Exploring The Potential Of Alpha Lipoic Acid For Diabetic Neuropathy

The treatment of diabetic neuropathy includes management of symptoms such as paresthesia and dysesthesia as well as efforts to interdict the progression of neuropathy. Although there is much discussion regarding the positive symptoms of neuropathy, such as pain or burning, it is the negative symptoms that are frequently responsible for deformity, ulceration and limb loss.

For example, think about the massive destruction that occurs in a patient with Charcot joint disease, typically absent any pain. The patient with a neuropathic ulcer and osteomyelitis will frequently present to the office or emergency department without significant pain. Many of the aspects of diabetic neuropathy occur absent any pain. Another example would be motor neuropathy, in which there is substantial loss of the intrinsic muscles of the foot (intrinsic minus foot) with the development of deformities such as hammertoes and associated prolapse of the metatarsal heads with increased plantar pressures and resultant ulceration. Yet another example of the painless aspects of neuropathy would include autonomic neuropathy. Patients with autonomic neuropathy exhibit lower extremity manifestations such as dry skin from loss of sweat gland innervation (sudomotor deficit), neuropathic edema, vasomotor instability or Charcot joint disease.

Strict control of diabetes mellitus can delay the onset and progression of diabetic neuropathy but has not been demonstrated to prevent neuropathy. When it comes to the treatment of painful neuropathy, many of the current medications — such as gabapentin (Neurontin, Pfizer), pregabalin (Lyrica, Pfizer), serotonin–norepinephrine reuptake inhibitors, tricyclic antidepressants or analgesics — provide pain relief but do not affect the actual disease process.

Thus, while helpful for relief of the symptoms of diabetic neuropathy, anti-nociceptive therapy with the use of analgesics, antidepressants or anti-seizure medications will do nothing to reverse the actual disease process causing the neuropathy itself. It is certainly important to rule out the presence of entrapment neuropathies that occur with increased frequency and intensity in a patient with diabetes. However, ultimately, diabetic neuropathy is a result of abnormal metabolic processes, which one must address in order to stop the progression of neuropathy or possibly reverse neuropathy itself.

The management of diabetic neuropathy involves proper control of diabetes and other concurrent medical issues such as hypertension and dyslipidemia as well as elimination of any contributing compression neuropathy. However, one must also include efforts to restore metabolic health to the nerve itself. This can occur through a variety of supplements and medical foods.

There is rather ample literature in peer-reviewed journals to support the utilization of nutritional therapy with medical foods or supplements to assist in the reversal of symptomatic and non-symptomatic diabetic sensory, motor and autonomic neuropathy. Alpha lipoic acid is one such agent that patients with diabetes can safely take. A substantial body of literature exists to support its use for the treatment of diabetic neuropathy.

What The Literature Reveals About Alpha Lipoic Acid

Alpha lipoic acid is a naturally occurring antioxidant substance. It is a liophilic free radical scavenger, a dithiol compound that plays an essential role in mitochondrial bioenergetic reactions assisting in the reduction of oxidation of stress in neurons and other tissues affected by diabetes. Alpha lipoic acid can inactivate reactive oxygen species, the results of oxidative stress, and reduce oxidized forms of other antioxidants.1 It is generally well-tolerated and has been well documented as being effective in the treatment of diabetic neuropathy.1

For this modality to be effective for the treatment of symptomatic diabetic neuropathy, one should administer alpha lipoic acid at a dosage of at least 600 mg daily although dosages as high as 1,800 mg daily may be required for some patients.2 When utilizing alpha lipoic acid for the treatment of diabetic neuropathy, it is important to emphasize to the patient that an adequate dosage of alpha lipoic acid is required in order to be effective in the relief of symptoms and reversal of the progression of neuropathy. There are many over-the-counter and other "neuropathy curing" products available to the diabetic patient that contain alpha lipoic acid. However, as noted, a minimum of 600 mg daily is required to effect clinical effectiveness.

Known as thioctic acid in Europe, alpha lipoic acid provided meaningful symptom improvement and delay in the progression of neurologic deficit in patients with diabetic neuropathy in the four-year NATHAN study (Neurological Assessment of Thioctic Acid in diabetic Neuropathy).3 Researchers have suggested that a decrease in the symptoms of diabetic neuropathy secondary to a reduction in oxidative stress may be a potential mechanism of action consistent with the antioxidant activity of alpha lipoic acid.4

Alpha lipoic acid is approved in Germany for the treatment of diabetic neuropathy although a recent Medline and EMBASE review noted unclear relevance to symptom improvement after the use of oral alpha lipoic acid.5 Numerous studies have demonstrated the ability of alpha lipoic acid at an adequate dose to relieve pain associated with diabetic neuropathy.6-9

Studies have also evaluated the effects of alpha lipoic acid on motor neuropathy as well as cardiac autonomic neuropathy.10,11 The combination of alpha lipoic acid with vitamin E has been helpful for the reduction of symptoms in diabetic neuropathy.12

Many patients suffer from the effects of symptomatic and non-symptomatic diabetic neuropathy. There is oftentimes a reluctance of the healthcare provider to utilize medications for the treatment of diabetic neuropathy given the potential side effects and sequela from these medications that require monitoring. Supplements and medical foods offer the ability to provide relief of symptoms and stop the progression of sensory, motor and autonomic neuropathy with few concerns for side effects.

For example, a study recently demonstrated that alpha lipoic acid attenuates oxidative stress pathway initiated apoptosis of Schwann cells in the presence of hyperglycemia.13 Researchers have suggested the reduction of oxidative stress with alpha lipoic acid for the effective management of advancing neuroprotection following brain injury and for protection of the optic nerve as well as other complications which may occur in association with diabetes and neuropathy.14,15

Final Notes

In my personal practice, I typically utilize medical foods and supplements for the treatment of symptomatic as well as non-symptomatic diabetic neuropathy. It has become increasingly clear from the medical literature that oxidative stress plays a significant role in the etiology of diabetic neuropathy and that methods and agents that reverse oxidative stress represent complementary and useful therapies for the management of diabetic neuropathy. Recent consensus panels have included the use of alpha lipoic acid in the treatment of diabetic neuropathy alongside other pharmacologic agents for the treatment of painful diabetic neuropathy.16

One must tailor the management of diabetic neuropathy — sensory, motor and autonomic —based upon each individual patient’s findings and symptoms. Although there are a number of proposed etiologies that suggest potential etiologic factors in the management of diabetic neuropathy, a final common pathway is oxidative stress and decreased vascular perfusion to the peripheral nerves. Studies have demonstrated the utilization of medical foods and supplements such Metanx (Pamlab) to be effective not only in reversing the symptoms of diabetic neuropathy but, in some individuals, interdicting or reversing the progression of the actual pathologic process itself.17 Many supplements and nutritional agents such as alpha lipoic acid demonstrate the ability to also reverse the progression of diabetic neuropathy and associated symptoms. Other supplements and nutrients that have proven to effective in the management of symptomatic neuropathy include acetyl L-carnitine, biotin, myo-inositol, zinc, magnesium, chromium and others.18

As noted earlier, when it comes to alpha lipoic acid, it is important to prescribe a minimum of 600 mg daily although as much as 1,800 mg may be required. Typically, I will prescribe several agents in an effort to reverse the effects of oxidative stress without the utilization of an analgesic or anti-nociceptive agent.

On follow-up appointments, it is important to note the patient's response to therapy and the presence or absence of any adverse reaction or sequela. Generally, I will allow an average of between 10 and 20 weeks in order to assess response to therapy and determine any changes that would be required.

References

1. Krzyzagorska E, Winiarska H, Wesolowska A, Zielinska-Kuzemko M, Dworacka M. The efficacy of [alpha]-lipoic acid (Neurolipon-MIP 600) in the management of peripheral neuropathy in type 2 diabetic patients. Przeglad Kardiodiabetologiczny. 2012;7(1).

2. Gemignani F. Symptomatic and pathogenic treatment of diabetic neuropathy: role of alpha-lipoic acid. Neural Ergen Res. 2010;5(10):781-788.

3. Papanas N, Maltezos E. a-lipoic acid, diabetic neuropathy, and Nathan’s Prophecy. Angiology. 2010;63(2):81-83.

4. Winler G, Kempler P. Pathomechanism of diabetic neuropathy: background of the pathogenesis-oriented therapy. Orv Hetil. 2010; 151(24):971-81.

5. Mijnhout GS, Kollen BJ, Alkhalaf A, et al. Alpha lipoic acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials. Int J Endocrinol. 2012; epub ahead of print.

6. Forst TL, Weber MM, Hohberg C, Pfutzner A. Pharmkologische aspeke in der therapie der diabetischen neuropathie. Diabetes Stoffwechsel Und Herz. 2010;19(4);261-295.

7. Ametov AS, Barinov A, Dyck PJ, et al. The sensory symptoms of diabetic polyneuropathy are improved with alpha-lipoic acid: the SYDNEY trial. Diabetes Care. 2003; 26(3):770–776.

8. Ziegler D, Hanefeld, M, Ruhnau KJ, et al. Treatment of symptomatic diabetic polyneuropathy with the anti-oxidant alpha lipoic acid. A 7-month multicentre randomized controlled trial (ALADIN III Study). Diabetes Care. 1999; 22(8):1296-1301.

9. Ziegler D, Hanefeld, M, Ruhnau KJ, et al. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia. 1995; 38(12):1425-33.

10. Negrisanu G, Bolte B, Rosu M, et al. Effects of three-month treatment with the antioxidant alpha lipoic acid in diabetic peripheral neuropathy. J Internal Med. 1999; 37(3):297-306.

11. Ziegler D, Schatz H, Cornrad F, et al. Effects of treatment with the antioxidant alpha-lipoic acid on cardiac autonomic neuropathy in NIDDM patients. A 4-month randomized controlled multicenter trial (DEKAN Study). Diabetes Care. 1997; 20(3):369-73.

12. González-Pérez O, Moy-López NA, Guzmán-Muñiz J. Alpha-tocopherol and alpha-lipoic acid. An antioxidant synergy with potential for preventive medicine. Rev Invest Clin. 2008; 60(1):58-67.

13. Sun LQ, Chen YY, Wang X, et al. The protective effect of alpha lipoic acid on Schwann cells exposed to constant or intermittent high glucose. Biochem Pharmacol. 2012; 84(7):961-73.

14. Rocamonde B, Paradells S, Barcia JM, et al. Neuroprotection of lipoic acid treatment promotes angiogenesis and reduces the glial scar formation after brain injury. Neuroscience. 2012;224:102-115.

15. Liu B, Ma X, Guo D, et al. Neuroprotective effect of alpha-lipoic acid on hydrostatic pressure-induced damage of retinal ganglion cells in vitro. Neurosci Lett. 2012; 526(1):24-28.

16. Tesfaye S, Vileikyte L, Raymon G, et al. Painful Diabetic Peripheral Neuropathy: Consensus Recommendations on Diagnosis, Assessment and Management. Diabetes Metab Res Rev. 2011 Jun 21. Epub ahead of print.

17. Jacobs A, Cheng D. Management of diabetic small-fiber neuropathy with combination L-methylfolate, methylcobalamin, and pyridoxal 5'-phosphate. Rev Neurol Dis. 2011; 8(1-2):39-47.

18. Head KA. Peripheral neuropathy: pathogenic mechanisms and alternative therapies. Altern Med Review. 2006; 11(4):294-329.



Dr John Hayes Jrsays: February 26, 2013 at 9:11 am

Dr. Jacobs, this is an excellent study and report. Our clinic findings correlate well with yours, especially when all supportive nutrients you mention are employed. The comprehensive approach to treating PN is the only one that gives patients lasting results. Thank you!

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Gerald Brunosays: February 26, 2013 at 5:38 pm

Excellent report. I believe you need a 600 mg minimum dose because of the poor bioavailability of most ALA products. I have been using a "solubilized" product for over 10 years and get a more profound effect with smaller doses. I also believe that you could shorten the time to a meaningful clinical effect by using a new high concentration topical oil (Tendonex) in conjunction with the oral dose of ALA.

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