63.7+2.9)* No. 30s-awakenings: in TGB (30.6+1.3) vs. placebo (35.4+1.8)* •fRatio SWS/(Stage N1+WASO) (%):: in TGB (0.9+0.21) vs. placebo (0.3+0.005)* |
|
|
8mg (n=41): Stage N1 (min): in TGB (30.5+3.2) vs. placebo (39.1+3.1)*SWS(min): in TGB (70.0+8.3) vs. placebo (35.2+4.4)*REM (min): in TGB (44.5+3.8) vs. placebo (63.7+2.9)* No. 30s-awakenings: in TGB (32.2+1.8) vs. placebo (35.4+1.8)* •fRatio SWS/(Stage 1+WASO) (%):: in TGB (0.6+0.1) vs. placebo (0.3+0.005)* |
||||||||
| Feld et al. (2013)86 | Randomised, double-blind, crossover (class I) | 12 | Healthy adults (only men) | Monotherapy | 10mg | Placebo |
Stage N1 (%): in TGB (4.23+1.16) vs. placebo (8.44+1.08)**
•fSWS (%): in TGB (24.30+3.34) vs. placebo (17.51+0.89)** REM(%): in TGB (12.37+2.14) vs. placebo (17.51+0.89)* |
|
| Taranto- Montemurro et al. (2017)87 | placebo- controlled, double-blind, crossover trial (class I) | 12 | Obstructive apnea | Monotherapy | 12mg | Placebo | No significative differences were found vs. placebo. | |
| Topiramate | Bonnani et al. (2004)88 | Prospective, non- randomized, non- blind (class III) | 14 | Focal epilepsy | Monotherapy | 200mg/day | 14 healthy controls |
After 2 months of TPM: Sleep parameters in PSG reported no significative changes. MSLT scores did not significantly change in patients as compared with pretreatment values. |
| Zonisamide | Romigi et al. (2013)90 | Open-label prospective (class III) | Baseline (n=12) Follow-up 3 months (n=12) |
Focal epilepsy | Adjunctive | 200-300mg/day | NA | No. Of awakenings in ZNS (12.72+10.65) vs. baseline (9.55±5.65)* |
| Eskandari et al. (2014)89 | Randomised, double-blind, parallel study with open extension phase (class II) | 47 (ZSM, n=22) | OSA | Adjunctive | 300mg | NA | Sleep-related variables at 4 weeks: no significative changes. |
Abbreviations: FEL = Felbamate; GBP = Gabapentin; LAC = Lacosamide; LTG = Lamotrigine; LEV = Levtircetam; PMP = Perampanel; PGB = Pregabalin; TGB = Tiagabine; TPM = Topiramate; ZNS = Zonisamide.
*
p<0,05;
**
p>0,01;
***
p<0,001.