**4. Focal neuropathies**

**3.7. Treatment of neuropathic pain**

336 Type 1 Diabetes

scending pain pathways [59].

some analgesic effects [62].

A significant number of patients with DSP (16-60%) have symptoms of neuropathic pain [52, 53]. One UK study suggested that painful symptoms were more prevalent in type 2 than type 1 diabetes [53]. Typical pain symptoms are delayed compared to signs of neuropathy in type 1 diabetes [54, 55]. The etiology of neuropathic pain in DSP has been thought to be due to abnormalities in C-fiber nerve endings causing aberrant signaling through protein kinase C [26], increased transient receptor potential vanilloid 1 expression [56], dysregulation of ion channels [57], abnormal nerve growth factor levels [58] and possibly dysregulation of de‐

Typical pain symptoms described include "burning", "stabbing", "needle-like", "shooting", "electric" etc. Patients often complain of allodynia, e.g. normal sensations become painful such as the touch of bedcovers to the feet, as well as hyperalgesia (painful sensations such as pinprick are unbearably painful). Pain is typically worse at night, and with activities such as walking and standing. Mononeuropathies such as carpal tunnel syndrome can also cause nocturnal paresthesias. Pain symptoms are typically not completely relieved with medications.

Medications used for neuropathic pain include traditional pain medications such as opioids and tramadol, antiepileptic agents and antidepressants (Table 2) [61]. Typically patients require large doses of opiates for pain relief, and long acting opiates are preferred to provide sustained relief. Sedation, constipation, pharmacologic tolerance and addiction issues are significant barriers and usually prohibit opiates as first line pain treatment in neuropathic pain. Mexiletine, a sodium channel blocker and anti-arrhythmic agent has also been shown to have

Alpha2-delta inhibitors gabapentin and pregabalin are the most commonly used anti-epileptic medications. These medications act at the dorsal horn of the spinal cord to inhibit voltage gated calcium channels [63, 64]. The advantage of gabapentin and pregabalin is their renal excretion and lack of interaction with other medications. Main side effects include drowsiness, dizziness, peripheral edema, weight gain, and myoclonic jerks at higher doses. Gabapentin is typically initiated at 300 mg up to three times a day and can be escalated up to 4800 mg in divided doses. Its short half-life requires three to four times a day dosing for optimal pain relief. Pregabalin has a longer half-life and is typically dosed twice a day although some patients benefit from dosing three times a day. Pregabalin is usually started at 75 mg twice a day and titrated up to 300 mg twice a day. Consultation with a nephrologist in dialysis dependent patients is needed due to renal excretion, but does not preclude use in these patients. Typically nephrologists will administer one dose after dialysis. Other anticonvulsants used for neuropathic pain include carbamazepine, oxcarbazepine, valproic acid, lamotrigine, lacosamide, and phenytoin.

Antidepressants acting on norepinephrine such as tricyclic antidepressants and the selective serotonin and norepinephrine reuptake inhibitor duloxetine are also helpful in treating neuropathic pain [65, 66]. Duloxetine is well tolerated, with few side effects. Caution should be used in patients with renal insufficiency as elevations of systolic blood pressure have been observed. Nausea can occur initially, but can be avoided with initiation at lower doses such

Pain can be moderate to severe with an average of 5.8/10 on a pain scale [60].

### **4.1. Overview and epidemiology**

Other types of neuropathy which can occur include mononeuropathies, typically at compres‐ sion points such as median mononeuropathy at the wrist, e.g. carpal tunnel syndrome, ulnar neuropathy at the elbow, and peroneal neuropathy at the knee. In the Rochester Diabetes Trial, these occurred at about the same frequency or higher in type 1 vs. type 2 patients [9]. Cranial neuropathies and truncal radiculopathy occur at an increased rate in diabetic patients, but prevalence data for type 1 and type 2 patients is not available. Pain is a common presenting symptom in ischemic ocular motor palsies and thoracic radiculopathies in diabetes [68, 69]. The Veterans Affairs study of type II patients showed decreased prevalence of cranial mono‐ neuropathies with stricter glucose control but data is lacking for type 1 patients [70]. It is not uncommon for mononeuropathies to occur prior to the development of DSP or identification of diabetes, particularly in type 2 patients [71, 72]. This has not been described in type 1 patients.

Mononeuropathies may be identified on testing with nerve conduction studies. This is more common in carpal tunnel syndrome, ulnar mononeuropathy, and fibular mononeuropathy which are often asymptomatic. Nerve conduction studies in compression mononeuropathies distally typically demonstrate slowing of conduction velocity across the compressed segment (ulnar, fibular, tibial nerve) or increased distal latency compared to nearby nerves (median nerve). Multiple nerves are often compared, or side to side comparisons are made to exclude

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For carpal tunnel syndrome, nerve ultrasound has become a more common procedure, demonstrating enlarged median nerve cross sectional area in the wrist in affected individ‐ uals compared to controls [84]. Thus far, no differentiation between ultrasound appear‐ ance of diabetic vs. non-diabetic nerves have been found [85]. Another study suggested a larger cross-sectional area of the tibial nerve at the tarsal tunnel in diabetic patients [86]. Further studies are still needed on the utility of this measure for diabetic patients. Magnet‐ ic resonance imaging is also used for assessment of carpal tunnel syndrome, but data in diabetes vs. control patients is lacking and cost is significantly higher than nerve conduc‐

Treatment of compression induced mononeuropathies is aimed at relieving the site of trauma. Bracing, avoiding extenuating activity, and changing postures are initial non-surgical ap‐ proaches. Data for surgical approach to compressive neuropathy is better known in median mononeuropathies at the wrist (carpal tunnel syndrome) because of larger reported cohort studies. However, data are conflicting in regards to outcome of carpal tunnel syndrome surgical release with some studies showing poorer outcomes and some not significantly different from non-diabetic patients [88, 89]. This may occur due to differences in patient selection. Results of surgical release of the ulnar nerve at the cubital tunnel, the second most common mononeuropathy (2.1%) are worse compared to carpal tunnel syndrome [81, 90]. It is not clear whether this is due to underlying diabetic polyneuropathy or due to patient

Treatment of ischemic induced mononeuropathies is typically supportive. Pain management is often needed for thoracic radiculopathies, meralgia paresthetica (lateral femoral cutaneous nerve palsy). Prisms or patching can be used for diploplia in ocular motor cranial nerve palsies (cranial nerve 3, 4, and 6). Taping of the eyelid and lubrication may be needed in facial nerve palsies to prevent corneal abrasion. Little data are available for prognosis. Many patients improve over 3-6 months, but some may have permanent muscle weakness or ptosis [91, 92]. Treatment with intravenous alpha-lipoic acid has also been reported as improving outcomes but was not placebo controlled [93]. Otherwise, treatment for mononeuropathies in diabetes

underlying DSP.

**4.4. Treatment**

tion studies or ultrasound [87].

selection bias (misdiagnosis).

is not significantly different than in non-diabetics.

Median mononeuropathy at the wrist, e.g. carpal tunnel syndrome is the most common mononeuropathy in diabetes and occurs three to four times as commonly in diabetics com‐ pared to healthy controls, and is more common in diabetics with DSP than without [72-74]. Median mononeuropathy has been reported as early as 11 years old [75]. Risk factors for development of carpal tunnel syndrome include obesity and lipid-lowering medications [74].
