David S. Klein, M.D.

Pain in the Diabetic Patient

Pain is the most common complaint that brings patients to seek medical care, and diabetes is a common medical condition in the general population. It follows, then, that many patients with diabetes will complain of pain. A diabetic with pain is a far cry from a patient with diabetic neuropathy. It is common to encounter patients who suffer from diabetes as well as any number of other medical conditions that present with pain, but it is most unfortunate to find that many of these patients are improperly diagnosed with diabetic neuropathy, when in fact they suffer from fibro-muscular pain, arthritic pain, or entrapment neuropathy.

Diabetic neuropathy does not imply nerve pathology coincidental to the presence of diabetes mellitus. Rather, diabetic neuropathy implies pathological changes of a characteristic nature that results from metabolic abnormalities. While this would appear to be a simplistic statement, the general approach to the complaint of pain in the diabetic population is probably the principal reason that diabetic neuropathy is often difficult to control. In the absence of an accurate diagnosis, successful treatment becomes unlikely.

NOTE:  I will have a separate section on nutriceutical recommendations, shortly. 

Also, I have a new video CD (download) coming available in December 2005, or shortly thereafter.

Etiology:

The precise metabolic factor or factors that cause the neuropathic damage may not yet be precisely identified. It is known, however, that high blood glucose, longer duration of diabetes, insulin level, abnormal serum lipid levels, and co-morbid endocrinopathies are important to the development of diabetic neuropathy. Ischemia of the peripheral nerve due to damage to the vasovasorum is certainly a factor.

• autoimmune factors that cause inflammation in nerves
• mechanical injury to nerves, such as carpal tunnel syndrome
• inherited traits that increase susceptibility to nerve disease

Diabetic neuropathy results in large part from damage to the microvasculature and nervous innervation of the peripheral nerves, themselves. That is, damage to the Nervi nervorum and vasonervorum. As these smaller nervous and vascular structures become damaged, and the peripheral nerve tissue becomes dysfunctional. The longer the nerve, the more susceptible to diabetic damage; the greater the degree of myelination, the greater the resistance to damage. The thin, unmyelinated portions of the peripheral nerves demonstrate dysfunction first, the thicker, myelinated portions demonstrate dysfunction last. The pathology is evident earliest in the autonomic nervous system, followed by the sensory portion of the peripheral nerve, and the motor component, last of all.

While diabetic neuropathy affects all nervous tissue, the peripheral nerves -- those that are outside of the brain and spinal cord, such as nerves in the arms, legs, hands, and feet are first to become involved. Diabetic neuropathy is different from diabetic myopathy, in which the small muscles of the foot, as well as some other muscles, become weaker.

Symptoms:

Typical complaints include numbness and tingling, beginning in the feet and hands. “Burning-numbness” is quite common. Symptoms are minimal, at first, and over the course of years, the severity can increase, insidiously. Nerve damage can take place over several years, and mild cases go unnoticed for a long time. Symptoms first involve the sensory and autonomic nervous system.

Symptoms may include:

• numbness, tingling, pain in the toes, feet, legs, hands, arms, and fingers
• painless sores on the toes and soles.
• indigestion, nausea, ‘GERD’
• diarrhea, constipation, bloating
• dizziness or faintness due to changes in postural blood pressure
• urinary hesitancy, difficulty voiding
• erectile dysfunction, vaginal dryness, loss of libido, dysorgasmia

The diabetic neuropathy that involves the autonomic nervous system results in changes in digestion, bowel and bladder function, sexual response, and perspiration. Other, later complaints can include extreme sensitivity to touch, vertigo, tinnitus, and loss of balance. Blisters and sores appear on desensitized areas of the foot due to pressure and painless- injury that goes unnoticed.

Diagnosis:

The diagnosis of ‘diabetic neuropathy’ is not a diagnosis of exclusion. Established only after other treatable causes are ruled-out, diabetic neuropathy results in objective.

• Nerve Conduction Velocity Testing (NCV): NCV is an electro-diagnostic test that measures nerve function. Through analysis of wave form velocity, amplitude, and wave-form morphology, diabetic neuropathy is easily detected, in most clinical circumstances. The NCV measures both sensory and motor components of the peripheral nerves of the extremities, but the sensory component is clearly the most sensitive, and the damage manifests earliest in the Sural Nerve. Using surface electrodes, instead of needles, there is little risk of damage to the vulnerable tissues of the feet and hands.

NCV should not be confused with Electro-myography (EMG), which is a needle study that looks for muscle pathology. Pathological changes in the muscle occur last, far after autonomic and sensory damage has occurred.

• Somato-sensory Evoked Potentials (SSEP): SSEP is a technique that involves electrical stimulation of the peripheral nerves with observation of the physiological response to the spinal cord, cortex and back to the periphery. This is most useful in providing supplemental information to the NCV, in establishing differential diagnosis. It is often the first clinical test to demonstrate Multiple Sclerosis.
• Impedence Cardiogram (ICG): The ICG is useful in the patient with known diabetic neuropathy. The cardiac output tracings that are available from the ICG demonstrate the presence and severity of autonomic nerve damage, as it influences cardiac performance. This non-invasive test is painless and provides information that is otherwise available only through cine-angiography.

Treatment:

NOTE:  A new medication was recently (9/05) introduced that demonstrates tremendous potential for the treatment of diabetic polyneuropathy.  Pregabalin (Lyrica) is available from Pfizer Pharmaceuticals.  This medication is particularly useful in situations where Neurontin has been tried with side-effect problems.

This medication is used once-daily, or on rarer occasions, twice daily, and has linear pharmacodynamics, that is, the more that is used, the more the medicinal effect.  Neurontin, on the other hand, demonstrates less effect as the dose is increased.

Why clinicians choose to increase doses remains a mystery to me.  However, starting doses at 50 mg at bed time, doubled to 100 or 150 mg over the course of a week to 10 days has provided substantial relief to many patients.

The good news:  The price does not go up as the dosage goes up.   (dsk)

Treatment of diabetic neuropathy is directed at the underlying pathology while simultaneously providing the patient with pain relief.

• Oral and topical medications are used to decrease the automaticity of the peripheral nerve tissue.
• GABA agonists are quite effective, and when combinations of GABA_(A) and GABA_(B) agents are used, dose requirements are dramatically reduced. One newer medication that seems to show promise is Lyrica (pregabalin), which is active at the A2D receptors calcium channel modulator.   This agent is particularly effective in the treatment of diabetic peripheral neuropathy.  It was released by the (US) FDA for distribution in Summer of 2005.  Lyrica should prove to be more effective than Neurontin, and the cost to the patient will be significantly less.
• Topical vasodilators provide rapid changes in blood flow, often within a minute or two of application. Topical nifedipine and clonidine work most consistently. Topical guanethidine is more difficult to make, and due to chemical instability, it has a short shelf life.
• Tricyclic anti-depressants (TCA’s), such as amitryptaline and desipramine, are in common use, but they provide little, if any, meaningful benefit. It should be remembered that TCA’s are also anti-histaminic and anti-cholinergic; it is these properties that tend to exacerbate the symptoms of Alzheimer’s Disease.

Oral analgesics are useful to provide symptomatic relief. Personal preference tends to guide selection. The clinician must understand that all analgesics are different, and patient response may be unpredictable.

DHEA Kalimi M, Regelson W, eds. The Biologic Role of Dehydroepiandrosterone (DHEA). New York: Walter de Gruyter, 1990.

Animal studies have demonstrated a correlation between diabetes and obesity that can be reversed by DHEA administration. DHEA's anti-glucocorticoid property may result in protection from diabetes, and insulin resistance appears to decrease when DHEA levels are returned to normal.

Cleary MP, Shepherd A, Jenks B. Effect of dehydroepiandrosterone on growth in lean and obese Zucker rats. J Nutr 1984;114:1242-1251.

Barrett-Connor E, Ferrara A. Dehydroepiandrosterone, dehydroepiandrosterone sulfate, obesity, waist-hip ratio, and non-insulin dependent diabetes in postmenopausal women: the Rancho Bernardo Study. J Clin Endocrinol Metab 1996;81:59-64.

Nestler JE. Insulin and adrenal androgens. Semin Reprod Endocrinol 1994;12:1-5.

The role of Insulin in Pain Modulation

NOTE:  This may explain a portion of the relationship between elevated insulin levels in diabetics and the presence of peripheral nerve pain-dsk

van der Heide LP, Kamal A, Artola A, Gispen WH, Ramakers GM:  Insulin modulates hippocampal activity-dependent synaptic plasticity in a N-methyl-d-aspartate receptor and phosphatidyl-inositol-3-kinase-dependent manner.  J Neurochem. 2005 Aug;94(4):1158-66.

Insulin and its receptor are both present in the central nervous system and are implicated in neuronal survival and hippocampal synaptic plasticity. Here we show that insulin activates phosphatidylinositol 3-kinase (PI3K) and protein kinase B (PKB), and results in an induction of long-term depression (LTD) in hippocampal CA1 neurones. Evaluation of the frequency-response curve of synaptic plasticity revealed that insulin induced LTD at 0.033 Hz and LTP at 10 Hz, whereas in the absence of insulin, 1 Hz induced LTD and 100 Hz induced LTP. LTD induction in the presence of insulin required low frequency synaptic stimulation (0.033 Hz) and blockade of GABAergic transmission. The TD or LTP induced in the presence of insulin was N-methyl-d-aspartate (NMDA) receptor specific as it could be inhibited by alpha-amino-5-phosphonopentanoic acid (APV), a specific NMDA receptor antagonist. LTD induction was also facilitated by lowering the extracellular Mg(2+) concentration, indicating an involvement of NMDA receptors. Inhibition of PI3K signalling or discontinuing synaptic stimulation also prevented this LTD. These results show that insulin modulates activity-dependent synaptic plasticity, which requires activation of NMDA receptors and the PI3K pathway. The results obtained provide a mechanistic link between insulin and synaptic plasticity, and explain how insulin functions as a neuromodulator.