eMedicine Specialties > Neurology > Neuromuscular Diseases
Diabetic Neuropathy: Treatment & Medication
Updated: Oct 22, 2009
- Overview
- Differential Diagnoses & Workup
- Treatment & Medication
- Follow-up
Treatment
Medical Care
Throughout this discussion on treatment, distinction is made between therapies for symptomatic relief and those that may slow the progression of neuropathy.
- General aspects of treatment
- Consider any patient with clinical evidence of diabetic peripheral neuropathy to be at risk for foot ulceration and provide education on foot care.18 If necessary, a podiatry referral should be provided.
- Patients with diabetic peripheral neuropathy require more frequent follow-up, with particular attention to foot inspection to reinforce the need for regular self-care. The provision of regular foot examinations and reinforcement of the educational message on foot care have been shown in several studies to have a major impact on rates of ulceration and even amputation.19
- Current treatments for pain
- Of all treatments, tight and stable glycemic control is probably the most important for slowing the progression of neuropathy.20 Because rapid swings from hypoglycemia to hyperglycemia have been suggested to aggravate and induce neuropathic pain, the stability of glycemic control may be as important as the actual level of control in relieving neuropathic pain. The DCCT demonstrated that tight blood sugar control in patients with type 1 diabetes decreased the risk of neuropathy by 60% in 5 years.2 The effect of tight glycemic control on polyneuropathy in patients with type 2 diabetes or those with impaired glucose tolerance/impaired fasting glucose is not as clear and requires further prospective study.
- Many medications are available for the treatment of diabetic neuropathic pain. These include tricyclic antidepressants, gabapentin, pregabalin, duloxetine, topical lidocaine, and capsaicin. Other medications such as carbamazepine, oxcarbazepine, phenytoin, lamotrigine, and opioids may also be used. Topical therapy with capsaicin or lidocaine patches may be useful in some patients, especially those with more localized pain or those in whom interactions with existing oral medications is a concern. Any of these medications may be associated with side effects, and patients should be counseled about possible problems before initiating treatment.21
- Chou et al performed a meta-analysis of head-to-head trials comparing the results of gabapentin and tricyclic antidepressants for pain relief in diabetic neuropathy. They reported no difference between gabapentin and tricyclic antidepressants in the likelihood of achieving pain relief of diabetic neuropathy or postherpetic neuralgia.22
- Alternative and complementary therapies for pain (eg, acupuncture) are under investigation.23
- Treatments for autonomic dysfunction
- Until now, the main therapy for erectile dysfunction of nonvascular or nonpsychological origin has been the intracorporeal injection of vasoactive substances such as papaverine. The oral agent sildenafil and related phosphodiesterase type 5 (PDE5) inhibitors are now available for the treatment of erectile dysfunction of diverse causes, including diabetes. Sildenafil is a selective inhibitor of cyclic guanosine monophosphate-specific PDE5, the predominant isoenzyme in human corpus cavernosum.
- Glycopyrrolate is an antimuscarinic compound that is the first specific treatment for diabetic gustatory sweating. When applied topically to the affected area, it results in a marked reduction in sweating while eating a meal.
- A number of medications are currently undergoing evaluation in clinical trials. Some are licensed for use in other countries.
- Aldose reductase inhibitors (eg, alrestatin, sorbinil, tolrestat, epralrestat): Although numerous studies of aldose reductase inhibitors have been published in the past 30 years, these inhibitors are not currently available in the United States.24,25 Aldose reductase inhibitors block the rate-limiting enzyme in the polyol pathway that is activated in hyperglycemic states. Many earlier aldose reductase inhibitor trials had problems related to poor study design (eg, enrolling patients with advanced neuropathy who were unlikely to benefit from treatment). Epralrestat is currently marketed only in Japan.
- Alpha-lipoic acid: Ziegler and colleagues conducted a multicenter placebo-controlled trial of the antioxidant alpha-lipoic acid patients with type 2 diabetes and symptomatic neuropathy. They reported short-term symptomatic relief.6 Studies of this drug are ongoing.
- Actovegin, a deproteinized hemoderivative of calf blood, contains inorganic substances (eg, electrolytes, trace elements) and organic components (eg, amino acids, oligopeptides, nucleosides, glycosphingolipids). Actovegin also contains inositol phospho-oligosaccharides (IPOs), which are thought to elicit central and peripheral insulin effects. In a multicenter, randomized, double-blind trial, the efficacy and safety of actovegin was evaluated in 567 patients with type 2 diabetes mellitus and diabetic polyneuropathy. Patients were randomized to receive 20 IV infusions of actovegin (2000 mg/d; n=281) or placebo (n=286) followed by actovegin 1800 mg/d PO or placebo for 140 days. Findings showed significant improvement in lower limb symptoms and sensory with sequential IV and oral actovegin compared with placebo.26
Surgical Care
Pancreatic transplantation in patients with diabetes and end-stage renal disease can stabilize neuropathy and in some instances improve motor, sensory, and autonomic function for as long as 48 months after uremia plateaus.19
Consultations
Patients with diabetic neuropathy should have regular monitoring by a primary care physician. Most patients benefit from consultation with an endocrinologist at periodic intervals, and those with more brittle diabetes may benefit from regular endocrinology consultations to assist in diabetes management. Patients with diabetes who develop neuropathy should see a neurologist early in the course of neuropathy. Patients who go on to develop neuropathy symptoms or signs that appear out of proportion to the severity of diabetes should be evaluated by a neurologist to help exclude other underlying causes of neuropathy.
Diet
Patients with diabetic neuropathy should work with nutritionists or their primary care physicians to develop a realistic diet for lowering blood glucose and minimizing large fluctuations in blood glucose.
Activity
Patients with diabetic neuropathy should be encouraged to remain as active as possible. However, those with significant sensory loss or autonomic dysfunction should be cautioned about exercising in extreme weather conditions, which may result in injury. For example, patients with extremity numbness may not be aware of frostbite injuries during prolonged cold exposure, or those with abnormal sweating may become easily overheated in hot conditions. In most cases, consultation with the patient's regular physician is reasonable before the initiation of a regular exercise program.
Medication
The pharmacologic agents listed below are used for the symptomatic treatment of diabetic neuropathy.
For related CME, see Medscape's CME Activity Treatment With Pregabalin May Reduce Pain of Diabetic Neuropathy.
Tricyclic antidepressants
This complex group of drugs has central and peripheral anticholinergic effects as well as sedative effects. They have central effects on pain transmission. They also block the active reuptake of norepinephrine and serotonin.
Amitriptyline (Elavil)
By inhibiting reuptake of serotonin and/or norepinephrine by presynaptic neuronal membrane, may increase synaptic concentration in CNS. Useful as analgesic for certain types of chronic and neuropathic pain.
Adult
10-25 mg/d PO hs
Increase to 30-100 mg PO qhs over several wk as needed
Pediatric
Children: 0.1 mg/kg/d PO hs and increase, as tolerated, over 2-3 wk to 0.5-2 mg/d hs
Adolescents: 10-25 mg/d PO; increase gradually to 100 mg/d as needed
Metabolized by P-450 2D6 system, thus drugs that inhibit this enzyme system (eg, cimetidine, quinidine) may increase tricyclic levels; phenobarbital may increase metabolism, decreasing its effects; may block uptake of guanethidine, thus preventing its hypotensive effects; may interact with thyroid medications, alcohol, CNS depressants, barbiturates, and disulfiram
Documented hypersensitivity; MAOIs in past 14 d
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution in patients with cardiac conduction disturbances, cardiac arrhythmias, seizures, glaucoma, urinary retention history, hyperthyroidism, and renal or hepatic impairment; because of its pronounced effects in cardiovascular system, best to avoid in elderly persons
Nortriptyline (Pamelor, Aventyl HCl)
Has demonstrated effectiveness in treatment of chronic pain; by inhibiting reuptake of serotonin and/or norepinephrine by presynaptic neuronal membrane, may increase synaptic concentration in CNS; pharmacodynamic effects such as desensitization of adenyl cyclase and down-regulation of beta-adrenergic receptors and serotonin receptors also appear to be involved in mechanisms of action.
Adult
25 mg PO qhs and increase over several wk as needed; not to exceed 150 mg/d
Pediatric
<25 kg: Not established
25-35 kg: 10-20 mg/d PO
35-54 kg: 25-35 mg/d PO
>54 kg: Administer as in adults
Cimetidine may increase levels; may increase PT in patients whose coagulation parameters have been stabilized with warfarin
Documented hypersensitivity; narrow-angle glaucoma; MAOIs in past 14 d
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Caution in renal or hepatic impairment, cardiac conduction disturbances, or history of hyperthyroidism
Anticonvulsants
These agents likely have central and peripheral effects on pain modulation.
Gabapentin (Neurontin)
Has properties common to other anticonvulsants and antineuralgic effects. Exact mechanism of action not known. Structurally related to GABA but does not interact with GABA receptors.
Adult
100 mg PO tid; titrate dose upward prn
Pediatric
<12 years: Not established
>12 years: Administer as in adults
Antacids may reduce bioavailability significantly (administer > 2 h following antacid); cimetidine may reduce clearance, but this may not be of clinical significance; may significantly increase norethindrone levels
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in severe renal disease
Carbamazepine (Tegretol, Carbatrol, Epitol)
Has antineuralgic effects; may depress activity of nucleus ventralis of thalamus or decrease synaptic transmission or summation of temporal stimulation, leading to neural discharge by limiting influx of sodium ions across cell membrane or other unknown mechanisms. Target blood serum concentration 4-12 mg/L.
Adult
200 mg PO bid initial dose; increase gradually prn over 2 wk to 200 mg tid
SR form: Therapeutic dose bid
Pediatric
<6 years: 10-20 mg/kg/d PO initial dose; titrate dose prn
6-12 years: 100 mg PO bid initial dose; titrate dose prn
>12 years: 200 mg PO bid initial dose; titrate dose prn
Cyclosporine, oral contraceptives, TCAs, warfarin, phenytoin, doxycycline, neuroleptics, fentanyl, calcium channel blockers, macrolide antibiotics, isoniazid, cimetidine, lamotrigine, propoxyphene
Documented hypersensitivity; bone marrow suppression; MAOIs within last 14 d
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
MAOIs should be discontinued for minimum of 14 d before starting this medication; use cautiously in patients with history of cardiac damage or hepatic disease; blood cell abnormalities have been reported following this medication; may worsen primary generalized epilepsy or atypical absence seizures; 0.5-1% risk of spina bifida in children born to mothers who take carbamazepine during pregnancy
Phenytoin (Dilantin)
May stabilize neuronal membranes and treat neuralgia by increasing efflux or decreasing influx of sodium ions across cell membranes in motor cortex during generation of nerve impulses. When serum level in or near therapeutic range, adjust dose in 30- to 50-mg increments. Small-dose increments may cause greater than expected increases in serum concentration (ie, Michaelis-Menten drug kinetics). Steady-state serum levels may take up to 3 wk to occur because half-life is concentration dependent.
Adult
300 mg/d PO initial dose; adjust to maintain serum levels of 10-20 mg/L
Pediatric
5 mg/kg/d PO bid
Rifampin, cisplatin, vinblastine, bleomycin, folic acid, theophylline, and continuous NG feedings may decrease serum levels and effects; may decrease effects of oral contraceptives, itraconazole, mebendazole, methadone, oral midazolam, valproic acid, cyclosporine, theophylline, doxycycline, quinidine, mexiletine, and disopyramide; isoniazid, chloramphenicol, or fluconazole may increase serum concentrations; may increase warfarin effects and rate of conversion of primidone to phenobarbital, resulting in increased phenobarbital serum concentrations
Documented hypersensitivity; heart block; sinus bradycardia
Pregnancy
D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus
Precautions
Discontinue if rash or lymphadenopathy develops; caution in patients with hepatic dysfunction; is approximately 90% protein bound; during pregnancy or low albumin states, better to adjust PO dose to maintain free serum concentrations of 1-2 mg/L
Lamotrigine (Lamictal)
Triazine derivative useful in treatment of neuralgia. Inhibits release of glutamate and inhibits voltage-sensitive sodium channels, which stabilizes neuronal membrane. Follow manufacturer's recommendation for dose adjustments.
Adult
50-100 mg/d PO divided bid initial dose; 100-400 mg/d PO qd or divided bid maintenance; not to exceed 500 mg/d
Pediatric
<2 years: Not established
2-12 years
Weeks 1-2: 0.6 mg/kg/d PO divided bid, rounded down to nearest 5 mg
Weeks 3-4: 1.2 mg/kg/d PO divided bid, rounded down to nearest 5 mg
Maintenance: 5-15 mg/kg/d PO; not to exceed 400 mg/d divided bid; to achieve usual maintenance dose, increase subsequent doses q1-2wk as follows: calculate 1.2 mg/kg/d and round down to nearest 5 mg; add this amount to previously administered daily dose
>12 years
Weeks 1-2: 50 mg/d PO Weeks 3-4: 100 mg/d PO divided bid
Maintenance: 300-500 mg/d PO divided bid; to achieve maintenance, increase by 100 mg/d q1-2wk
Acetaminophen increases renal clearance, decreasing effects; phenobarbital and phenytoin increase metabolism, causing decrease in levels; concomitant valproic acid increases half-life
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Caution in patients with impaired renal or hepatic function
Pregabalin (Lyrica)
Structural derivative of GABA. Mechanism of action unknown. Binds with high affinity to alpha2 -delta site (a calcium channel subunit). In vitro, reduces calcium-dependent release of several neurotransmitters, possibly by modulating calcium channel function. FDA approved for neuropathic pain associated with diabetic peripheral neuropathy or postherpetic neuralgia and as adjunctive therapy in partial-onset seizures.
Adult
50 mg PO tid initially; if needed, may increase to 100 mg tid within 1 wk
Pediatric
Not established
May cause additive effects on cognitive and gross motor functioning when coadministered with drugs that cause dizziness or somnolence
Documented hypersensitivity
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Discontinue gradually (over a minimum of 1 wk) to minimize increased seizure frequency in patients with seizure disorders; may cause insomnia, nausea, headache, or diarrhea with abrupt withdrawal; common adverse effects include dizziness, somnolence, blurred vision, weight gain, and peripheral edema; may elevate creatinine kinase level, decrease platelet count, and increase PR interval; doses >300 mg/d associated with higher rate of adverse effects and treatment discontinuation; decrease dose with renal impairment (ie, CrCl <60 mL/min)
Analgesics, topical
Topical analgesics may provide localized, temporary pain relief.
Lidocaine (Anestacon, Dermaflex gel, Dilocaine, Lidoderm)
Several recent studies have advocated topical administration of lidocaine as treatment of postherpetic neuralgia. Lidocaine gel (5%) in placebo-controlled study showed significant relief in 23 patients studied. Lidocaine tape also decreases severity of pain.
Adult
Apply to affected area prn
Pediatric
Administer as in adults
None reported
Documented hypersensitivity
Pregnancy
B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions
For external or mucous membrane use only; do not use in eyes
Capsaicin cream (Dolorac, Capsin, Zostrix)
Natural chemical derived from plants of Solanaceae family. By depleting and preventing reaccumulation of substance P in peripheral sensory neurons, may render skin and joints insensitive to pain. Substance P thought to be chemomediator of pain transmission from periphery to CNS.
Adult
Apply to skin tid/qid for 3-4 consecutive wk and evaluate efficacy; not to exceed 4 applications per day
Pediatric
Administer as in adults
None reported
Documented hypersensitivity; do not use on areas of broken or irritated skin
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Avoid contact with eyes; do not bandage tightly; if condition worsens or symptoms persist for 14-28 d, discontinue use and consult physician; for external use only
Selective serotonin and norepinephrine reuptake inhibitors
Potentiates serotonergic and noradrenergic activity in the CNS.
Duloxetine (Cymbalta)
Indicated for diabetic peripheral neuropathic pain. Potent inhibitor of neuronal serotonin and norepinephrine reuptake.
Adult
60 mg PO qd; may initiate with lower dose in patient unable to tolerate 60 mg/d
Pediatric
Not established
Metabolized by CYP1A2 and CYP2D6; coadministration with drugs that inhibit CYP1A2 (eg, fluvoxamine, cimetidine, ciprofloxacin, enoxacin) may increase duloxetine blood levels and toxicity; coadministration with drugs that inhibit CYP2D6 (eg, paroxetine, fluoxetine, quinidine) may increase duloxetine blood levels and toxicity; duloxetine moderately inhibits CYP2D6 and may decrease elimination of CYP2D6 substrates (eg, tricyclic antidepressants, phenothiazines [eg, thioridazine], type 1C antiarrhythmics [eg, propafenone, flecainide]); coadministration with MAOIs may cause serious, sometimes fatal reactions that include hyperthermia, rigidity, myoclonus, autonomic instability, mental status changes including extreme agitation, delirium, and coma (see Contraindications)
Documented hypersensitivity; uncontrolled narrow-angle glaucoma; do not administer within 14 d after stopping MAOI use or initiate MAOIs within 5 d after stopping duloxetine
Pregnancy
C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions
Observe closely for clinical worsening and suicidality when initiating treatment or following dosage change; gradually decrease dose when discontinuing, do not abruptly discontinue; caution with hepatic impairment or end-stage renal disease; may cause slight blood pressure increase; may activate mania or hypomania; common adverse effects include nausea, dry mouth, constipation, decreased appetite, fatigue, somnolence, and increased sweating
More on Diabetic Neuropathy |
| Overview: Diabetic Neuropathy |
| Differential Diagnoses & Workup: Diabetic Neuropathy |
 Treatment & Medication: Diabetic Neuropathy |
| Follow-up: Diabetic Neuropathy |
| References |
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Further Reading
Keywords
diabetic polyneuropathy, diabetic amyotrophy, proximal diabetic neuropathy, mononeuropathy multiplex, diabetic autonomic neuropathy, distal symmetric sensorimotor polyneuropathy, painful diabetic neuropathy, generalized sensorimotor polyneuropathy of diabetes mellitus, diabetic peripheral neuropathy, peripheral neuropathies, chronic hyperglycemia, entrapment neuropathies, diabetic neuropathy, carpal tunnel syndrome, numbness, feeling of wearing gloves, lossof balance, electric shocklike feelings, hypersensitivity to touch, foot slapping, toe scuffing, postural lightheadedness, fainting, urinary urgency, urinary dribbling, urinary incontinence, nocturnal diarrhea, constipation
erectile impotence, ejaculatory failure, nighttime painful paresthesias, impaired proprioception, impaired vibratory perception, sensory ataxia, anhidrosis, bladder atony, unreactive pupils, painless electric tingling, snug bandlike sensation around ankles, snug bandlike sensation around feet, absent ankle jerk reflexes, proprioceptive sensory impairment, gait instability, orthostatic hypotension, resting tachycardia, loss of sinus arrhythmia, sluggish light reflex
diabetic neuropathic cachexia, median neuropathy of the wrist, MNW, ulnar neuropathy of the elbow, UNE, single somatic mononeuropathies, multiple somatic mononeuropathies, single monoradiculopathies, multiple monoradiculopathies, diabetic lumbosacral radiculoplexoneuropathy, DLSRPN, diabetic thoracolumbar radiculoneuropathy, DTLRN, diabetic autonomia, cranial mononeuropathy, anterior ischemic optic neuropathy, diabetic oculomotor cranial mononeuropathies, acute periorbital pain, facial neuropathy, mononeuritis multiplex
diabetic polyradiculopathy, thoracoabdominal neuropathy, lumbosacral radiculoplexopathy, thoracolumbar neuropathy, thoracoabdominal radiculopathy, thoracic radiculopathy, truncal neuropathy, asymmetric proximal motorneuropathy, diabetic femoral neuropathy, femorosciatic neuropathy, diabetic myelopathy, Bruhn-Garland syndrome, poorly controlled diabetes, acute painful neuropathy, chronic inflammatory demyelinating polyneuropathy, CIDP, diabetes mellitus-CIDP, demyelinating neuropathy, diabetic neuropathy
