Treating Diabetic Peripheral Neuropathic Pain

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SORT: KEY RECOMMENDATIONS FOR PRACTICE

CLINICAL RECOMMENDATION	EVIDENCE RATING	REFERENCES
First-line treatment of diabetic peripheral neuropathic pain includes tricyclic antidepressants (e.g., amitriptyline, nortriptyline [Pamelor]). If these agents are contraindicated, newer anticonvulsants (e.g., gabapentin [Neurontin], pregabalin [Lyrica]) should be considered.	B	6, 8–11
Serotonin-norepinephrine reuptake inhibitors (e.g., venlafaxine [Effexor], duloxetine [Cymbalta]) or opiates and opiate analogs (e.g., morphine, tramadol [Ultram]) may be used if first-line treatments are unsuccessful.	B	8, 13, 14, 18,44
Topical treatments (e.g., capsaicin cream [Zostrix], lidocaine 5% patches [Lidoderm]) may be added to systemic treatments at any time.	B	19, 20

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A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case series. For information about the SORT evidence rating system, go tohttp://www.aafp.org/afpsort.xml.

Medications Used to Treat Diabetic Peripheral Neuropathic Pain

DRUG*	DOSAGE	COST OF GENERIC (BRAND)†	COMMENTS
Amitriptyline‡	10 to 150 mg at bedtime	$12 (NA)§	NNT = 1.3, NNH = 28 (major adverse events)
Nortriptyline‡ (Pamelor)	25 to 150 mg at bedtime	$13 ($692)§	NNH = 6 (minor adverse events)8||
Desipramine‡ (Norpramin)	25 to 150 mg at bedtime	$23 ($44)
Pregabalin (Lyrica)	150 to 600 mg per day, divided into two or three doses	NA ($168)	NNT = 3.3, NNH = 3.79
	300 mg twice per day		NNT = 4.010||
	100 mg three times per day		NNT = 6.010||
	50 mg three times per day		NNT = 19.110||
Gabapentin (Neurontin)	300 to 1,200 mg three times per day	$60 ($182)	NNT = 4.3, NNH = 3.711||
Carbamazepine (Tegretol)	200 to 600 mg twice per day	$10 ($86)§	NNT = 3.3, NNH = 1.99||
			NNT = 2.5, NNH = 3.712
Venlafaxine, extended release (Effexor XR)	150 to 225 mg per day	$142 ($150)	NNT = 3.1, NNH = 16.2 (major adverse effect)
			NNH = 9.6 (minor adverse effect)8
Duloxetine (Cymbalta)	60 to 120 mg per day	NA ($154)	NNT = 5.1,5,13 NNH = 155||
Morphine	15 to 120 mg per day	$17	Adverse effects and potential for addiction may limit use; decreased tolerated dose with similar effectiveness when used with gabapentin14,15
Oxycodone, controlled release (Oxycontin)	10 to 40 mg twice per day	$61 ($152)	NNT = 2.6 based on single small RCT16
			Another RCT showed benefit17||
			NNH = 816 (adverse effects led to withdrawal from study)
Tramadol (Ultram)	200 to 400 mg per day	$64 ($246)	NNT = 3.8, NNH = 7.7 (adverse effects led to withdrawal from study)18
Capsaicin cream (Zostrix)	0.075% topical cream four times per day	NA ($22 per 57-g tube)	NNT = 5.7 (adverse effects make blinded trials difficult)
			NNH = 2.5 (local adverse effect)
			NNH = 9.8 (adverse effects led to withdrawal from study)19
Lidocaine 5% patch (Lidoderm)	Up to three patches per day, each patch worn up to 12 hours; patches may be worn at the same time; a 12-hour drug-free interval is necessary	NA ($217 for one patch per day)	NNT = 4.4,20,21 NNH = 2920
l-carnitine	1,000 mg three times per day	$40	Review of two RCTs showed improved pain and nerve fiber regeneration22
Alpha-lipoic acid	600 mg per day	$10	Two RCTs showed conflicting results; long-term studies with oral formulation are needed23
Acupuncture	Types variable	$60 to 120 per treatment	Small RCT and pilot study have shown benefit; a Cochrane review is underway 24–26
Frequency-modulated electromagnetic neural stimulation	30 minutes per day	Depends on cost of hardware	Two small studies showed benefits alone and in conjunction with amitriptyline27–29

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NA = not available; NNH = number needed to harm; NNT = number needed to treat; RCT = randomized controlled trial.

*—Listed in order of recommended use.

†—Estimated retail price of one month's treatment based on lowest dosage provided. Information obtained at http://www.drugstore.com (accessed April 23, 2010). Generic price listed first; brand price listed in parentheses..

‡— Adverse effects make blinding difficult; numerous adverse effects and contraindications.

§—In retail discount program; may be available at discounted prices ($10 or less for one month's treatment) at one or more national retail chains.

||—NNT based on diabetic peripheral neuropathic pain specifically (others based on generalized neuropathic pain).

Information from references 5, and 8 through 29.

Common Adverse Effects from Treatment for Diabetic Peripheral Neuropathic Pain

DRUG	ADVERSE EFFECT	PATIENTS WHO EXPERIENCED EFFECT (%)
Amitriptyline*8,30	Constipation	14
	Dizziness	28
	Dry mouth	90
	Somnolence	66
Capsaicin cream (Zostrix)19	Cough	8
	Skin irritation	54
Duloxetine (Cymbalta)5,19	Constipation	9
	Diarrhea	6
	Fatigue	9
	Headache	10
	Nasopharyngitis	6
	Nausea	22
	Somnolence	8
	Sweating	6
Gabapentin (Neurontin)11	Confusion	7
	Diarrhea	10
	Dizziness	24
	Headache	10
	Nausea	8
	Somnolence	20
Lidocaine 5% patch (Lidoderm)20	No adverse effects significantly different from placebo	—
Opiates14	Constipation	33
	Dizziness	21
	Nausea	33
	Somnolence	29
	Vomiting	15
Pregabalin (Lyrica)†9,10	Dizziness	7 to 28
	Edema	6 to 16
	Somnolence	5 to 13
	Weight gain	4 to 9
Tramadol (Ultram)18	Constipation	22
	Headache	17
	Nausea	23
	Somnolence	12
Venlafaxine (Effexor)8	Anorexia	5
	Dyspepsia	10
	Flatulence	6
	Impotence	5
	Insomnia	10
	Myalgia	5
	Nausea	10
	Sinusitis	7
	Somnolence	15
	Sweating	10
	Vomiting	5

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*—Amitriptyline chosen to represent tricyclic antidepressants.

† —Range of percentages is based on range of doses in study; adverse effects were dose-related.

Information from references 5, 8 through 11, 14, 18 through 20, and 30.