Systematic review and network meta-analysis of the efficacy and safety of lidocaine 700 mg medicated plaster vs. pregabalin

Figures & data

Figure 1. PRISMA study flow chart.

Table 1. Study characteristics of 43 randomised controlled trials (see Figure 1).

Population	Main study ID	Arm name; maximum dose/number of plasters (sample size)	Age: mean (SD)	Male (%)	Mean baseline pain (SD) (scale type)	Follow-up weeks	Concomitant medications	Duration of pain/painful condition years (SD)
Diabetic peripheral neuropathy (DPN)	Arezzo 2008^16	Placebo/no treatment (n = 85)	58.3 (10.9)	52.9	6.58 (1.58) (NR)	13	No	4.4(3.7)
		Pregabalin; 600 mg (n = 82)	58.2 (9.6)	70.7	6.28 (1.47) (NR)	13	No	4.9(3.4)
	Baron 2009^17	Pregabalin; 600 mg (n = 106)	60.9 (8.8)	46.7	NR	4	No	4.5(3.9)
		LMP; 4 (n = 107)	60.9 (10)	42.9	NR	4	No	5.2(5)
	Eli Lilly 2010^18	Placebo/no treatment (n = 89)	55.32 (10)	58.4	NR	5	NR	NR
		Pregabalin; 300 mg (n = 45)	56.89 (8.19)	62.2	NR	5	NR	NR
	Huffman 2015^53*	Placebo/no treatment (n = 102)	58.4 (9.3)	69.6	NR	14	No	4.8(4.6)
		Pregabalin; 300  (n = 101)	59.1 (8.5)	60.4	NR	14	No	4.7(4.3)
	Jiang 2011^19	Placebo/no treatment (n = 20)	59.65 (12.5)	70	75.37 (12.9) (VAS)	4	NR	4.7(4.2)
		Pregabalin; 600 mg (n = 20)	55.1 (14.36)	55	70.78 (18.76) (VAS)	4	NR	10.1(11.5)
	Lesser 2004^20	Placebo/no treatment (n = 97)	57.8 (11.6)	60.8	6.6 (1.5) (NRS)	5	No	NR
		Pregabalin; 300 mg fixed (n = 81)	59 (9.2)	59.3	6.2 (1.4) (NRS)	5	No	NR
		Pregabalin; 600 mg (n = 82)	62 (9.7)	63.4	6.2 (1.5) (NRS)	5	No	NR
	Mu 2018^21	Placebo/no treatment (n = 309)	60.9 (9.5)	45.3	6.67 (1.15) (NRS)	11	No	2.4(NR)
		Pregabalin; 300 mg (n = 314)	60.2 (10.3)	49.2	6.65 (1.12) (NRS)	11	No	2.2(NR)
	Raskin 2014^56*	Placebo/no treatment (n = 147)	58.3 (10.5)	54.4	3 (1.4) (NRS)	13 (efficacy), 19 (safety)	No	5.8(NR)
		Pregabalin; 300 mg (n = 147)	58.8 (9.2)	51	3.1 (1.42) (NRS)	13 (efficacy), 19 (safety)	No	5.4(NR)
	Raskin 2016^57*	Placebo/no treatment (n = 147)	58.4 (9.5)	51	NR	14	No	3.2 (median)(NR)
		Pregabalin; 300 mg (n = 154)	59.4 (9.8)	57.8	NR	14	No	3.4 (median)(NR)
	Rauck 2013^22	Placebo/no treatment (n = 120)	60.1 (10.63)	61	6.49 (1.26) (NRS)	13	NR	NR
		Pregabalin; 300 mg (n = 66)	57.7 (10.59)	52	6.51 (1.27) (NRS)	13	NR	NR
	Richter 2005^23	Placebo/no treatment (n = 85)	57.1 (10.3)	54	6.9 (1.6) (NRS)	6	No	10.6(8.3)
		Pregabalin; 600 mg (n = 82)	57.8 (9.5)	56.1	6.7 (1.7) (NRS)	6	No	9.3(8.8)
	Rosenstock 2004^24	Placebo/no treatment (n = 70)	60.3 (10.3)	57.1	NR	8	No	NR
		Pregabalin; 300 mg fixed (n = 76)	59.2 (12.3)	55.3	NR	8	No	NR
	Satoh 2011^25	Placebo/no treatment (n = 136)	61.3 (9.6)	76.3	6.1 (1.4) (NRS)	13	NR	4.2(3.1)
		Pregabalin; 300 mg (n = 136)	61.3 (10.3)	76.1	6 (1.4) (NRS)	13	NR	4.3(3.6)
		Pregabalin; 600 mg (creatinine clearance >60 mL/min) or 300 mg (creatinine clearance 30–60 mL/min) (n = 45)	62.2 (10.3)	71.1	6.1 (1.3) (NRS)	13	NR	4.5(3.9)
	Tolle 2008^26	Placebo/no treatment (n = 96)	58.93 (11.7)	53.1	6.4 (NR) (NRS)	12	No	NR
		Pregabalin; 300 mg (n = 99)	57.28 (10.5)	53.5	6.4 (NR) (NRS)	12	No	NR
		Pregabalin; 600 mg (creatinine clearance >60 mL/min) or 300 mg (creatinine clearance 30–60 mL/min) (n = 101)	59.7 (11.3)	60.4	6.6 (NR) (NRS)	12	No	NR
	Ziegler 2015^27	Placebo/no treatment (n = 62)	58.9 (8.6)	58	6.6 (1.27) (NRS)	7	No	6.1(5.02)
		Pregabalin; 300 mg (n = 70)	59.6 (8.75)	51	6.6 (1.26) (NRS)	7	No	5.3(4.38)
Post herpetic neuralgia (PHN)	Baron 2009^17	Pregabalin; 600 mg (n = 48)	63.8 (11.9)	54.2	NR	4	No	3.7(6.1)
		LMP; 3 (n = 50)	66 (11.7)	56	NR	4	No	2.4(3)
	Binder 2009^58*	Placebo/no treatment (n = 35)	72.3 (8.3)	31.4	3.6 (1.6) (NRS)	2	Yes	2.4(2.3)
		LMP; 3 (n = 36)	70.8 (9.1)	47.2	3.7 (1.5) (NRS)	2	Yes	3.6(4)
	Dworkin 2003^28	Placebo/no treatment (n = 84)	70.5 (11.3)	52.4	6.5 (1.5) (NRS)	8	No	2.9(3.1)
		Pregabalin; 600 mg (creatinine clearance >60 mL/min) or 300 mg (creatinine clearance 30–60 mL/min) (n = 89)	72.4 (10.5)	41.6	6.3 (1.4) (NRS)	8	No	2.8(3)
	Galer 1999^51*	Placebo/no treatment (n = 32)	77.4	43.8	NR	4	NR	7.3 (4.8)
		LMP; 3 (n = 32)
	Galer 2002^29	Placebo/no treatment (n = 29)	74 (8.3)	37.9	53.8 (9.7) (Neuropathic Pain Scale)	3	NR	NR
		LMP; 1 (n = 67)	74 (6.2)	37.3	51.7 (10.8) (Neuropathic Pain Scale)	3	NR	NR
	Lin 2008^30	Placebo/no treatment (n = 23)	63 (16)	NR	55 (17) (VAS)	2 days	Yes	DPN: 3.0, PHN: 1.3(NR)
		LMP; 1 (n = 23)	65 (10)	NR	60 (21) (VAS)	2 days	Yes	DPN: 2.8, PHN: 1.3(NR)
	Liu 2017^31	Placebo/no treatment (n = 110)	64.1 (9.6)	56.9	6.08 (1.266) (NRS)	8	No	NR
		Pregabalin; 300 mg (n = 112)	65.7 (8.6)	51.4	5.93 (1.304) (NRS)	8	No	NR
	Ogawa 2010^32	Placebo (n = 98)	71.1 (8.6)	58.2	6.3 (NR) (NRS)	13	NR	2.8(NR)
		Pregabalin; 300 mg (n = 89)	70.9 (9.8)	50.6	6.1 (NR) (NRS)	13	NR	3(NR)
		Pregabalin; 600 mg (creatinine clearance >60 mL/min) or 300 mg (creatinine clearance 30–60 mL/min) (n = 97)	68.4 (12.5)	54.6	6.2 (NR) (NRS)	13	NR	2.8(NR)
	Rowbotham 1996^33	Placebo/no treatment; 3 (n = 35)	75 (NR)	57.1	NR	4	NR	4 (NR)
		LMP; 3 (n = 35)	75 (NR)	57.1	NR	4	NR	4 (NR)
	Sabatowski 2004^34	Placebo/no treatment (n = 81)	73.2 (10.3)	46	6.6 (1.6) (NRS)	8	No	3.7(3.9)
		Pregabalin; 300 mg fixed (n = 76)	71.9 (10.3)	41	7 (1.6) (NRS)	8	No	3.4(3.5)
	Stacey2008^35	Placebo/no treatment (n = 90)	65.6	56.7	6.5 (1.5) (NRS)	4	Yes	2.1(NR)
		Pregabalin; 300 mg fixed (n = 88)	67.9	55.7	6.4 (1.5) (NRS)	4	Yes	3.1(NR)
		Pregabalin; 600 mg (n = 91)	68.6	54.9	6.5 (1.4) (NRS)	4	Yes	2.4(NR)
	van Seventer 2006^36	Placebo/no treatment (n = 93)	70.9 (10.4)	43	6.85 (1.49) (NRS)	13	Yes	3.6(3.7)
		Pregabalin; 300 mg (n = 98)	70.7 (11.9)	55.1	6.72 (1.41) (NRS)	13	Yes	4(4.4)
		Pregabalin; 600 mg (creatinine clearance >60 /min) or 300 mg (creatinine clearance 30–60 mL/min) (n = 90)	70.7 (10.6)	42.2	6.65 (1.44) (NRS)	13	Yes	2.8(3.1)
PHN/DPN	Freynhagen 2005^37	Placebo/no treatment (n = 65)	61.7 (12.6)	56.9	6.63 (1.7) (NRS)	12	No	DPN: 4.5, PHN: 3.23(DPN: 3, PHN: 2.83)
		Pregabalin; 600  (n = 132)	61.8 (11)	54.5	6.81 (1.56) (NRS)	12	No	DPN: 4.6, PHN: 2.9(DPN: 4.1, PHN: 2.75)
		Pregabalin; 600 mg (n = 141)	62.7 (10.6)	52.5	6.78 (1.58) (NRS)	12	No	DPN: 5, PHN: 3.23(DPN: 5.2, PHN: 4.4)
	Gilron 2011^38	Placebo/no treatment (NR)	NR	NR	2.5 (1.2) (NR)	10	Yes	NR
		Pregabalin; 600 mg (NR)	NR	NR	2.7 (1.4) (NR)	10	Yes	NR
Post surgical pain**	Cheville 2009^49*	Placebo/no treatment (n = 14)	58.6 (11.3)	21.4	NR	8	Yes	NR
		LMP; 3 (n = 14)	65 (6.4)	42.9	NR	8	Yes	NR
	Grunenthal 2011^39	Placebo/no treatment (n = 20)	46.53 (14.83)	36.8	6.32 (1.72) (NRS)	1	NR	2.7(2.3)
		Pregabalin; 300 mg (n = 19)	50.53 (14.55)	36.8	6.13 (1.49) (NRS)	1	NR	5.3(4.6)
	Palladini 2019^40	Placebo/no treatment (n = 183)	52.6 (13.5)	NR	6.47 (1.38) (NRS)	12	Yes/no	1.1(0.7)
		LMP; 3(n = 180)	51.7 (14.2)	NR	6.66 (1.41) (NRS)	12	Yes/no	1.1(0.8)
	Penide 2012^41	Pregabalin; 300 mg fixed (n = 32)	NR	NR	NR	52	NR	NR
		LMP; 1 (n = 28)	NR	NR	NR	52	NR	NR
	Pickering 2017^42	Placebo/no treatment (n = 12)	65.3 (8.2)	33.3	5.8 (0.7) (Neuropathic pain questionnaire )	11	Yes	NR
		LMP; 2 (n = 24)	71 (6)	41.7	5.1 (0.9) (Neuropathic pain questionnaire )	11	Yes	NR
Persistent Inguinal postherniorrhaphy pain	Bischoff 2013^48*	Placebo/no treatment (n = 21)	57 (13)	100	6 (NR) (NRS)	4	Yes	3.9(NR)
		LMP; 1 (n = 21)	57 (13)	100	6 (NR) (NRS)	4	Yes	3.9(NR)
Post thoracotomy pain	Sansone 2017^43	Placebo/no treatment (n = 30)	50.2 (11.8)	47.1	5.8 (1) (NRS)	8	NR	0.8(0.6)
		LMP; NR (n = 33)	51.4 (11)	52.9	6.2 (NR) (NRS)	8	NR	0.6(0.4)
Post traumatic/surgical pain**	Jenkins 2012^54*	Placebo/no treatment (n = 12)	49.4 (11.8)	41.7	5.96 (0.88) (NR)	7	No	NR
		Pregabalin; 300 mg (n = 13)	50.2 (16.7)	46.2	6.03 (1.29) (NR)	7	No	NR
	Markman 2018^44	Placebo/no treatment (n = 267)	53.5 (12.6)	49.4	6.5 (1.3) (NRS)	15	No	NR
		Pregabalin; 600 mg (n = 275)	52.8 (12.9)	51.8	6.41 (1.3) (NRS)	15	No	NR
	van Seventer 2010^45	Placebo/no treatment (n = 127)	51 (13)	59.1	6.3 (1.7) (NRS)	8	Yes	4.4(NR)
		Pregabalin; 600 mg (n = 127)	52 (14)	39.4	6 (1.6) (NRS)	8	Yes	4.3(NR)
PNP	Demant 2015^50*	Placebo/no treatment (n = 46)	NR	42.5	NR	8	No	2.2 (median)(NR)
		LMP; 3 (n = 46)	NR	42.5	NR	8	No	2.2 (median)(NR)
	Guan 2011^46	Placebo/no treatment (n = 102)	60 (10.2)	44.1	6.4 (1.5) (NRS)	8	No	NR
		Pregabalin; 600 mg (n = 207)	60.1 (8.9)	47.6	6.3 (1.6) (NRS)	8	No	NR
	Hewitt 2011^52*	Placebo/no treatment (n = 51)	59.3 (11)	56.3	NR	6	Yes	NR
		Pregabalin; 600 mg (n = 53)	61.7 (10.8)	73.3	NR	6	Yes	NR
	Meier 2003^55*	Placebo/no treatment (n = 40)	65.3 (12.5)	38	NR	2	Yes	3.8(4.4)
		LMP; 4(n = 40)	65.3 (12.5)	38	NR	2	Yes	3.8(4.4)
	Moon 2010^47	Placebo/no treatment (n = 78)	61.3 (12.9)	41	NR	10	Yes	NR
		Pregabalin; 600  (creatinine clearance >60 mL/min) or 300 mg (creatinine clearance 30–60 mL/min) (n = 162)	59.7 (10.8)	48.8	NR	10	Yes	NR

* Cross-over or enriched enrolment type of study.

** For the diagnostic criteria for neuropathic pain used in these studies please see Supplementary Appendix 5.

Abbreviations. DPN: diabetic peripheral neuropathy; mg: milligrams; min: minute; mL: millilitre; NR: not reported; NRS: numeric rating scale; PHN: post-herpetic neuralgia; PNP: peripheral neuropathic pain; SD: standard deviation; VAS: visual analog scale; LMP: lidocaine medicated plaster.

Table 2. Cochrane risk of bias assessment of RCTs.

	$\text{Adequate sequence?}$	$\text{Adequate allocation?}$	$\text{Blinding?}$	$\text{Incomplete outcome}\text{data addressed?}$	$\text{Free of selective}\text{reporting?}$	$\text{Free of other bias?}$
Arezzo 2008^16
Baron 2009^17
Binder 2009^58
Bischoff 2013^48
Cheville 2009^49
Demant 2015^50
Dworkin 2003^28
Eli Lilly 2010^18
Freynhagen 2005^37
Galer 1999^51
Galer 2002^29
Gilron 2011^21
Grunenthal 2011^39
Guan 2011^46
Hewitt 2011^52
Huffman 2015^53
Jenkins 2012^54
Jiang 2011^19
Lesser 2004^20
Lin 2008^30
Liu 2017^31
Markman 2018^44
Meier 2003^55
Moon 2010^47
Mu 2018^21
Ogawa 2010^32
Palladini 2019^40
Penide 2012^41
Pickering 2017^42
Raskin 2014^56
Raskin 2016^57
Rauck 2013^22
Richter 2005^23
Rosenstock 2004^24
Rowbotham 1996^33
Sabatowski 2004^34
Sansone 2017^43
Satoh 2011^25
Stacey 2008^35
Tolle 2008
van Seventer 2006^36
van Seventer 2010^45
Ziegler 2015^27
Colour Codes:	Yes	$\text{No}$	Unclear

Figure 2. Network meta-analysis for all potential comparisons of LMP, placebo and pregabalin (300 mg or 600 mg).

Table 3. Studies included in the NMA for each outcome in each population.

Population	Outcome (follow-up weeks)	LMP vs. placebo	LMP vs pregabalin 600 mg	Pregabalin 600 mg vs. placebo	Pregabalin 300 mg vs. placebo	Pregabalin 600 mg vs. pregabalin 300 mg
PHN	Number of patients with NRS 50% or greater reduction (mixed <12 and > =12)	NA	Baron 2009^17	Stacey 2008^35; Van Seventer 2006^36; Ogawa 2010^32	Stacey 2008^35; Van Seventer 2006^36; Ogawa 2010^32; Sabatowski 2004^34	Stacey 2008^35; Van Seventer 2006^36; Ogawa 2010^32
	Number of patients with NRS 30% or greater reduction (mixed <12 and > =12)			Stacey 2008^35; Van Seventer 2006^36	Stacey 2008^35; Van Seventer 2006^36; Liu 2017^31	Stacey 2008^35; Van Seventer 2006^36
	Number of patients with NRS 30/50% or greater reduction (<12 only)			NA	NA	Stacey 2008 ^35
	Mean NRS (mixed <12 and > =12)			Van Seventer 2006^36; Ogawa 2010^32	Van Seventer 2006^36; Ogawa 2010^32; Liu 2017^31	Van Seventer 2006^36; Ogawa 2010^32
	Mean NRS (<12 only)			NA	NA	Ogawa 2010^32
	EQ-5D (<12 only)			NA	NA	NA
DPN	Number of patients with NRS 50% or greater reduction (mixed <12 and > =12)	NA	Baron 2009 ^17	Richter 2005^23; Arezzo 2008^16; Lesser 2004^20; Satoh 2011^25; Tolle 2008^26	Rosenstock 2004^24; Lesser 2004^20; Ziegler 2015^27; Huffman 2015^53; Mu 2018^21; Raskin 2016^57; Satoh 2011^25; Tolle 2008^26	Lesser 2004^20; Satoh 2011^25; Tolle 2008^26
	Number of patients with NRS 50% or greater reduction (<12 only)			Richter 2005^23; Lesser 2004^20	Rosenstock 2004 ^24; Lesser 2004 ^20; Ziegler 2015 ^27; Huffman 2015 ^53; Mu 2018 ^21	Lesser 2004^20
	Number of patients with NRS 30% or greater reduction, (<12 only)			Lesser 2004^20	Lesser 2004^20; Ziegler 2015^27; Huffman 2015^53; Mu 2018^21	Lesser 2004^20
	Mean NRS (mixed <12 and > =12)			Richter 2005^23; Lesser 2004^20; Satoh 2011^25	Rosenstock 2004^24; Lesser 2004^20; Ziegler 2015^27; Huffman 2015^53; Mu 2018^21; Raskin 2016^57; Satoh 2011^25; Rauck 2013^22	Lesser 2004^20; Satoh2011^25
	Mean NRS (<12 only)			Lesser 2004^20; Richter 2005^23; Satoh 2011^25	Rosenstock 2004^24; Lesser 2004^20; Ziegler 2015^27; Huffman 2015^53; Mu 2018^21; Raskin 2016^57; Satoh 2011^25	Lesser 2004^20; Satoh 2011^25
	EQ-5D (<12 only)			NA	NA	NA
Post-surgical/traumatic	Number of patients with discontinue due to lack of efficacy (mixed <12 and > =12)	Palladini 2019^40	NA	Van Seventer 2010 ^45; Markman 2018 ^44	NA	NA
	Number of patients with discontinue due to lack of efficacy, (> =12 only)			Markman 2018 ^44	NA	NA
	Number of patients with NRS 30/50% (mixed <12 and > =12)			Van Seventer 2010^45; Markman 2018^44	Grünenthal 2011^39	NA
	Number of patients with NRS 30/50% (> =12)			Markman 2018^44	NA	NA
	Mean NRS (<12 only)	Palladini 2019^40; Sansone 2017^43; Cheville 2009^49; Pickering 2017^42	NA	Van Seventer 2010^45	Grünenthal 2011^39; Jenkins 2012^54	NA
	Mean NRS (> =12 only)	Palladini 2019^40		Markman 2018^44	NA	NA
	EQ-5D (> =12 only)			Markman 2018^44	NA	NA
Mixed PNP	Mean NRS (<12)	Demant 2015^50	NA	Hewitt 2011^52; Moon 2010^47	NA	NA
Any PNP	any AE	Palladini 2019^40	Baron 2009^17	Ogawa 2010^32; Stacey 2008^35; Van Seventer 2010^45; Markman 2018^44; Moon 2010^47; Hewitt 2011^52; Arezzo 2008^16; Freynhagen 2005^37; Guan 2011^46	Ogawa 2010^32; Stacey 2008^35; Grünenthal 2011^39; Mu 2018^21; Liu 2017^31; Rauck 2013^22	Ogawa 2010^32; Stacey 2008^35
	any SAE			Ogawa 2010^32; Tolle 2008^26; Van Seventer 2010^45; Markman 2018^44; Moon 2010^47; Hewitt 2011^52; Arezzo 2008^16; Jiang 2011^19; Guan 2011^46	Ogawa 2010^32; Tolle 2008^26; Mu 2018^21; Liu 2017^31; Sabatowski 2004^34; Grünenthal 2011^39	Ogawa 2010^32; Tolle 2008^26
	Discontinuation due to AE			Ogawa 2010^32; Tolle 2008^26; Stacey 2008^35; Van Seventer 2010^45; Freynhagen 2005^37; Markman 2018^44; Moon 2010^47; Hewitt 2011^52; Arezzo 2008^16; Jiang 2011^19; Guan 2011^46; Richter 2005^23	Ogawa 2010^32; Tolle 2008^26; Stacey 2008^35; Mu 2018^21; Liu 2017^31; Sabatowski 2004^34; Rauck 2013^22; Rosenstock 2004^24; Grünenthal 2011^39	Stacey 2008^35; Tolle 2008^26; Ogawa 2010^32
	Somnolence	NA		Ogawa 2010^32; Tolle 2008^26; Stacey 2008^35; Lesser 2004^20; Satoh 2011^25; Van Seventer 2006^36; Van Seventer 2010^45; Freynhagen 2005^37; Markman 2018^44; Moon 2010^47; Hewitt 2011^52; Guan 2011^46; Richter 2005^23; Dworkin 2003^28	Ogawa 2010^32; Tolle 2008^26; Stacey 2008^35; Lesser 2004^20; Satoh 2011^25; Van Seventer 2006^36; Mu 2018^21; Liu 2017^31; Sabatowski 2004^34; Rauck 2013^22; Rosenstock 2004^24; Grünenthal 2011^39; Eli Lilly 2010^18	Ogawa 2010^32; Tolle 2008^26; Stacey 2008^35; Lesser 2004^20; Satoh 2011^25; Van Seventer 2006^36
	Somnolence (continued)	NA	Baron 2009 ^17
	Dizziness			Ogawa 2010^32; Tolle 2008^26; Stacey 2008^35; Lesser 2004^20; Satoh 2011^25; Van Seventer 2006^36; Van Seventer 2010^45; Freynhagen 2005^37; Markman 2018^44; Moon 2010^47; Hewitt 2011^52; Guan 2011^46; Richter 2005^23; Dworkin 2003^28; Jiang 2011^19	Ogawa 2010^32; Tolle 2008^26; Stacey 2008^35; Lesser 2004^20; Satoh 2011^25; Van Seventer 2006^36; Mu 2018^21; Liu 2017^31; Sabatowski 2004^34; Rauck 2013^22; Rosenstock 2004 ^24; Grünenthal 2011^39; Eli Lilly 2010^18	Ogawa 2010^32; Tolle 2008^26; Stacey 2008^35; Lesser 2004^20; Satoh 2011^25; Van Seventer 2006^36
	Peripheral oedema			Ogawa 2010^32; Tolle 2008^26; Stacey 2008^35; Lesser 2004^20; Satoh 2011^25; Van Seventer 2006^36; Van Seventer 2010^45; Freynhagen 2005^37; Moon 2010^47; Richter 2005^23; Dworkin 2003^28	Ogawa 2010^32; Tolle 2008^26; Stacey 2008^35; Lesser 2004^20; Satoh 2011^25; Van Seventer 2006^36; Mu 2018^21; Liu 2017^31; Sabatowski 2004^34; Rauck 2013^22; Rosenstock 2004^24; Raskin 2016^57; Huffman 2015^53	Ogawa 2010^32; Tolle 2008^26; Stacey 2008^35; Lesser 2004^20; Satoh 2011^25; Van Seventer 2006^36
	Weight gain			Ogawa 2010^32; Tolle 2008^26; Stacey 2008^35; Richter 2005^23; Satoh 2011^25; Van Seventer 2006^36; Van Seventer 2010^45; Freynhagen 2005^37; Moon 2010^47; Guan 2011^46	Ogawa 2010^32; Tolle 2008^26; Stacey 2008^35; Satoh 2011^25; Van Seventer 2006^36; Sabatowski 2004^34; Rauck 2013^22; Huffman 2015^53	Ogawa 2010^32; Tolle 2008^26; Stacey 2008^35; Satoh 2011^25; Van Seventer 2006^36

DPN: diabetic peripheral neuropathy; NA: not applicable ; NRS: numeric rating scale; PHN: post-herpetic neuralgia; PNP: peripheral neuropathic pain; AE: adverse event; SAE: serious adverse event; LMP: lidocaine medicated plaster.

Table 4. Result of the main NMA (random effects) for each outcome in each population.

Population	Outcome (follow-up weeks)	Effect measure (95% CI)	LMP vs. pregabalin 600 mg*	LMP vs. pregabalin 300 mg
PHN	Number of patients with NRS 50% or greater reduction (mixed <12 and > =12)	RR	1.69 (0.66, 4.25)	1.99 (0.69, 5.80)
	Number of patients with NRS 50% or greater reduction (<12 only)	RR	1.71 (0.47, 5.99)	1.89 (0.34, 9.87)
	Number of patients with NRS 30% or greater reduction (mixed <12 and > =12)	RR	1.18 (0.44, 3.17)	1.22 (0.36, 4.08)
	Number of patients with NRS 30% or greater reduction (<12 only)	RR	1.18 (0.92, 1.76)	0.95 (0.62, 1.82)
	Mean NRS (mixed <12 and > =12)	MD	−0.41 (−1.19, 0.98)	−0.76 (−1.64, 0.61)
	Mean NRS (<12 only)	MD	−0.40 (−1.38, 0.98)	−0.57 (−1.57, 1.06)
	EQ-5D (<12 only)	MD	0.12 (0.01, 0.22)	NA
DPN	Number of patients with NRS 50% or greater reduction (mixed <12 and > =12)	RR	1.08 (0.57, 2.07)	1.43 (0.67, 2.96)
	Number of patients with NRS 50% or greater reduction (<12)	RR	1.09 (0.67, 2.65)	1.63 (0.82, 4.90)
	Number of patients with NRS 30% or greater reduction (<12)	RR	1.06 (0.58, 3.11)	1.00 (0.41, 4.58)
	Mean NRS (mixed <12 and > =12)	MD	0.005 (−0.73, 1.25)	−0.58 (−1.48, 0.90)
	Mean NRS (<12 only)	MD	0.005 (−0.73, 1.25)	−0.43 (−1.31, 1.08)
	EQ-5D (<12 only)	MD	0.07 (0.005, 0.13)	NA
Post-surgical/ traumatic	Number of patients with discontinue due to lack of efficacy (mixed <12 and > =12)	RR	2.00 (0.31, 14.56)	NA
	Number of patients with discontinue due to lack of efficacy, (> =12 only)	RR	0.98 (0.27, 3.58)	NA
	Number of patients with NRS 50% (mixed <12 and > =12)	RR	0.65 (0.16, 2.47)	1.21 (0.19, 7.49)
	Number of patients with NRS 50% (> =12)	RR	0.69 (0.40, 1.18)	NA
	Number of patients with NRS 30% (mixed <12 and > =12)	RR	1.00(0.23, 4.03)	1.69 (0.30, 9.10)
	Number of patients with NRS 30% (> =12)	RR	1.17 (0.80, 1.73)	NA
	Mean NRS (<12 only)	MD	−0.53 (−2.65, 1.60)	−1.59 (−3.47, 0.32)
	Mean NRS (> =12 only)	MD	−0.01 (−0.58, 0.56)	NA
	EQ-5D (> =12 only)	MD	−0.02 (−0.12, 0.07)	NA
Mixed PNP	NRS (<12 only)	MD	0.34 (−0.03, 0.71)	NA
Any local neuropathic pain	Any AE	RR	0.40 (0.20, 0.82)	0.51 (0.23, 1.11)
	Any SAE	RR	2.92 (0.26, 32.91)	3.01 (0.24, 36.35)
	Discontinuation due to AE	RR	0.23 (0.06, 0.90)	0.20 (0.04, 0.92)
	Somnolence	RR	0.06 (0.002, 2.34)	0.07 (0.002, 3.04)
	Dizziness	RR	0.03 (0.001, 0.81)	0.04 (0.001, 1.03)
	Peripheral oedema	RR	0.17 (0.01, 1.80)	0.12 (0.01, 1.43)
	Weight gain	RR	0.11 (0.01, 2.25)	0.09 (0.004, 2.07)

*Results for PHN and DPN based on single RCT head-to-head comparison. This explains the almost identical results for different lengths of follow-up: the difference is entirely due to random error as a results of the Bayesian analysis.

DPN: diabetic peripheral neuropathy; NA: not applicable ; NRS: numeric rating scale; PHN: post-herpetic neuralgia; PNP: peripheral neuropathic pain; AE: adverse event; SAE: serious adverse event; LMP: lidocaine medicated plaster; RR: risk ratio; MD: mean difference; CI: confidence interval.

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