Neurostimulation: Can It Have An Impact For Painful Diabetic Neuropathy?

While current modalities for the symptoms of painful diabetic neuropathy include oral medications, topical therapies and surgical treatment, emerging research suggests the potential benefits of neurostimulation. Accordingly, these authors review the current literature and offer insights on proper patient selection for appropriate referrals.

   Peripheral neuropathy is a common long-term complication of diabetes. Approximately 7.5 percent of unselected adults attending a hospital diabetes clinic have painful neuropathic symptoms, mostly in the lower extremities.1 Patients suffering from diabetic neuropathy report sensory complaints of numbness, tingling and pain as well as weakened motor function. This alteration in motor function can progress into changes in biomechanics as well as deformities of the foot and, subsequently, ulceration.

   The sensory symptoms occur in a “stocking and glove” distribution. Patients with diabetic neuropathy also experience a loss of sudomotor function in the extremities with additional complaints of thick dry skin associated with the autonomic system.2 This painful neuropathy can have a major impact on the quality of life of these patients and also poses a significant financial burden. It can be associated with substantial costs from utilization of healthcare services, work loss and disability.3 Additionally, nighttime exacerbation of the pain and contact hypersensitivity to clothing and bedding may result in loss of sleep. This in itself can be disabling and frustrating.4

   The exact pathophysiology of chronic sensory motor diabetic neuropathy is not completely understood. However, metabolic as well as microvascular systems appear to be involved.4 Patients with diabetes often suffer from angiopathy with the impaired microcirculation affecting the function of peripheral nerves.

   Dellon described two metabolic changes that occur in the peripheral nerves of patients with diabetes.2 The first is increased water content within the nerve as a result of glucose being metabolized into sorbitol. This increased volume makes the nerve more susceptible to chronic compression, especially in areas of anatomic narrowing such as the tarsal tunnel. The second metabolic change is a decrease in the slow anterograde component of axoplasmic flow, which transports the lipoproteins necessary to maintain and rebuild the nerve. Increased external pressure increases the intraneural pressure. This subsequently decreases blood flow and results in an ischemic condition for the peripheral nerve.

Current Treatments For Painful Diabetic Neuropathy

Conventional treatment for painful peripheral diabetic neuropathy is largely symptomatic and often ineffective with undesirable side effects.4 A starting point in the management of patients with diabetic neuropathy should include an evaluation of their glycemic control.2 To monitor this, one may use laboratory tests such as blood glucose levels and glycohemoglobin (hemoglobin A1c).

   Physicians have used a variety of pharmacological agents in the treatment of neuropathic symptoms. Dellon reports the classic triad of neuropathic medications to include carbamazepine (Tegretol®, Novartis), phenytoin (Dilantin®, Pfizer) and amitriptyline (Elavil®). Many patients are unable to tolerate the side effects of carbamazepine and phenytoin is often not effective. A common side effect of amitriptyline is drowsiness. Many patients with neuropathy suffer from difficulty sleeping, which makes this side effect of amitriptyline a desirable one.2

   Duloxetine (Cymbalta®, Eli Lilly), gabapentin (Neurontin®, Pfizer), pregabalin (Lyrica®, Pfizer) and Metanx® (Pamlab) are additional modalities physicians may employ to help treat symptoms of neuropathy. Many patients do not tolerate the doses required of non-narcotic neuropathic pain medication or simply cannot accept the decrease in cognitive function these drugs induce.2 One may employ topical agents such as capsaicin cream and lidocaine patches for localized pain.

   Podiatrists may consider surgical treatment such as a tarsal tunnel release in patients with a diagnosed entrapment neuropathy.

How Does Electrical Spinal Cord Stimulation Work?

Electrical spinal cord stimulation (ESCS) involves the delivery of a low-voltage electrical current to the dorsal structures of the spinal cord to reduce pain. The treating physician, typically an interventional pain specialist, would insert an electrode/lead in the cervical, thoracic or lumbar epidural space. This is connected to a stimulator box (pulse generator), which is subcutaneously implanted into the abdominal wall.3 Placement of the leads is based on the patient’s description of the paresthesia.

   When the symptomatology is primarily in the lower extremities, the treating physician places the leads over the thoracic segments of the spinal cord.5 The patient has the ability to switch the stimulation on and off, and adjust the intensity of the pulses via the stimulator box.

   There are two types of leads: percutaneous round leads and neurosurgical flat leads. The majority of stimulator trials use the percutaneous leads since the implantation process is less invasive. The treating physician can insert these round leads via a 14-gauge Tuohy needle into the epidural space. The neurosurgical leads require a partial laminectomy performed by a neurosurgeon or orthopedic spine surgeon.6

   Prior to the implantation of permanent leads, the patient must undergo a trial period that typically ranges from three to 14 days. If patients meet the criteria for spinal cord stimulation (SCS) and experience an improvement in pain or function of 50 percent during this trial period, one may consider permanent implantation in these patients. One week must elapse between the removal of the temporary leads and the time of permanent implantation.

A Closer Look At The Possible Mechanisms Of SCS

The exact underlying mechanisms of spinal cord stimulation remain unclear. The gate control theory of pain proposed by Melzack and Wall in 1965 has been widely used to explain the action of SCS.7 This theory postulated that an inhibitory mechanism in the dorsal horn of the spinal cord is activated by the recruitment of large diameter fibers. Small diameter fibers carry pain impulses while large diameter fibers carry nonpainful impulses. Activation of the substantia gelatinosa induces inhibition of second order neurons processing nociceptive information.7 In other words, the patient’s perception of a painful stimulus is inhibited.

   Neurophysiological mechanisms have also been proposed. Suggested variations of the neurophysiology of pain relief under spinal cord stimulation include the simple blocking of pain transmission by a direct effect on spinothalamic tracts, segmental inhibition, coarse fiber activation, effects on the central sympathetic system as well as brain stem loops to thalamocortical mechanisms.7 While the mechanism(s) behind the pain relieving effects of SCS may not be clearly understood, the fact that intermittent use of spinal cord stimulation can produce several hours of sustained pain relief after the device is switched off indicates long lasting changes in pain transmission and modulation.3

What The Research Reveals About SCS For Diabetic Neuropathy

Electrical spinal cord stimulation has been used for over 30 years to treat chronic, intractable pain of various etiologies including failed back surgery, complex regional pain syndrome, refractory angina and inoperable critical limb ischemia.3 More recently, several studies have focused on the application and benefits of this form of treatment for chronic painful diabetic neuropathy.

   Researchers have suggested that SCS improves microcirculatory blood flow. Although SCS was initially in use to manage patients with chronic intractable pain, several authors additionally observed and documented a marked improvement in lower extremity blood flow.1 Based on these findings, SCS has attracted greater interest for its potential application in the treatment of ischemic rest pain and neuropathic diabetic pain. Peripheral nerves in patients with diabetic neuropathy have impaired blood flow. With SCS reportedly improving microvascular blood flow in patients with severe limb ischemia, it is speculated that improvement in pain scores in patients with painful diabetic neuropathy is due in part to improvement in nerve blood flow.

   In 1990, Jacobs and colleagues found that the number of capillaries perfused and red blood cell velocity were significantly increased by SCS.1 Eight years later, Ghajar and Miles found that the position of the SCS electrode influences the effect on capillary blood flow in the affected limbs and attributed this to the segmental nature of the sympathetic nervous system.5

   While performing studies on rats, Tanaka and co-workers found that SCS antidromically activates afferent fibers in the dorsal root. This, in turn, causes peripheral release of the calcitonin gene-related peptide (CGRP), which results in cutaneous vasodilation.5 Reported benefits of spinal cord stimulation for patients with diabetic neuropathy include significant pain relief, improvements in activities of daily living and an overall improvement in functional capacity.3

   Furthermore, as a result of SCS, many patients are able to discontinue or significantly reduce their use of medications.5

Keys To Ensuring Proper Patient Referrals For SCS

When evaluating for diabetic peripheral neuropathy, one needs to undertake a thorough history and physical, including an assessment of neuropathic symptoms. Additional information that may be of assistance in the diagnosis and treatment process includes ankle brachial indices, evaluation of vibration perception threshold (VPT) as well as motor and sensory nerve conduction velocities.4 A more invasive diagnostic workup may include nerve biopsies or examination of cerebrospinal fluid to exclude other etiologies for the neuropathy.3

   Physicians should only consider referring the patient for spinal cord stimulation after the failure of conservative therapy. It is recommended that physicians attempt three to six months of conservative therapy prior to initiating or referring patients for SCS.6

   In a study of 60 patients with diabetes, Petrakis and Sciacca noted that clinical improvement and spinal cord stimulation success were associated with increases in TcPO2 during a two-week trial period.7 They suggest that one could use TcPO2 changes as a predictive index of SCS therapy success and physicians should consider this in terms of cost effectiveness before the final decision for permanent implantation.7

   When studying SCS for painful diabetic neuropathy, Solomon and colleagues noted that the only patients who did not respond to SCS during the trial stimulation had unrecordable VPTs. This led them to believe that the absence of vibration and joint position sense on clinical exam may characterize patients who are unlikely to have a positive response to SCS.4

   Prior to implantation, a psychological assessment of the patient is essential because SCS has proven to be more effective in those without major psychological overlay.4,6

   As with any treatment option, there are several contraindications to SCS. The programmable generators cannot be implanted in patients requiring pacemakers. Also bear in mind that patients with SCS are no longer candidates for MRIs. Other contraindications include:

   • significant bony canal abnormalities;
   • uncorrected coagulopathy;
   • active infection:
   • lack of patient competence regarding the use of the device; and
   • less than 50 percent improvement in pain relief or function during the trial period.5,6

What You Should Know About Complications Of SCS

When it comes to SCS, infection is a potential complication. Superficial infections are more frequent in comparison to the rare incidence of deep epidural infections. Other reported complications include meningitis, local irritation, lead migration (more often seen with the percutaneous round leads), lead fracture and spinal cord or nerve root injury.6 Subdural puncture resulting in headaches can also occur depending on the experience of the physician. Lack of patient understanding of the device has been associated with shock when patients improperly use the programmer.6

   Most of these complications present as early complications. One study reported an incidence of “late failure,” in which the patient gained initial pain relief and eventually failed to respond to SCS after four months.4

Is SCS Cost-Effective In This Patient Population?

Researchers have estimated that the yearly cost for treatment of chronic painful neuropathic pain is $6,000 and considerably higher if the patient is unable to work due to the condition. In 2002, researchers estimated that the mean cumulative cost for electrical spinal cord stimulation therapy for a five-year period was $24,000, mostly due to hardware and implantation costs during the first year of treatment. However, this figure does not take into account improvements in quality of life and return to employment.3

   In a systematic literature review regarding the cost effectiveness of spinal cord stimulation, Taylor and colleagues concluded that in the medium- to long-term (one to three years), SCS is economically favorable in comparison to other therapies. They found that the initial acquisition costs of SCS appear to be offset by a reduction in healthcare resources, such as drug therapy, physician visits and hospitalization.8

Final Notes

Can neurostimulation have an impact for painful diabetic peripheral neuropathy? Spinal cord stimulation studies have shown statistically significant effects on chronic diabetic neuropathic pain, indicating that physicians may consider SCS as a clinically effective therapy for this patient group.5

   Treatment modalities for painful neuropathy have increased over time, resulting in a large number of medications and the existence of multidisciplinary pain teams that can offer cognitive behavioral treatments and a more systematic approach to the patients’ symptoms.3

   While physicians have effectively utilized spinal cord stimulation to treat other forms of intractable pain for over 30 years, the use of this modality for painful diabetic neuropathy is more recent. While there are varying descriptions for the exact mechanism of SCS effects in this group, it has been proven to increase microcirculatory blood flow, provide pain relief and improve functional capacity with some patients even being able to return to work.1,3,5 As we continue to advance our understanding of the complex pathophysiology of diabetic neuropathy, our ability to effectively treat this often frustrating condition will also evolve.

   Dr. Brietstein is the Residency Director of the Northwest Medical Center Podiatric Medicine and Surgery Training Program in Margate, Fla. He is a Clinical Professor in the Department of Geriatrics at the Nova Southeastern College of Osteopathic Medicine in Davie, Fla. Dr. Brietstein is the Clinical Director of the University Hospital Wound Healing Center in Tamarac, Fla. He is a member of the Editorial Advisory Boards of WOUNDS and Ostomy/Wound Management. He is a Fellow of the American Professional Wound Care Association.

   Dr. Strauss is the Assistant Director of the Northwest Medical Center Podiatric Medicine and Surgery Training Program. He is a Clinical Professor in the Department of Geriatrics at the Nova Southeastern College of Osteopathic Medicine. Dr. Strauss is an Associate of the American Professional Wound Care Association.

   Dr. Andes is a second-year resident at the Northwest Medical Center Podiatric Medicine and Surgery (PM&S-36) Training Program. She graduated from the Barry University School of Podiatric Medicine in 2008.

   The authors would especially like to thank A. Cüneyt Özaktay, MD, an Interventional Pain Specialist with Anesthesia Pain Care Consultants in Tamarac, Fla., for his expertise and expansion of their knowledge on this topic as well as providing some research materials.

   For further reading, see “Essential Insights On Managing Painful Diabetic Neuropathy” in the October 2009 issue of Podiatry Today.

References:

1. Petrakis E, Sciacca V. Does autonomic neuropathy influence spinal cord stimulation therapy success in diabetic patients with critical lower limb ischemia? Surg Neurol 2000;53(2):182-9. 2. Dellon AL. Diabetic neuropathy: Review of a surgical approach to restore sensation, relieve pain, and prevent ulceration and amputation. Foot Ankle Int 2004;25(10):749-55. 3. Daousi C, Benbow SJ, Macfarlane A. Electrical spinal cord stimulation in the long-term treatment of chronic painful diabetic neuropathy. Diabet Med 2005:22(4):393-8. 4. Solomon T, Watt J, et al. Electrical spinal-cord stimulation for painful diabetic peripheral neuropathy. Lancet 1996;348(9043):1698-1701. 5. De Vos C, Rajan V, et al. Effect and safety of spinal cord stimulation for treatment of chronic pain caused by diabetic neuropathy. J Diabetes Complications 2009;23(1):40-45. 6. American Neuromodulation Society. Fundamentals of Spinal Cord Stimulation [Brochure]. Minneapolis, MN. Retrieved from https://www.algosresearch.org/ Education/OriginalArticles/SpinalCordStimPrimer.doc. (Accessed on February 5, 2010) 7. Petrakis E, Sciacca V. Prospective study of transcutaneous oxygen tension (TcPO2) measurement in the testing period of spinal cord stimulation. Int Angiol 2000;19(1):18-25. 8. Taylor RS, Taylor RJ, et al. The cost effectiveness of spinal cord stimulation in the treatment of pain: A systematic review of literature. J Pain Symptom Manage 2004:27(4):370-378.