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ADA/PDR: Medications for the Treatment of Diabetes, Ch. 18, Pt. 1

Feb 26, 2011

Diabetic Neuropathic Disorders


John R. White, Jr., PharmD, PA
R. Keith Campbell, PharmB, MBA, CDE
Travis E. Sonnett, PharmD

Adaptation by Matthew Szabo, PharmD (candidate)


The two most common forms of neuropathy that affect diabetes patients are diabetic peripheral neuropathy (DPN) and diabetic autonomic neuropathy (DAN). 

Diabetic Peripheral Neuropathy

DPN occurs in patients affected by both Type 1 and Type 2 diabetes, and results from damage that has occurred in multiple pathways. The main mechanism from which DPN is thought to develop is chronic hyperglycemia, which causes both neuronal and microvascular damage.  Blood vessels that have sustained damage display a poor ability to vasodilate when acted upon by nitric oxide, resulting in widespread ischemia of the microvasculature. Eventually, hypoxia occurs leading to neural cell death. Other changes include an increase of sodium in nerve cells, resulting in slower motor and sensory nerve conduction. Low antioxidant levels are also theorized to contribute to DPN in diabetic patients, as free radicals can form through the oxidation of glucose and other mechanisms in their absence, leading to neural cell death. 

The clinical symptoms of DPN reveal themselves as sensation changes in the extremities, usually starting in the toes and the feet. “Tingling,” “burning,” or “crawling” are words typically used by patients to describe the affected areas, but complete lack of sensation may also arise. Symptoms may continue to progress with time, which increases the patient’s risk of developing other problems, including foot ulceration. Fortunately, treatment options for DPN exist.

Diabetic Autonomic Neuropathy

DAN is arguably the most dangerous type of neuropathy affecting diabetes patients due to the involvement of the cardiovascular, gastrointestinal and genitourinary systems. DAN does not require large nerve fibers to be involved in the disease process, which is why some consider it to be a broader form of DPN. Problems that arise from DAN in the cardiovascular realm include hypotensive episodes, arrhythmias, instability related to anesthetic administration, and increased risk of heart attack and sudden death. DAN can often affect the entire GI tract, which manifests as gastroparesis and esophageal issues. Damage to the genitourinary system can affect smooth muscle coordination, leading to urinary incontinence and sexual dysfunction in both sexes. Therapy exists to treat problems affecting each of these systems, and usually involve a high level of glucose control, as well as medications that treat symptoms affecting each system.

DPN Treatment Options 

GABA Analogues (Gabapentin, Pregabalin)

  • Available for treatment of neuropathic pain associated with post-herpetic neuralgia and DPN
  • These two agents share mechanism of action, but have kinetic differences.
  • Structurally related to the neurotransmitter gamma aminobutyric acid (GABA) but do not use this pathway in their mechanism of action
  • Binds to neural presynaptic voltage-gated calcium channels, decreasing calcium flow resulting in limiting neuronal excitation
  • This mechanism is theorized to explain the analgesic effect and decrease in neuropathic pain associated with use.
  • Other possible mechanisms: suppression of substance P, glutamate, and upregulation of GABA transporters
  • Pregabalin follows a linear kinetics model, peaking at 1.5 hours after administration and achieving steady state after 1-2 days continual dosing.
  • Gabapentin in a nonlinear agent, with bioavailability based on dose
  • CYP450 system affects neither drug’s metabolism.
  • Both are mainly cleared renally, and dose adjustments may be required based on renal function and in elderly patients.
  • Both agents have a half-life of 5-7 hours.
Clinical Advantages
  • Pregabalin, due to its linear kinetics, may have a more predictable dose/response than gabapentin.
  • Gabapentin’s FDA approved max dose is 3600mg/day, but higher doses have shown success in studies.
  • Gabapentin tolerance may develop with continued use, and thus dose increases may be required to treat pain. Pregabalin tolerance has yet to be reported but continued monitoring is recommended.

Therapeutic Considerations

  • Increased risk of suicidal ideation has been associated with GABA analogues during clinical trials.
  • Common side effects include: sedation, dizziness, CNS depression, blurred vision, balance issues, tremor and confusion.
  • GABA analogues are classified pregnancy risk category C, and should only be used when the benefit outweighs the risk; excretion in breast milk is unknown.
  • Administration with other CNS depressants may increase the risk of sedation and other side effects.
  • Pregabalin administered with thiazolidinediones (e.g., Actos) should be done with caution due to the increased risk of weight gain and edema.
  • Gabapentin should be administered at least 2 hours before or after antacid therapy due to a decrease in bioavailability of gabapentin by 20%.
  • Discontinuation of either agent should involve a downward titration to avoid withdrawal-like symptoms.
  • Pregabalin is a schedule C-V controlled substance, and monitoring for misuse should be done when prescribing this medication.
  • First agent FDA approved for DPN
  • Similar to venlafaxine, but only medication in SNRI class approved for use in both major depressive disorder and DPN
  • Analgesic effect achieved as a dual acting serotonin-norepinephrine reuptake inhibitor (SNRI)
  • Serotonin and norepinephrine both cause neurogenic transmission in the brainstem and spinal column, and are theorized to result in the minimization of pain transmission from the periphery to the CNS via these pathways.
  • Comes in an encapsulated form with enteric coated pellets to avoid degradation in the stomach and allow for absorption in the small intestine
  • Absorption occurs in 2 hours, with peak concentration in 6 hours.
  • Steady state levels are achieved after 3 days of continuous dosing.
  • 90% protein bound, increasing risk of interactions with other protein bound medications
  • Metabolism occurs via CYP450 2D6 and 1A2.
  • Half-life is 8-17 hours.
  • Primary elimination is through the urine (70%), and secondarily the feces (20%).
Clinical Advantages
  • Potentially the optimal agent for diabetic suffering from both depression and DPN
  • Has fixed dosing and tolerance has not been reported

Therapeutic Considerations

  • Substrate of CYP2D6 and A12, and thus will be affected by both inhibitors and inducers of these isoenzymes
  • Inhibitor of CYP2D6, and has been shown to increase levels of medications such as flecainide and propafenone
  • Monitoring for cardiovascular changes should occur with initiation of therapy, as increases in blood pressure and heart rate may occur.
  • Common side effects include: nausea, vomiting, dizziness, fatigue, and somnolence.
  • Adverse effects may occur within the first eight weeks of treatment initiation or at dosage increase, but normally diminish with time.
  • Shown to be well tolerated by the elderly, and renal and hepatic dose adjustments are not necessary
  • Discontinuation should occur via a downward dose titration.
Tricyclic Antidepressants
  • Have been available for more than 40 years
  • First medication class to be used in placebo-controlled trials for neuropathic pain.
  • Considered first-line agents for treatment of DPN by many healthcare professionals
  • Primary mechanism of action occurs via the inhibition of serotonin and norepinephrine reuptake and related to the antidepressant effect
  • Analgesic effect is postulated to occur via a secondary mechanism related to alpha-adrenergic, H1-histaminergic, and muscarinic receptor blockade, sodium-channel blockade, or possibly N-methyl-D-aspartate blockade.
  • Peak plasma levels occur within 24 hours, but peak effect may not be seen for 2-4 weeks after the initiation of therapy.
  • Highly protein-bound, and thus must be monitored for interactions with other protein-bound agents
  • Half-life varies among agents, ranging from 6-100 hours.
  • Metabolism is mainly via the liver, with excretion occurring in the urine and feces.
Clinical Advantages
  • Though not FDA approved for DPN, studies have shown success in the treatment of DPN for all of the agents covered.
  • Medication utility is limited by medication side effect profiles, however nortryptyline and desipramine are the preferred agents in the class due to a safer side effect profile and frequency
  • Often useful for use in patients with other comorbid conditions, such as depression, sleep disorders, urinary incontinence, and behavioral disorders

Therapeutic Considerations

  • TCA are separated into two categories: secondary amines (nortriptyline, desipramine) and tertiary amines (amitryptyline, imipramine).
  • The mechanisms of each class are the same, but the side effect profile of the secondary amines is much less severe than the tertiary group.
  • The most common side effect is anticholinergic effects.
  • Patients with history of suicidal ideation should be monitored for increases in this type of behavior, due the potential to use TCAs inappropriately causing toxicity and death.
  • Elderly patients should be closely monitored for adverse events, as aged patients are more susceptible to experience confusion, delirium and acute dementia.
  • Not recommended to use during pregnancy, deemed pregnancy category C or D depending on the agent, and agents should not be used in nursing mothers as TCAs actively cross into breast milk
  • Patients currently on antidepressant therapy should be monitored for serotonin syndrome when starting a TCA.
  • TCAs are not recommended to be used with monoamine oxidase inhibitors.
  • Dosages of TCAs vary greatly between agents, and can have a large variation within the medication itself.
  • Titration of dose is recommended and can require several weeks to months to reach the target dose. Patients should be advised that TCAs may take two to four weeks to reach peak effect, even after a change in dose, and compliance must be maintained to increase the chance of successful treatment.
  • One of the oldest medications studied and used for neuropathy
  • Clinical trials dating back to the 1960s have shown success when targeted specifically for trigeminal neuralgia and DPN.
  • Risk of adverse effects may outweigh the benefits when compared to newer medications.
  • Usually considered a third line treatment option for DPN
  • Classified as an iminostilbene derivative, similar to the tricyclic antidepressants in structure
  • Mechanism is related to its ability to block voltage-dependent sodium channels, thus reducing ectopic nerve discharge and stabilizing neural membranes while minimizing effects on normal conductance.
  • Though chemically similar to TCAs, carbamazepine does not seem to have a mechanistic effect on neurotransmitters.
  • Carbamazepine’s kinetics are responsible for complicating therapy management.
  • The therapeutic treatment window for seizures is 4-12 mcg/mL, however no standard range for neuropathic pain exists.
  • Oral forms of the drug have a bioavailability of 70-80% which is increased in the presence of food.
  • Protein binding is 76%.
  • Mainly metabolized via CYP450 3A4
  • Accumulation of its active metabolite plays a large role in associated toxicity
  • Simultaneous use with lamotrigine or valproic acid increases toxicity risk.
  • Half-life is 25-65 hours, and excretion occurs in both the urine and feces.
Clinical Advantages
  • Considered a third-line treatment option for DPN
  • Side effects limit use, but reports have suggested success with carbamazepine therapy when other treatment classes have failed, possibly due to its unique mechanism of action in comparison with other agents.

Therapeutic Considerations

  • Adverse events are a common occurrence with use, resulting in effects occurring 50% of the time.
  • Common side effects include: dizziness, drowsiness, blurred vision, and nausea.
  • Less common side effects include rare blood disorders that can occur even after established use, as well as increased suicidal ideation and behavior.
  • Patients with a history of hypersensitivity to barbiturate, hydantoin, or TCA medications should not use carbamazepine as cross-sensitivity can occur in 30-80% of patients.
  • Caution for use in patients with existing liver or cardiac disease
  • Elderly patients should be monitored for increased risk of confusion, delirium, and acute dementia.
  • Classified as pregnancy category D, and is not recommended for use in pregnant or nursing mothers
  • Topical patches have been clinically studied for use in DPN treatment.
  • Shown to decrease pain levels in DPN, as well as increase quality of life and reduce the negative impact neuropathy may have on the activities of daily living
  • Mechanism of action is via inhibition of voltage-gated sodium channels, which are theorized to spontaneously activate in damaged neurons.
  • Lidocaine patches have been found to reach effect in 5-15 minutes, with peak plasma concentrations occurring after 18 hours.
  • Topical lidocaine reaches systemic levels only 1/10 the level necessary to treat cardiac arrythmias, and thus does not have an appreciable effect on the cardiovascular system.
  • Metabolism occurs primarily in the liver, with excretion via the kidneys.
Clinical Advantages
  • Can be used as an adjunct to oral therapy, and is not considered primary therapy
  • Has not been shown to be as effective at reducing pain as other oral therapies

Therapeutic Considerations

  • Common side effects include skin site reactions, irritations and discoloration. These reactions usually occur within minutes to hours, and are mild in nature.
  • Systemic reactions are extremely rare.
  • No adjustments due to age, hepatic, or renal function are necessary.
  • Successfully utilized in the treatment of neuropathic pain associated with both post-herpetic neuralgia and DPN
  • Derived from the herb Capsicum officinalis
  • Theorized to stimulate sensory afferent C-fibers, depleting substance P and desensitizing receptors
  • Lasts four to six hours after application, and must be applied three to four times daily to achieve maximal effect
  • Therapeutic effect may be seen as early as two weeks, but maximal effect takes between six to eight weeks.
Clinical Advantages
  • Considered an adjunct to oral therapy, and is not considered a primary agent
  •  Limited studies have shown pain reduction, but study populations were limited by intolerance to adverse effects.

Therapeutic Considerations

  • Initial application may result in an unpleasant burning sensation, which sometimes persists for several days after initial use, and thus causes many patients to discontinue the medication.
  • Other side effects include tingling, stinging, redness, or irritation of the skin.
  • Application of heat with capsaicin may increase the effect and intensify the sensation.
  • No adjustments due to age, hepatic, or renal function are necessary.

Next Week: Part 2 — Gastroparesis & Erectile Dysfunction Treatment Options

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