Table 3. Effects of non-pharmaceutical and pharmaceutical treatment of Raynaud’s phenomenon (RP).

Treatment	Type of study Patient number	Raynaud’s attacks
Publication		Number of attacks	Duration	Severity of attacks
Form of RP
Low-level laser	Placebo-controlled, double-blind crossover study; n = 48 patients	Laser treatment: reduction in RP from 2.5 ± 1.5 attacks per day to 1.6 ± 1.0; (−36% compared to baseline); sham treatment: reduction from 2.1 ± 1.2 to 2.0 ± 1.2; (−4.8 % compared to baseline); ARR: 0.31; NNT: 4	Not determined	Reduction on VAS (10 cm) from 3.2 ± 1.2 to 2.3 ± 1.0 (−28 % compared to baseline); control treatment: reduction from 2.9 ± 1.2 to 2.8 ± 1.1; (−3.4% compared to baseline); ARR: 0.25; NNT: 4
Hirschl, 2004 (25)
Primary
Complementary. Use of galvanic current	Single-blinded randomized controlled study with parallel design; n = 34 patients	Reduction from 31.29 ± 21.02 attacks per week to 11.53 ± 8.55 following active treatment in week 7 (−63% compared to baseline) and further to 8.23 ± 9.97 at the end of the observation phase in week 15 (−74 % compared to baseline); increase in attacks in the control group from 25.11 ± 9.9 to 27.17 ± 8.16 in week 7 (+8% compared to baseline) and to 28.00 ± 7.83 in week 15 (+12% compared to baseline) ARR: 0.71; NNT: 2 (week 7) ARR: 0.86; NNT: 2 (week 15)	Not determined	Reduction on the VAS from 2.64 ± 2.22 to 1.66 ± 1.92 in week 7 (−37 % compared to baseline) and further to 2.59 ± 2.64 in week 15 (−2 % compared to baseline); increase in the control group from 3.60 ± 2.58 to 4.4 ± 2.66 in week 7 (+22 % compared to baseline) and further to 4.79 ± 2.33 in week 15 (+33 % compared to baseline) ARR: 0.59; NNT: 2 (week 7) ARR: 0.35; NNT: 3 (week 15)
Tapia-Haro, 2020 (26)
Primary and secondary
Calcium alcium channel blockers (primarily nifedipine)	Meta-analysis of 23 randomized controlled studies; n = 528 patients	MWD –6.13 (−6.60 to –5.67) attacks per week (−45 % compared to control group); after exclusion of an older study that showed an overproportionately positive effect, the MWD was only –2.93 (−3.44 to –2.43) attacks per week (−21 % compared to control group); mean value for the control group (placebo) 13.7 attacks per week (no confidence interval given)	MWD –1.67 (−3.29 to 0) min (−9% compared to control group) mean value for the control group (placebo) 18.8 min (no confidence interval given)	MWD –0.62 (−0.72 to –0.51) on the VAS (10 cm); −9 % compared to the control group;mean value for the control group (placebo) 6.7 cm (no confidence interval given)
Rirash, 2017 (28)
Primary and secondary
Selective serotonin reuptake inhibitor fluoxetine	Prospective randomized crossover study over 16 weeks during the winter period with two 14-day washout periods;fluoxetine 20 mg/day versus nifedipine 40 mg/day; n = 53 patients	Cannot be reliably determined, since no numerical treatment effects and confidence intervals were given for the two treatment groups compared to the respective baseline value; the figures point to a decrease of around 1.3 attacks per day with fluoxetine from a baseline of 2.98 ± 0.31 attacks (–44%) and a decrease of around 0.5 attacks per day with nifedipine from a baseline of 2.72 ± 0.26 attacks per day (around –18%).	Not investigated	Cannot be reliably determined, since no numerical treatment effects and confidence intervals were given for the two treatment groups compared to the respective baseline value; the figures point to a difference of around –2 cm on VAS under fluoxetine from a baseline value of 4.35 ± 0.39 (about –46%) and a difference of about –0.8 cm under nifedipine from a baseline value of 3.82 ± 0.36 (about –21%).
Coleiro, 2001 (29)
Primary (n = 26) and secondary (n = 27)
Sartans (losartan)	Prospective controlled randomized parallel-group study over 15 weeks. Losartan 50 mg/day versus nifedipine 2 x 20 mg/day retarded with an initial 3-week washout period; n = 52 patients	Losartan: reduction from 3.52 ± 2.16 attacks to 1.96 ± 1.90 attacks per day (−44 % compared to baseline); nifedipine: increase from 3.65 ± 3.01 attacks to 4.40 ± 4.17 attacks per day (+21 % compared to baseline); ARR: 0.65; NNT: 2	Not determined	Losartan: reduction on VAS from 5.50 ± 2.46 to 2.84 ± 2.40 cm (−48% compared to baseline);nifedipine: reduction on VAS from 4.48 ± 2.40 to 3.90 ± 2.77 cm (−13 % compared to baseline); AAR: 0.35; NNT: 3
Dziadzio, 1999 (31)
Primary (n = 25) and secondary (n = 27) (systemic sclerosis)
Phosphodiesterase-5 inhibitors (sildenafil, vardenafil, tadalafin)	Systematic review and meta-analysis of 6 RCT; n = 244 patients	MWD –0.49 (–0.71 to –0.28) attacks per day (−19 % compared to baseline); baseline in the control groups (placebo) 2.64 ± 2.0 attacks per day	MWD –14.62 (–20.25 to –9.0) min per day (−28 % compared to baseline); baseline in the control groups (placebo) 51.87 ± 68.64 min per day	MWD –0.46 (–0.74 to –0.17) on the Raynaud Condition Score; (−13 % compared to baseline); baseline in the control group (placebo) 3.51 ± 2.34
Roustit, 2013 (32)
Secondary (91.8 % systemic sclerosis)
Prostanoids (iloprost)*	Meta-analysis of 7 RCT; n = 332 patients	Undeterminable; baseline in the control group not reported	MWD 0.0 (−7.28 to –7.28) min;baseline in the control group not reported	MWD –0.69 (−1.12 to –0.26) on the Raynaud Condition Score (when including a study of 11 patients and nine controls with an exceptionally strong treatment effect); baseline in the control group not reported
Pope 2000 (34)
Secondary (systemic sclerosis)
Prostanoids (cyclic iloprost)	12-Month prospective randomized single-blinded parallel-group study, 46 patients, Iloprost i. v. 2 μg/kg BW, min for 8 h on 5 consecutive days, followed by 1 infusion day every 6 weeks versus oral nifedipine retard 2 x 20 mg/day; n = 46 patients	Reduction in RP with iloprost from initially 2.17 ± 0.2 to 1.22 ± 0.13 attacks per day (−44% compared to baseline; under nifedipine, reduction from 2.08 ± 0.34 attacks per day to 1.33 ± 0.22 (−36% compared to baseline, ARR: 0.08; NNT: 13	Not determined	Not determined
Scorza 2001 (35)
Secondary (systemic sclerosis)

* The review included one study with cisaprost. Only results for iloprost compared to placebo are given, since cisaprost is not available.

MWD (mean weighted difference): effect measure for continuous endpoints. The MWD is pooled to describe the overall effect in meta-analyses.

In this context, individual studies are weighted differently, for example, due to the size of the study or other quality characteristics.

ARR, absolute risk reduction, and NNT, number needed to treat (1/ARR), were calculated from the published data; i. v., intravenous; BW, body weight; VAS, visual analog scale