Table 1.

Treatment recommendations.

Tier I	Medications	Randomized placebo-controlled trials
Supported by evidence from three or more randomized clinical trials in painful diabetic neuropathy Safety profile Tolerability Number of significant drug interactions Cost	Tricyclic antidepressants:
	Amitriptyline	Max et al. (1987) Max et al. (1992) Bansal et al. (2009) Morello et al. (1999)
	Desipramine	Max et al. (1991) Max et al. (1992) Sindrup (1990)
	Imipramine	Sindrup et al. (1989) Kvinesdal et al. (1984) Sindrup et al. (2003)‡
	Duloxetine	Goldstein et al. (2005) Raskin et al. (2005) Wernicke et al. (2006) Armstrong (2007)
	Pregabalin	Rosenstock et al. (2004) Arezzo et al. (2008) Lesser et al. (2004) Richter et al. (2005) Freynhagen et al. (2005) Bansal et al. (2009) Tolle et al. (2008)
	Gabapentin	Backonja et al. (1998) Backonja (1999) Morello et al. (1999) Sandercock et al. (2009)* Simpson (2001)
Tier II	Medications	Randomized placebo-controlled trials
Supported by evidence from two or more randomized clinical trials in painful diabetic neuropathy Safety profile Tolerability Number of significant drug interactions Cost	Venlafaxine	Rowbotham et al. (2004)$ Kadiroglu et al. (2008) Sindrup et al. (2003)‡
	Carbamazepine	Wilton (1974) Rull et al. (1969) Gomez-Perez et al. (1996)
	Valproate	Kochar et al. (2002) Kochar et al. (2004) Agrawal et al. (2009)§
Tier III	Medications	Supportive randomized controlled trials	Conflicting randomized trials
Supported by evidence from two or more randomized clinical trials in painful diabetic neuropathy but with conflicting data Safety profile Tolerability Number of significant drug interactions Cost	Lamotrigine	Eisenberg et al. (2001) Jose et al. (2007)||	McCleane (1999)¶ Vinik et al. (2007)#
	Oxcarbazepine	Dogra et al. (2005)** Beydoun et al. (2006)‡‡	Grosskopf et al. (2006)$$
	Alpha lipoic acid	Ruhnau et al. (1999) Ziegler et al. (2006) Ametov et al. (2003)	Reljanovic et al. (1999) Ziegler et al. (1999)
Breakthrough pain	Medications	Randomized placebo-controlled trials
Supported by evidence from randomized clinical trials including painful diabetic neuropathy To be used as adjuvant therapies	Tramadol	Freeman et al. (2007)§§ Harati et al. (1998) Sindrup et al. (1999)
	Lidocaine	Meier et al. (2003)| | | |
	Capsaicin	The Capsaicin Study Group (1991) Scheffler et al. (1991) Tandan et al. (1992)

^*This study examined use of gabapentin extended release which is not currently commercially available.

^$This study examined use of venlafaxine extended release.

^‡This was a randomized control trial of venlafaxine versus imipramine in neuropathic pain and included 15 patients with painful diabetic neuropathy.

^§This was a double-blind randomized placebo-controlled trial in diabetic neuropathy which found that both valproate and a combination of valproate plus glyceryl trinitrate spray improved pain control.

^||This was a randomized control trial comparing lamotrigine with amytriptiline and placebo for the treatment of painful diabetic neuropathy.

^¶This study examined lamotrigine dosing at 200mg/day for neuropathic pain.

^#This study examined lamotrigine doses up to 400 mg/day.

^**This study examined oxcarbazepine dosing at 1800 mg/day.

^$$This study examined oxcarbazepine dosing at 1200mg/day.

^‡‡This study examined oxcarbazepine dosing at 600, 1200 and 1800mg/day. The primary efficacy variable did not reach statistical significance, however patients with diabetic neuropathy who received the 1200 or 1800mg/day dosing did have improvements in pain when compared with the placebo group and 600mg/day dosing group.

^§§This was a placebo-controlled trial examining tramadol with acetaminophen in the treatment of painful diabetic neuropathy.

^||||This was a placebo-controlled trial of lidocaine patches in the treatment of multiple types of painful neuropathy, including diabetic neuropathy.