Compounding Meds For Diabetic Neuropathic Pain: Can They Have An Impact?

Topical compounded medications may play a key role in the armamentarium of treatments for diabetic neuropathy, particularly patients who have multiple comorbidities and polypharmacy issues. Accordingly, this author demonstrates how compounding can optimize drug concentration at the site of pain with a lower risk of adverse sequelae.

The treatment of diabetic neuropathy includes efforts to correct the underlying metabolic disorder as well as addressing symptomatology associated with diabetic neuropathy.

Neuropathy secondary to diabetes is likely the most common peripheral neuropathy that podiatrists treat. The pathologic basis for diabetic neuropathy remains unclear and there are no proven therapies that studies have demonstrated to universally interdict or reverse the progression of diabetic neuropathy. However, some therapies are helpful at reducing symptomatology secondary to diabetic sensory neuropathy, preventing further nerve degeneration and possibly enhancing the regrowth of nerves.¹

Diabetic neuropathy typically begins as a small fiber neuropathy affecting the small unmyelinated or thinly myelinated nerve fibers that subserve pain, temperature perception, heart rate, blood pressure, sweat function and gastrointestinal function.²

The signs and symptoms of diabetic neuropathy include manifestations of sensory, motor and autonomic dysfunction.³ These symptoms may include numbness, dysesthesia, paresthesia or allodynia. Decreased thermal sensation and vasomotor dysfunction are also early manifestations of diabetic neuropathy. Edema, imbalance and ulceration are known complications of diabetic neuropathy.
Motor neuropathy may be characterized by an intrinsic minus foot with atrophy of the normal intrinsic muscles, resulting in hammertoes and prolapse of metatarsal heads. Symptoms such as cramping, aching, and decreased knee and ankle reflexes may also occur. Autonomic neuropathy may be associated with vascular calcification, skin xerosis with sudomotor dysfunction, neuropathic edema, resting tachycardia or Charcot joint disease.³

A variety of metabolic disorders occur in patients with diabetic neuropathy. This includes sorbitol accumulation, increased fructose, decreased myo-inositol, glycation end products, the generation of reactive oxygen species, decreased nitric oxide production, activated protein kinase C, increased cytokine activity and decreased neural growth factors.

Pertinent Considerations In The Treatment Of Diabetic Neuropathy
The treatment options for diabetic neuropathy include the management of serum glucose, which will delay the onset of the condition and slow the progression of neuropathy. A variety of supplements such as L-methylfolate/methylcobalamin/pyridoxal-5’ phosphate (Metanx, Pamlab), alpha lipoic acid, carnitine, benfotiamine and others have been effective in the stabilization of symptomatology associated with diabetic sensory neuropathy.⁴ In addition, pain management for dysesthesia and paresthesia may be required.

The use of antinociceptive medications may be helpful in the treatment of painful paresthesia and dysesthesia in the patient with diabetes. However, such medications do not assist in reversal of the underlying metabolic deficits responsible for the etiology. Similarly antinociceptive medications are not helpful in the treatment of motor neuropathy or autonomic neuropathy, in the patient with diabetes.

The reversal of the actual metabolic defects and remittive therapy for neuropathy generally require good control of diabetes as well as supplements or nutritional therapy. Additionally, decompression surgery may be of benefit in decreasing the progression of, or reversing, symptomatic and non-symptomatic diabetic neuropathy.⁵

The majority of patients with diabetic neuropathy demonstrate sensory anesthesia, motor dysfunction and autonomic dysfunction, and not paresthesia or dysesthesia. However, between 20 and 30 percent of patients with diabetes have disturbances with paresthesia and dysesthesia, requiring pain management.^6-8

When it comes to painful neuropathy, clinicians initially rule out non-diabetic causes of neuropathy and look to stabilize glycemic control.⁹ The treatment of symptomatic diabetic neuropathy typically involves the use of tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors, anticonvulsant medications or opioid or opioid-like medications.¹⁰ Unfortunately, concern about potential adverse reactions with these oral medications prevents their use in many patients. Tricyclic antidepressants, for example, may be associated with weight gain, edema, anticholinergic side effects, neuropsychiatric side effects and cardiac conduction abnormalities.¹¹ Similarly, antidepressants may be associated with a significant risk of incoordination, falls and other neuropsychiatric side effects.¹²

Since these oral medications for the treatment diabetic neuropathy have a significant side effect profile, many podiatric physicians generally do not employ them as they are understandably reluctant to utilize such medications to provide relief from painful paresthesia and dysesthesia.
 
Comparing Oral Medications To Topical Compounds And Their Mechanisms Of Action For Diabetic Neuropathy
Numerous physiologic mechanisms transmit pain and we can generally reduce these mechanisms to transduction or transmission functions. A variety of receptors participate in either the initiation of pain conduction or the blockade of pain transmission. Typically, oral medications for the treatment of painful diabetic neuropathy act at one receptor site. This may explain why some patients do well, for example, with an anticonvulsant, and do not respond to other agents such as antidepressants. It is difficult to predict in each individual patient which transmission site or sites are most important for the degeneration of diabetic neuropathic pain. Therefore, the prescription of medications is somewhat “hit or miss.”

As an example, antidepressants have activity in the generation of peripheral analgesia by activation of adenosine a1 receptors while inhibiting noradrenaline release as well as the uptake of 5-hydroxytryptamine. Topical agents such as capsaicin have long been known to produce analgesia by activation of vanilloid receptor-1, blockade of substance P and release of calcitonin gene-related peptide.¹³ Local anesthetics may act on voltage-gated calcium-2 channels and reduce ectopic repetitive firing of primary nerve afferents following injury.

Topically applied compounded medications provide relief of diabetic paresthesia and dysesthesia via multiple mechanisms of action. Since they affect multiple receptor sites and can simultaneously inhibit the production of substances that initiate pain, topical compounded medications provide an increased ability to resolve pain.

Topical compounded medications can simultaneously provide an anti-inflammatory medication, a tricyclic antidepressant or an anticonvulsant. They offer the opportunity to provide direct anti-inflammatory and antinociceptive relief with marked reduction in the potential adverse reactions associated with oral medications. Therefore, the utilization of a topical compounded medication can reduce the production of proinflammatory cytokines and affect opioid receptors, calcium channel blockers, sodium channel blockers, glutamate receptors and other receptor sites involved in the transmission or production of pain.

Many patients with diabetes are also taking medications for a variety of comorbid conditions. These patients may be less than ideal candidates for anti-inflammatories due to declining renal function, a history of gastrointestinal pathology or coexisting hypertension. Similarly, a variety of significant drug interactions may occur between antidepressants, anticonvulsants, opioid analgesics and the medications that the patient with diabetes is taking not only for the management of diabetes but for a variety of comorbidities. Other factors such as renal dysfunction may limit the dosage of antinociceptive medications. Utilization of the same medications topically in compounded form significantly reduces the risk of drug interactions in these patients. Compounding also increases the possibility of providing pain relief in these patients while reducing the risks of adverse sequelae.

Examples of pain inhibitory activity affected by the use of compounded medication include stimulation of opioid receptors and effects on adenosine, cannabinoid receptors, gamma-aminobutyric acid (GABA), morphinan and somatostatin among other pain conducting blockade activities.

Conversely, the blockade of agents that will produce pain, such as bradykinin, prostaglandins, histamine, serotonin, adenosine triphosphate (ATP) and others, can occur at the same time. Accordingly, the administration of topically applied antinociceptive therapy offers the opportunity to provide pain relief via multiple mechanisms of action.

As a result, the patient benefits from the administration of pain management at multiple receptor sites while reducing the incidence of potential adverse sequelae. The healthcare provider can prescribe a topical mixture of agents that either interdict the production of substances initiating pain or concurrently interfere with the transmission of pain.

Topically applied medications for the treatment of diabetic neuropathy may concurrently include various mixtures of ketamine, gabapentin (Neurontin, Pfizer), clonidine, lidocaine, imipramine, doxepin (Silenor, Pernix Therapeutics), nifedipine (Procardia, Pfizer), anti-inflammatory medication, calcium channel blockers, vasodilators, muscle relaxants and other agents as the clinician determines to be appropriate.
As the plasma concentration of topically applied medications for the treatment of diabetic neuropathy is 5 to 15 percent of the corresponding oral medications, the incidence of side effects is dramatically lower than systemic use of the same medications.¹⁴
 
What Advantages Do Compounded Medications Provide?
The use of compounded medications for the treatment of diabetic neuropathy allows for optimization of drug concentration at the origin site of pain while providing lower systemic levels and a reduced risk of side effects. Additionally, few drug interactions exist when one utilizes the medications topically. Furthermore, titration of the medication, which one would typically employ with oral medications, is not required.
The use of compounded medication for the treatment of diabetic neuropathy allows the practitioner to individualize each prescription. One may utilize vasodilators when indicated and combine them with calcium channel blockers, local anesthetics, anticonvulsants or whatever agents the treating healthcare provider determines to be necessary. Similarly, clinicians can make compounded medications in strengths not typically available by oral administration. The use of these medications in a compounded form is helpful for patients who cannot swallow pills. These medications are also particularly helpful for the treatment of patients who are drug resistant and do not wish to take additional oral medications.

The utilization of compounded medications for the treatment of symptomatic neuropathy is part of an overall program for the treatment of diabetic neuropathy. Included in this overall program is proper management of diabetes and the use of supplements such as Metanx, carnitine, alpha lipoic acid or other agents to reverse the underlying metabolic defect, and prevent or reverse nerve damage. Additionally, decompression surgery may be helpful for the treatment of diabetic neuropathy.¹⁵

The basic principles guiding the treatment of diabetic neuropathy are:
• optimal management of diabetes;
• optimal management of the comorbid conditions that exacerbate diabetic neuropathy;
• reversal of metabolic deficits within the nerve;
• pain relief with analgesics or adjunctive analgesics, and physical therapy modalities; and
• evaluation for superimposed entrapment neuropathy.
 
What You Should Know About Topical Agents And Compounding
To a large extent, the selection of specific agents utilized for the topical compounded management of painful diabetic neuropathy is hit or miss. Physician experience and patient response determines the selection.

Anti-inflammatories. A variety of topically applied anti-inflammatory agents, such as ibuprofen, flurbiprofen, ketoprofen or diclofenac (Voltaren, Endo Pharmaceuticals), are in use in daily practice for the management of musculoskeletal pain. These agents work by the inhibition of prostaglandins such as PGE-2, which lower the threshold for pain conduction and act synergistically with other agents that initiate pain, such as bradykinin, serotonin or 5-hydroxytryptamine. The oral administration of these agents in the patient with diabetes may be limited as they may exacerbate concurrent renal dysfunction or hypertension. Compounding for neuropathy management may include such agents as diclofenac and ibuprofen although clinicians may utilize other topical anti-inflammatories.

Local anesthetics. I have found local anesthetic agents such as lidocaine, tetracaine or bupivacaine particularly helpful in the management of pain diabetic neuropathy. In addition, these agents provide local vasodilation, which may be helpful for the management of reduced neural vascular flow or in the treatment of painful neuropathic ulceration or vasospastic contributions to neuropathy pain. Typically, one utilizes a prescription of 5 to 10% for these agents.

Calcium channel blockers. Calcium channel blockers such as topical nifedipine or verapamil are vasodilators, and may increase neural vascular perfusion, contributing to the resolution of any ischemic neuropathy component. Concentrations of 2 to 15% are typical.

Gabapentin. Topical gabapentin may contribute to neuropathic pain relief while avoiding potentially troublesome neuropsychiatric side effects. Gabapentin contributes to pain relief by blocking the transmission of pain by interdiction of glutamate at the NMDA receptor and diminution of the AMPA receptor active through reduction of sodium channel activity. One typically prescribes 6% to 10% topical gabapentin.

Tricyclic antidepressants. Tricyclic antidepressants such as amitriptyline and imipramine, or drugs with tricyclic antidepressant-like activity such as cyclobenzaprine are effective in the management of painful diabetic sensory neuropathy. As adjuvant analgesics, these agents derive their activity from the interdiction of norepinephrine and 5-hydroxytryptamine uptake, binding to opioid receptor sites, blocking NMDA receptor sites, blockage of AMPA-Na receptor sites, and other activity such as that which occurs at muscarinic receptors. The topical concentration of tricyclic antidepressants is usually between 5 and 10%.

Baclofen. Baclofen, a muscle relaxant, may provide pain relief with topical administration. Baclofen exerts its analgesic activity through agonist activity for GABA-b and modulating neurotransmitter release by mimicking GABA. When including baclofen as part of a compounded prescription for topical application, a 2% concentration is typically required.

Clonidine. Clonidine is an alpha-2 agonist that blocks norepinephrine release to prevent the activation of peripheral adrenergic receptors. Use a 0.2% concentration when combining clonidine with other topical agents.

Ketamine. Not infrequently, physicians employ 5% to 10% ketamine as a part of the topical compounded treatment of painful diabetic sensory neuropathy. Ketamine efficacy derives from its NMDA-Ca channel blocking activity and blocking of peripheral NMDA receptors, thus interdicting pain transmission.

When it comes to compounding formulations for painful diabetic neuropathy, typical prescriptions include ketamine, verapamil, gabapentin, clonidine, lidocaine, imipramine, carbamazepine, baclofen, bupivacaine and cyclobenzaprine.  

In Conclusion
Topical compounded medications may contribute to the resolution or decreased frequency and intensity of painful diabetic sensory neuropathy. They are typically part of a more global clinical approach to the management of painful diabetic sensory neuropathy. Topical compounding offers the potential benefits of site-directed treatment with reduced potential for adverse sequelae.

Dr. Jacobs is a Fellow of the American College of Foot and Ankle Surgeons, and a member of the Academy of Physicians in Wound Healing. He is in private practice in St. Louis.   

Dr. Jacobs writes a DPM Blog for Podiatry Today, which you can read at www.podiatrytoday.com/blog/290 .
 
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