Painful diabetic neuropathy is under-recognized and undertreated, which indicates the opportunity for improved patient care. A growing number of drugs have strong evidence to support their use, but many other drugs have not shown benefit in clinical trials. However, further studies are needed to develop new drugs and to determine the order and combinations that can best limit neuropathic pain. Limitations of past studies need to be tackled by using standardized assessments of pain, side effects, and QOL; studying drugs for longer periods of time; and evaluating the cost effectiveness of different strategies.
The main treatments for painful diabetic neuropathy remain management of the underlying diabetes and drugs for the relief of pain. However, emerging evidence points to major differences between type 1 and type 2 diabetes, including the ability of glycemic control to prevent neuropathy. Enhanced glucose control is much more effective at preventing neuropathy in patients with type 1 diabetes than in those with type 2 disease. The impact of the metabolic syndrome on neuropathy in patients with type 2 diabetes may account for the difference between the two types of diabetes and requires further study.
Both type 1 diabetes, caused by insulin deficiency, and type 2 diabetes, caused by insulin resistance, are metabolic diseases that result in hyperglycemia. Diabetes affects 8.5% of people in Europe and 8.3% in the United States. The most common complication is diabetic sensorimotor polyneuropathy, which occurs in 10-54% of patients with type 1 diabetes, while retinopathy occurs in 26.5% of patients and nephropathy in 32%. Similar rates exist in type 2 disease. Symptoms of diabetic sensorimotor polyneuropathy typically manifest earlier in the course of type 2 diabetes than in type 1 disease — 8% of patients have neuropathy at the time of diagnosis of type 2 diabetes. A third of patients with diabetic sensorimotor polyneuropathy develop painful diabetic neuropathy, and this condition is more prevalent in type 2 diabetes than in type 1 disease. Painful diabetic neuropathy has a negative impact on physical and mental quality of life (QOL) compared with painless diabetic neuropathy.
Diabetic sensorimotor polyneuropathy is characterized by symmetric numbness, paresthesias, or pain in the distal lower limbs (or a combination thereof). Examination may disclose stocking and glove sensory loss, impaired vibration and proprioception in the toes, reduced or absent Achilles tendon reflexes, and weakness or atrophy of the intrinsic muscles of the foot, which can result in foot abnormalities such as pes cavus and hammertoes. Signs and symptoms progress in a centripetal fashion and are not confined to a single nerve or dermatomal distribution.
In 2009, the Toronto consensus panel was convened to update the definition of diabetic sensorimotor polyneuropathy. The panel proposed the following definition: “a symmetrical, length-dependent sensorimotor polyneuropathy attributable to metabolic and microvessel alterations as a result of chronic hyperglycemia exposure and cardiovascular risk covariates.” It further defined painful diabetic polyneuropathy as “pain arising as a direct consequence of abnormalities in the peripheral somatosensory system in people with diabetes. The symptoms are distal, symmetrical, often associated with nocturnal exacerbations, and commonly described as prickling, deep aching, sharp, like an electric shock, and burning.
Small fiber neuropathy is another phenotype of painful diabetic neuropathy. Small diameter myelinated and unmyelinated fibers are affected, resulting in pain such as that seen in “burning feet” syndrome. The Toronto consensus panel defined “possible” small fiber neuropathy as symptoms or signs of small fiber involvement. “Probable” small fiber neuropathy requires the addition of a normal sural nerve sensory response on nerve conduction studies. “Definite” small fiber neuropathy requires the same criteria for probable small fiber neuropathy as well as a confirmatory test such as skin biopsy or quantitative sensory testing. Of note, most patients with diabetes and small fiber neuropathy have concomitant large fiber involvement or develop abnormalities in large fibers, transitioning to typical diabetic sensorimotor polyneuropathy.
Other subtypes of painful diabetic neuropathy include diabetic lumbosacral radiculoplexus neuropathy, mononeuropathy, treatment-induced neuropathy, and mononeuritis multiplex.
Diabetic lumbosacral radiculoplexus neuropathy presents with asymmetric pain and weakness in the proximal lower limb. Weight loss and improved glucose control, such as after starting insulin, can be associated features. Cervical and thoracic subtypes are also described. No treatment has been proved to be effective in diabetic lumbosacral radiculoplexus neuropathy or its cervical and thoracic subtypes.
Carpal tunnel syndrome is the most common mononeuropathy seen in patients with diabetes. Other mononeuropathies that cause pain and are common in patients with diabetes include ulnar mononeuropathies at the elbow and lateral femoral cutaneous neuropathies (meralgia paresthetica).
Treatment induced neuropathy is characterized by the acute onset of pain and autonomic dysfunction in the setting of improved glucose control. This condition can occur after insulin or oral hypoglycemic drugs are started and patients often improve with time, particularly those with type 1 diabetes.
Diabetic mononeuritis multiplex results in a stepwise progressive dysfunction of specific nerves and leads to pain, sensory loss, and weakness. Peroneal and ulnar nerves are particularly susceptible. Perivascular infiltrates can be seen on biopsy, supporting an immune mediated vasculopathy.
Diabetic sensorimotor polyneuropathy is considered in patients with diabetes who have numbness, paresthesias, or pain and in those who present with ulcerations, loss of balance, falls, or injury owing to loss of sensation. The condition may also be recognized in patients with diabetes through screening algorithms that use monofilament testing or other quantitative sensory testing.
For greater specificity, both in clinical practice and in research, the diagnosis of diabetic sensorimotor polyneuropathy often requires abnormalities in at least one diagnostic test. The most commonly performed diagnostic tests are nerve conduction studies, which are reliable when performed by an experienced technician. Such studies survey only large myelinated fibers, and the earliest changes noted are slowing of the conduction velocity of the sural sensory or peroneal motor responses and prolonged F wave latencies. These are followed by a decrease in amplitude of the sural and peroneal responses, as well as prolonged distal latency of the peroneal motor response.
These changes occur after years of hyperglycemia in type 1 diabetes, yet in type 2 diabetes they are often detected before diagnosis, when the patient is in a pre-diabetic state.
Another common clinical and research diagnostic test is to measure the perception of pressure and light touch with monofilaments of varying weights and stiffness. Protocols for monofilament testing may require the monofilament to be applied to one area (often the dorsum of the great toe), although results are more reliable and sensitive when multiple areas are tested. Both monofilament testing and vibration perception thresholds can reliably identify patients at high risk of having foot ulcers, infections, or amputations.
Sural nerve biopsy is not commonly used as a diagnostic test because of the side effects of the procedure, including a pain syndrome in the lateral part of the foot. In addition, nerve biopsy is rarely used in research studies because it cannot be repeated in the same location, which limits its usefulness as an endpoint in longitudinal studies. Sural nerve biopsy is usually abnormal—showing decreased myelinated nerve fiber density, swelling of axons, and segmental demyelination—even when signs of diabetic sensorimotor polyneuropathy are minimal or absent.
The treatment of diabetic sensorimotor polyneuropathy is mostly preventive and symptom oriented. Management of the underlying diabetes continues to be the main approach to preventing the onset and delaying the progression of neuropathy. Multiple large clinical trials of patients with type 2 diabetes have shown that intensive glycemic therapy delays the onset of diabetic sensorimotor polyneuropathy to a small degree, although this effect was not significant in a meta-analysis. This is in contrast to several studies conclusively showing a large, significant benefit of preventing neuropathy with aggressive glycemic control in type 1 diabetes.
Non-pharmacologic treatments used in painful diabetic neuropathy include transcutaneous electrical nerve stimulation, electromagnetic stimulation, low level laser treatment and massage, all of which have failed to demonstrate efficacy. No placebo controlled studies exist for acupuncture.
Anti-neuropathic medications are the mainstay of management in painful diabetic neuropathy. These drugs include:
These drugs have known efficacy in the treatment of painful diabetic neuropathy. Placebo controlled studies show that oxycodone, morphine sulfate, tramadol, and tapentadol significantly improve pain in painful diabetic neuropathy. Important drawbacks to opioid treatment include tolerance, withdrawal symptoms on discontinuation, and risk of misuse.
A systematic review of α lipoic acid in the treatment of diabetic neuropathic pain found that this drug may help relieve pain and improve neuropathy, possibly through its potent antioxidant properties and ability to reduce glutathione concentrations. The largest trials included in the review are the SYDNEY, ALADIN, and SYDNEY2 trials. All of these trials showed that this drug provided benefit in patients with painful diabetic neuropathy. The NATHAN 1 trial suggested that use of α lipoic acid (600 mg daily) improved neuropathy scores, and possibly delayed progression. However, pain was not a predefined endpoint in these studies and the effect on pain control was only moderate.
Capsaicin cream is approved for topical relief of neuropathic pain but many patients cannot tolerate it because of the initial pain on application. Lidocaine cream or patches can be used for focal areas of pain but are less effective for more diffuse pain.
A randomized double-blind crossover trial demonstrated the pain-relieving effect of botulinum toxin A for diabetic foot pain (Yuan et al., 2009). This pilot study included 20 patients with type 2 diabetes who suffered from neuropathic pain in both feet and had been diagnosed with diabetes for at least 3 years.
Participants were randomly assigned to receive either botulinum toxin A or saline injections as their first treatment and were crossed over to the alternate treatment in the second half of the study. The injections were given at 12 evenly spaced sites across the dorsum of each foot. Each injection comprised either approximately 14 U botulinum toxin A or 0.9% saline, 0.10 ml, using a 8 mm (5/16-inch) 30-gauge needle. Since the dorsal area of each foot is over 100 cm2 for most people, the average dosage adopted for this trial was below 0.5 U/cm2. This dosage is much lower than the therapeutic dosage in the study of botulinum toxin A for trigeminal neuralgia. At 4, 8 and 12 weeks, significant reductions in VAS occurred in the botulinum toxin A group compared with the placebo group. Within the botulinum toxin A treatment group, 44.4% experienced good responses (a reduction in VAS by ≥3) within 3 months after the initial injection, whereas no good responses were found in the placebo group.