Diabetic Neuropathy and Oxidative Stress: Therapeutic Perspectives

Table 1

Current pharmacotherapy in DN.

NNT	Study outcome	Treatment duration	Study design	Daily dose (mg)	Trial size	Trial	Drug used	Drug class
—	Amitriptyline > placebo	2 × 6 wk	Crossover	Up to 150 mg	29	Max [15]	Amitriptyline	Antidepressants: TCAs:
2.1	Amitriptyline > placebo	2 × 6 wk	Crossover	≤150 mg	29	Max et al. [16]	Amitriptyline
2.2	Amitriptyline = desipramine > placebo	2 × 6 wk	Crossover	Amitriptyline: 105 mg; desipramine: 111 mg	38	Max et al. [17]	Amitriptyline and desipramine
—	Amitriptyline > maprotiline > placebo	4 wk	Crossover	75 mg	37	Vrethem et al. [18]	Amitriptyline and maprotiline
—	Amitriptyline > placebo	2 × 6 wk	Crossover	25–75 mg	24	Morello et al. [19]	Amitriptyline
—	Clomipramine > desipramine > placebo	6 wk	Crossover	Desipramine: 200 mg and clomipramine: 75 mg (in extensive metabolisers). 50 mg of both drugs (in poor metabolisers)	19	Sindrup et al. [20]	Desipramine and clomipramine
	Desipramine > placebo	6 wk	Crossover	201 mg	20	Max et al. [21]	Desipramine
—	Imipramine > placebo	5 + 5 wk	Crossover	100 mg	12	Kvinesdal et al. [22]	Imipramine
—	Combination > placebo	8 wk	Crossover	Nortriptyline: 10 mg; fluphenazine: 0.5 mg	18	Gomez-Perez et al. [23]	Nortriptyline and fluphenazine
—	Citalopram > placebo	2 × 3 wk	Crossover	40 mg	15	Sindrup et al. [24]	Citalopram	SSRI:
—	Venlafaxine + gabapentin > placebo in patients who do not respond to gabapentin	2 × 8 wk	Parallel	—	11 and 42	Simpson [25]	Venlafaxine and gabapentin	SNRIs
5.2 for venlafaxine and 2.7 for imipramine.	Venlafaxine > imipramine > placebo	4 wk	Crossover	Venlafaxine: 225 mg; imipramine: 150 mg	29	Sindrup et al. [26]	Venlafaxine versus imipramine
4.5	Venlafaxine > placebo	6 wk	Parallel	150–225 mg	244	Rowbotham et al.; [27]	Venlafaxine
—	Venlafaxine > placebo	8 wk	Parallel	75–150 mg	60	Kadiroglu et al. [28]	Venlafaxine
11 (60 mg group); 5 (120 mg group)	Duloxetine > placebo	12 wk	Parallel	60, 120 mg	348	Raskin et al. [29]	Duloxetine
4.3 (60 mg group); 3.8 (120 mg group)	Duloxetine > placebo	12 wk	Parallel	20, 60, 120 mg	457	Goldstein et al. [30]	Duloxetine
6.3 (60 mg group); 3.8 (120 mg group)	Duloxetine > placebo	12 wk	Parallel	60, 120 mg	334	Wernicke et al. [31]	Duloxetine
5.2 and 4.9 (duloxetine 60 mg once daily and 60 mg BID, resp.)	Duloxetine > placebo	3 × 12 wk	Parallel	60 mg	1024	Kajdasz et al. [32]	Duloxetine
3.6 (300 mg group); 3.3 (600 mg group)	Pregabalin (300, 600 mg) > placebo	5 wk	Parallel	75, 300, 600 mg	338	Lesser et al. [33]	Pregabalin
3.9	Pregabalin > placebo	8 wk	Parallel	300 mg	146	Rosenstock et al. [34]	Pregabalin
4.2 (600 mg group)	Pregabalin (600 mg) > placebo	6 wk	Parallel	150, 600 mg	246	Richter et al. [35]	Pregabalin
3.6	Flexible and fixed > placebo	12 wk	Parallel	Flexible: 150, 300, 450, 600 mg; fixed: 300, 600 mg	338	Freynhagen et al. [36]	Pregabalin
6.3 (600 mg group)	Pregabalin (600 mg) > placebo	12 wk	Parallel	150, 300, or 600 mg	395	Tölle et al. [37]	Pregabalin
—	Pregabalin > placebo	13 wk	Parallel	600 mg	167	Arezzo et al. [38]	Pregabalin
4.04 (600 mg group); 5.99 (300 mg group); 19.06 (150 mg group)	150, 300, 600 mg TID > placebo; 600 mg BID > placebo	5 to 13 wk	Parallel	150, 300, 600 mg administered TID or BID	—	Freeman et al. [39]	Pregabalin
4	Gabapentin > placebo	8 wk	Parallel	Titrated from 900 to 3600 mg	165	Backonja et al. [40]	Gabapentin
—	Gabapentin = placebo	2 × 6 wk	Crossover	900 mg	40	Gorson et al. [41]	Gabapentin
—	Sodium valproate > placebo	4 wk	Parallel	600–1200 mg	52	Kochar et al. [42]	Sodium valproate
—	Sodium valproate > placebo	16 wk	Parallel	500 mg	39	Kochar et al. [43]	Sodium valproate	Anticonvulsants:
—	Sodium valproate = placebo	4 wk	Crossover	1500 mg	31	Otto et al. [44]	Sodium valproate
4	Lamotrigine > placebo	6 wk	Parallel	Titrated from 25 to 400 mg	59	Eisenberg et al. [45]	Lamotrigine
—	Lamotrigine = placebo	19 wk	Parallel	200, 300, 400 mg	360	Vinik et al. [46]	Lamotrigine
—	Lamotrigine = amitriptyline	6 wk	Crossover,	Lamotrigine: 25, 50, 100 mg twice daily; amitriptyline: 10, 25, 50 mg at night time	53	Jose et al. [47]	Lamotrigine and amitriptyline
—	Carbamazepine > placebo	2 wk	Crossover	200–600 mg	30	Rull et al. [48]	Carbamazepine
—	Oxcarbazepine > placebo	16 wk	Parallel	300 mg titrated to a maximum dose of 1800 mg	146	Dogra et al. 2005 [49]	Oxcarbazepine
7.9 (1200 groups); 8.3 (1800 groups)	Oxcarbazepine > placebo (1200, 1800 mg groups)	16 wk	Parallel	600, 1200, 1800 mg	347	Beydoun et al. [50]	Oxcarbazepine
—	Oxcarbazepine = placebo	16 wk	Parallel	1200 mg	141	Grosskopf et al. [51]	Oxcarbazepine
—	Lacosamide > placebo	—	Parallel	400 mg	94	Rauck et al. [52]	Lacosamide
—	Lacosamide (400 mg group) > placebo	18 wk	Parallel	200, 400, 600 mg	—	Wymer et al. [53]	Lacosamide
3.1	Tramadol > placebo	6 wk	Parallel	210 mg	131	Harati et al. [54]	Tramadol
4.3	Tramadol > placebo	2 × 4 wk	Crossover	200–400 mg	45	Sindrup et al. [55]	Tramadol
—	Tramadol/acetaminophen > placebo	8 wk	Parallel	Tramadol: 37.5 mg; acetaminophen: 325 mg	311	Freeman et al. [56]	Tramadol/; acetaminophen
—	Oxycodone > placebo	6 wk	Parallel	10–100 mg	159	Gimbel et al. [57]	Oxycodone	Opioids:
2.6	Oxycodone > placebo	4 wk	Crossover	10–80 mg	45	Watson et al. [58]	Oxycodone
—	Oxycodone + gabapentin > placebo + gabapentin	12 wk	Parallel	Oxycodone: 10–80 mg + gabapentin: 100–3600 mg	338	Hanna et al. [59]	Oxycodone
—	Morphine + gabapentin > morphine > gabapentin > placebo	4 × 4 wk	Crossover	120, 60 mg morphine + 2400 mg gabapentin, 3600 mg gabapentin	57	Gilron et al. [60]	Morphine
—	Capsaicin > vehicle	8 wk	Parallel	0.075% capsaicin	252	Anonymous et al. [61]	Capsaicin
—	Capsaicin > vehicle	8 wk	Parallel	0.075% capsaicin	—	Scheffler et al. [62]	Capsaicin
—	Capsaicin > vehicle	8 wk	Parallel	0.075% capsaicin four times a day	22	Tandan et al. [63]	Capsaicin
—	Capsaicin > vehicle	8 wk	Parallel	0.075% capsaicin four times a day		Anonymous et al. [64]	Capsaicin	Topical medications:
—	Isosorbide > placebo	2 × 4 wk	Crossover	30 mg	22	Yuen et al. [65]	Isosorbide dinitrate spray
—	Glyceryl > placebo	2 × 4 wk	Crossover	—	48	Agrawal et al. [66]	Glyceryl trinitrate spray
4.4	Lidocaine > placebo	4 wk	Crossover	5% lidocaine patch	40	Meier et al. [67]	Lidocaine patch
—	Lidocaine significantly improved pain and quality of life	3 wk study with a 5 wk extension	Open label, flexible dosing	5% lidocaine patch	56	Barbano et al. [68]	Lidocaine patch
—	Mexiletine > placebo	10 wk	Crossover	10 mg	16	Dejgard et al. [69]	Mexiletine	Anesthetics/; antiarrhythmics:
	Mexiletine > placebo	3 wk	Parallel	675 mg	216	Oskarsson et al. [70]	Mexiletine
—	Mexiletine = placebo	3 wk	Parallel	600 mg	29	Wright et al. [71]	Mexiletine
4	Dextromethorphan > placebo	2 × 6 wk	Crossover	Mean 381 mg	14	Nelson et al. [72]	Dextromethorphan	NMDA antagonists:
3.2	Dextromethorphan > placebo	2 × 9 wk	Crossover	400 mg	19	Sang et al. [73]	Dextromethorphan
3.03 at 12 weeks	Botulinum toxin > placebo	24 wk	Parallel	Intradermal of subtype A (20–190 units) into the painful area	29	Ranoux et al. [74]	Botulinum toxin	Other drugs:
—	Botulinum toxin > placebo	12 × 12 wk	Crossover	50 units of subtype A in 1.2 mL 0.9% saline given intradermally into each foot, each injection 4 U subtype A	18	Yuan et al. [75]	Botulinum toxin
—	Improved pain and nerve fiber regeneration	2 × 52 wk	Parallel	500 and 1,000 mg, three times per day	—	Sima et al. [76]	Acetyl-L-carnitine
—	α-lipoic acid = placebo	28 wk	Parallel	600 mg	509	Ziegler et al. [77]	α-lipoic acid
—	α-lipoic acid ≥ placebo with clinically meaningful degree	3 wk	Parallel	600 mg	1258	Ziegler et al. [78]	α-lipoic acid

NNT: number needed to treat; TCAs: tricyclic antidepressants; SSRI: selective serotonin reuptake inhibitor; SNRIs: serotonin norepinephrine reuptake inhibitors; NMDA: N-methyl-D-aspartate; TID: three times daily; BID: twice daily.