Medication Summary
For the treatment of diabetic neuropathy, acute cases may be able to be managed with standard analgesics, but other agents will likely be necessary for chronic pain. Occasionally, muscle relaxants may be of benefit in the first 2 weeks of therapy.
Each type of pain or a combination of pain types should be treated. Reevaluation of the painful neuropathy should be performed every 6 weeks.[87] Every effort should be made to taper and eventually to stop therapies. Therapies may need to be reinstated at later dates if symptoms flare up.
The pharmacologic agents listed below are commonly used for the symptomatic treatment of diabetic neuropathy. Most are not specifically approved by the United States Food and Drug Administration for this use, however.[16, 71, 73, 74, 59, 23, 18, 88, 89, 90]
Nonsteroidal Anti-Inflammatory Drugs (NSAIDs)
Class Summary
In patients with acute painful neuropathy, simple analgesics such as nonsteroidal anti-inflammatory drugs [NSAIDs] and acetaminophen may provide pain control.[87] They also may be used as first-line therapy in painful peripheral neuropathy. With chronic painful neuropathy, simple analgesics are typically not effective. More often, chronic neuropathic pain requires treatment with off-label medications.
Ibuprofen (Advil, Motrin, Ibuprin)
NSAIDs may help decrease inflammation caused by diabetic neuropathy. They also decrease pain.
Naproxen (Naprosyn, Anaprox, Naprelan)
For relief of mild-to-moderate pain; inhibits inflammatory reactions and pain by decreasing activity of cyclo-oxygenase, which results in a decrease of prostaglandin synthesis.
Analgesic, Topical
Class Summary
Identifying the type of pain can direct the course of therapy. Dysesthetic pain can be relieved with capsaicin cream (Dolorac, Capsin, Zostrix) applied qid. Capsaicin cream may cause pain during the initial few applications; patients need to be made aware of this potential effect. Additionally, few patients comply with the frequent dosing, and the cream is messy on socks and shoes. 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.
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.
Anticonvulsant
Class Summary
Gabapentin (Neurontin) has been reported to work excellently in the treatment of dysesthetic pain.[88] Carbamazepine (Tegretol, Carbatrol, Epitol) has been used mainly for partial seizures and can be used in peripheral neuropathy as a third-line agent if all other agents fail to reduce or improve symptoms of diabetic neuropathy. Carbamazepine is a potentially effective treatment for chronic neuropathic pain.[91] However, the studies evaluating carbamazepine for chronic neuropathic pain must be interpreted with caution.
Pregabalin (Lyrica) is approved for the treatment of pain due to generalized diabetic peripheral neuropathy and may be considered as a first-line agent in diabetic peripheral neuropathic pain.[92]
According to the 2011 American Academy of Neurology (AAN)/American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM)/American Academy of Physical Medicine and Rehabilitation (AAPMR) guideline, lamotrigine (Lamictal) should probably not be recommended for diabetic neuropathy treatment due to relative inefficacy in pain control when compared with placebo.[93]
Gabapentin (Neurontin)
Excellent in treating pain described as dysesthetic, such as burning or pins and needles. Gabapentin should be used after all other first-line measures have been used without relief. This drug is a second-generation anticonvulsant. Gabapentin increases brain GABA levels, binds to the alpha2-delta subunit of voltage-gated calcium channels, and inhibits branched chain amino acid transferase.
Carbamazepine (Tegretol, Carbatrol, Epitol)
AED used mainly in partial seizures. Can be used in peripheral neuropathy as a third-line agent if all other agents fail to reduce or improve symptoms of diabetic neuropathy.
First-generation anticonvulsant. Slows the recovery rate of voltage-gated Na channels, minor Ca2+ channel antagonist effect, and is related chemically to tricyclic antidepressants.
Pregabalin (Lyrica)
FDA approved for the treatment of pain due to generalized diabetic peripheral neuropathy. Excellent in treating pain described as dysesthetic, such as burning or pins and needles. Pregabalin may be considered as a first-line agent in diabetic peripheral neuropathic pain. This drug is also a second-generation anticonvulsant. Pregabalin binds to the alpha-2-delta subunit of voltage-gated calcium channels and inhibits branched chain amino acid transferase. This reduces inappropriate calcium influx into a hypersensitized cell.
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.
Antidepressant, Tricyclic
Class Summary
For paresthetic pain, tricyclic antidepressants such as imipramine (Tofranil), nortriptyline (Pamelor, Aventyl), and amitriptyline (Elavil) have been shown to be useful as analgesics for paresthetic pain.[90]
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.
Imipramine (Tofranil)
This is the original TCA used for depression. These agents have been suggested to act by inhibiting reuptake of norepinephrine at synapses in central descending pain modulating pathways located in the brainstem and spinal cord.
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.
Antidepressant, Selective Serotonin/norepinephrine Reuptake Inhibitor (ssnri)
Class Summary
Duloxetine (Cymbalta) was the first medication to be approved specifically for the treatment of diabetic neuropathy. Venlafaxine (Effexor) has been recommended by the AAN/AANEM/AAPMR guidelines for consideration in diabetic neuropathy pain management.[94]
Duloxetine (Cymbalta)
Indicated for diabetic peripheral neuropathic pain. Potent inhibitor of neuronal serotonin and norepinephrine reuptake.
Antidepressant, Serotonin Reuptake Inhibitor
Class Summary
Paroxetine (Paxil) can be used as second-line or third-line treatment of painful diabetic neuropathy and is helpful in patients who are already depressed. Citalopram (Celexa) can be used as a second- or third-line therapy in neuropathy resulting from paresthesia.[90]
Citalopram (Celexa)
One of the newest antidepressants can be used as a second- or third-line therapy in neuropathy resulting from paresthesia.
Paroxetine (Paxil)
SSRI that can be used in second-line or third-line treatment of painful diabetic neuropathy; good for patients who already are depressed.
Antiarrhythmic Agent, Class I-b
Lidocaine anesthetic (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.
Prokinetic Agents
Class Summary
Medications for diabetic gastroparesis are erythromycin (E-Mycin, Erythrocin, Ery-Tab, E.E.S.), cisapride (Propulsid), and metoclopramide (Reglan, Maxolon, Clopra). However, in 2009 the FDA issued a black box warning that long-term use of metoclopramide has been linked to the development of tardive dyskinesia.[95]
Erythromycin (E-Mycin, Erythrocin, Ery-Tab, E.E.S.)
Macrolide antibiotic that duplicates the action of motilin, which is responsible for the migrating motor complex activity. Binds to and activates motilin receptors. IV administration of this drug enhances the emptying rate of both liquids and solids. Effect can be seen with PO erythromycin. Substitution of the enteric-coated form may be tolerated better by the patient.
Cisapride (Propulsid)
Voluntarily withdrawn from the US market in July 2000. Available for gastroparesis via a limited access treatment IND. Facilitates release of acetylcholine from the myenteric plexus. Increases lower esophageal sphincter pressure, lowers esophageal peristalsis, and increases rate of gastric emptying of both liquids and solids. Increases postprandial/postantral motility and appears to normalize fasting and fed gastric motor patterns.
Metoclopramide (Reglan, Maxolon, Clopra)
Dopamine antagonist that stimulates acetylcholine release in the myenteric plexus. Acts centrally on chemoreceptor triggers in the floor of the fourth ventricle, which provides important antiemetic activity; side effects and tachyphylaxis are problems.
Antidepressant, Tetracyclic
Desipramine (Norpramin)
These agents have been suggested to act by inhibiting reuptake of noradrenaline at synapses in central descending pain modulating pathways located in the brainstem and spinal cord.
Synthetic Adrenocortical Steroids
Class Summary
Florinef is used in severely symptomatic orthostatic hypotension. Use if salt tablets and pressure stockings fail to alleviate hypotension.
Fludrocortisone acetate (Florinef)
Used to increase standing blood pressure. Acts to increase sodium retention and expand plasma volume.
Cholinergic Agent
Bethanechol hydrochloride
Used for selective stimulation of the bladder to produce contraction to initiate micturition and empty the bladder. Found to be most useful in patients who have bladder hypocontractility, provided they have functional and coordinated sphincters. Rarely used due to difficulty in timing effect and because of gastrointestinal stimulation.
Laxative, Bowel Evacuant
Polyethylene glycol (PEG) solution (MiraLax, GlycoLax)
For treatment of occasional constipation. In theory, less risk of dehydration or electrolyte imbalance with isotonic polyethylene glycol compared with hypertonic sugar solutions. Laxative effect generated because polyethylene glycol is not absorbed and continues to hold water by osmotic action through small bowel and colon, resulting in mechanical cleansing.
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| Fiber Type | Size | Modality | Myelination |
| A-alpha (I) | 13-20 micrometers | Limb proprioception | Yes |
| A-beta (II) | 6-12 micrometers | Limb proprioception, vibration, pressure | Yes |
| A-delta (III) | 1-5 micrometers | Mechanical sharp pain | Yes |
| C (IV) | 0.2-1.5 micrometers | Thermal pain, mechanical burning pain | No |
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