Diabetic neuropathy

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Treatment strategies for DN may be divided into those targeting the underlying pathogenic mechanisms, and those targeting the relief of symptoms.

The former is most challenging; the only demonstrated method available is tight glycemic control in patients with type 1 diabetes. The latter comprises numerous symptomatic approaches. Specific symptomatic therapies are generally recommended, as they can improve the patient's quality of life.

All patients with diabetes require regular foot inspection and care. Patients with peripheral neuropathy are particularly at risk of painless injuries, so this is especially important. Those with concomitant nephropathy are at much higher risk of foot ulceration.

Patients with longer diabetes duration and more advanced stage of disease may present with a broad spectrum of symptoms and signs consistent with both distal symmetric polyneuropathy and autonomic neuropathy. Therefore, they may require multiple therapeutic approaches. In such cases the treating physician should decide on the combination of agents that would best address the patient's specific deficits in the safest way, while avoiding most drug interactions.

Glycemic control and other modifiable risk factors

The Diabetes Control and Complications Trial (DCCT) demonstrated that intensive therapy of type 1 diabetes reduced the incidence of neuropathy by 60% over a 5-year period in patients who did not have neuropathy at baseline.[9][122] Intensive therapy during the DCCT significantly reduced the risk of diabetic peripheral neuropathy (DPN) and cardiovascular autonomic neuropathy (CAN) at the end of the trial, and the prevalence and incidence of DPN and CAN remained significantly lower in the intensive therapy group compared with the conventional therapy group through the observational follow-up study in 2013 to 2014.[123] The Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial found that compared with standard intervention, intensive glucose treatment and intensive blood pressure intervention reduced the risk of CAN by 16% and 25%, respectively.[124]

There is some evidence for a reduction in risk of DN with optimal blood glucose control achieved using multiple insulin injections in people with type 2 diabetes, but the evidence is not as strong as that for type 1. One meta-analysis that included 17 randomized studies of patients with type 1 or type 2 diabetes found high-quality evidence that tight glucose control could prevent the development of DN and reduce the incidence of clinical neuropathy in people with type 1 diabetes.[34] In type 2 diabetes, enhanced glucose control had no impact on vibration perception threshold and failed to significantly reduce the incidence of clinical neuropathy.[34]

A 2014 review that included additional data showed that implementing and maintaining tight glucose control as early as possible in type 1 diabetes prevents early neuropathy development and promotes long-term protection, especially for CAN. For type 2 diabetes, the effects of glycemic control on DPN or CAN are less clear, with earlier data suggesting that glucose control is beneficial in patients with fewer comorbidities if started earlier in the disease course, but later studies not confirming these findings.[63]

The type of glucose lowering approach may also have different effects on DPN. Among more than 2000 patients with type 2 diabetes followed for up to 4 years during the BARI 2D trial, glycemic control therapy with insulin sensitizers (metformin and/or thiazolidinediones) significantly reduced the incidence of DPN compared with an insulin provider (sulfonylurea and/or insulin) therapy, especially in men.[19] Pancreatic transplantation appears to halt the progression of DN.[125][126] Two studies have shown an improvement in corneal nerve parameters following simultaneous pancreas and kidney transplantation.[111][127] When treating painful neuropathy, maintaining stable blood glucose levels may provide symptom relief.[128]

In addition to good glycemic control, treatment of other modifiable risk factors (including obesity, lipids and blood pressure) may help to prevent progression of DPN in type 2 diabetes, and may reduce disease progression in type 1 diabetes.[39][129][130][131]

Control of these modifiable risk factors (glucose, blood pressure, and lipids) in addition to adhering to a healthy lifestyle may prevent other associated microvascular complications of diabetes (retinopathy and nephropathy).[39]

Foot care

Proper care of the foot begins with educating the patient.[132] Patients at risk should be counseled on the implications of foot deformities, loss of protective sensation, and peripheral arterial disease.[39] They should also receive information on how to properly care for their feet, including the importance of daily monitoring.[39]

Offloading footwear is recommended for high-risk patients with diabetes, such as those with loss of protective sensation (severe peripheral neuropathy), and can prevent foot ulcer occurrence or worsening.[39][120][121]

Patients with diabetes-related foot disease, including ulcers and infections, may require debridement and antibiotic therapy.[39][120][121]

Guidelines on the prevention and management of diabetes-related foot disease vary between countries.

See Diabetes-related foot disease.

Lifestyle interventions

One observational study found that diet and exercise can improve neuropathic symptoms and intraepidermal nerve fiber density (IENFD) in patients with neuropathy and impaired glucose tolerance (N=32).[133] In a pretest posttest study of 17 patients with DPN, improvements in IENFD measures were found with a 10-week exercise program of moderately intense aerobic and resistance training.[134] In a large UK Biobank cohort study (18,092 individuals with type 2 diabetes mellitus), any level of leisure-time physical activity was associated with a lower risk of neuropathy, with the minimal effective physical activity level corresponding to <1.5 hours of walking per week.[135]

Treatment of pain in peripheral neuropathy: pharmacologic therapy

Painful DN has a significant impact on quality of life and should be treated appropriately. If pharmacologic intervention is required, patients should be advised that although treatment will reduce their pain, it may not eliminate the pain entirely.[66] It is important to manage patient expectations in this way to increase likelihood of treatment satisfaction.[66]

The American Academy of Neurology (AAN) and American Diabetes Association (ADA) both recommend offering an oral agent from one of the following classes for the treatment of painful DN:[39][66]

Gabapentinoid
Serotonin-norepinephrine reuptake inhibitor (SNRI)
Tricyclic antidepressant
Sodium-channel blocker.

The AAN found these drug classes to be comparable in their ability to reduce pain in a systematic review and meta-analysis.[66] Other factors such as potential adverse effects, comorbidities, and patient preferences should therefore be considered when recommending a treatment for painful DN.[66]

In the UK, the National Institute of Health and Care Excellence (NICE) recommends the gabapentinoids pregabalin and gabapentin, the SNRI duloxetine, and the tricyclic antidepressant amitriptyline as first-line treatment options for neuropathic pain.[136] One systematic review and meta-analysis of pharmacotherapy for neuropathic pain by the Neuropathic Pain Special Interest Group resulted in a strong recommendation for first-line treatment with SNRIs, pregabalin, gabapentin, and tricyclic antidepressants.[137]

The ADA advises that referral to a neurologist or pain specialist may be indicated when pain control is not achieved with initial treatment, depending on the scope of practice of the treating physician.[39]

Pharmacologic treatment options are discussed in more detail below.

Gabapentinoids

Pregabalin
- Is approved by the Food and Drug Administration (FDA) for treatment of painful DN.
- Binds to and modulates voltage-gated calcium channels.
- Is a more potent regulator of calcium channels than gabapentin (it is this mode of action that may modulate neuropathic pain).
- Has been found to decrease mean pain score in people with painful DN compared with placebo.[138] [ ]
- Can cause somnolence and pedal edema.
- Unlike gabapentin, pregabalin may possibly be habit forming.
Gabapentin
- Is not FDA-approved for the treatment of painful DN, but is widely used.
- Has been found to improve pain in people with DN, with 38% of participants in one meta-analysis having substantial benefit (at least 50% pain relief) with gabapentin compared to placebo.[139] [ ]
- May have adverse effects that require discontinuation of therapy. These include somnolence, dizziness, peripheral edema, and gait disturbance.[139] [ ]

SNRIs

Duloxetine
- Is approved by the Food and Drug Administration (FDA) and the European Medicines Agency for treatment of painful DN.
- Clinical studies have found it is safe and effective in the management of painful DN.[140]
- Nausea can occur, but slow-dose titration of the drug and taking it with food can usually reduce or avoid this common adverse effect. Somnolence may also occur.[141]
- Pregabalin or gabapentin may be combined with duloxetine if necessary.[142][143]
Venlafaxine
- A 2015 Cochrane review found little compelling evidence to support the use of venlafaxine in neuropathic pain; however, US guidelines advise that it may be effective in some patients.[39][66][144]
- In the UK, NICE recommends against initiating venlafaxine for neuropathic pain unless advised by a specialist to do so.[136]
- Venlafaxine is metabolized to its major active metabolite, desvenlafaxine, by CYP2D6.[145]
Desvenlafaxine
- Unlike venlafaxine, desvenlafaxine is not subject to significant metabolism by CYP2D6, and so may be preferred in people with drug-drug interactions and genetic polymorphisms that affect this enzyme.[145] However, it is rarely used.
- Has been investigated for the treatment of painful DN in one clinical study.[66][146] Patients receiving desvenlafaxine experienced a greater reduction in pain than those receiving placebo.[146]
- The safety profile of desvenlafaxine was consistent with that for other SNRIs, with the most common adverse events reported as nausea and dizziness.[146]

Tricyclic antidepressants

Not approved for the treatment of painful DN but may be effective in some patients.[66][147] The AAN advises that tricyclic antidepressants are possibly more likely than placebo to improve pain, but this is based solely on studies of amitriptyline.[66]
Act across multiple neurotransmitter pathways and are therefore associated with more adverse effects than other antidepressants.[148]
Cochrane reviews do not support the use of amitriptyline, nortriptyline, imipramine, or desipramine as first-line treatments for painful DN.[149][150][151][152] Studies assessing the efficacy of these agents were methodologically flawed and potentially subject to major bias.
Commonly used tricyclic antidepressants may be ranked in order of greatest to least risk of anticholinergic effects: amitriptyline; imipramine; nortriptyline; and desipramine.[153] Anticholinergic adverse effects may be less tolerated in diabetic patients with preexisting constipation, urinary retention, or orthostatic hypertension.[66]

Sodium-channel blockers

Not approved for the treatment of painful DN but may be effective in some patients.[66]
Agents in this class include carbamazepine and valproic acid derivatives.
One Cochrane review found limited evidence to suggest that valproic acid or sodium valproate reduce pain in DN, and did not recommend these treatments as first-line therapy for neuropathic pain.[154]
Valproic acid should not be prescribed for painful DN unless patients have failed treatment on multiple other agents, due to risk of serious adverse events such as hepatotoxicity, pancreatitis, hyponatremia, and pancytopenia.[66]
Valproic acid (and its derivatives) must not be used in female patients of childbearing potential unless other options are unsuitable, there is a pregnancy prevention program in place, and certain conditions are met. Precautionary measures may also be required in male patients owing to a potential risk that use in the 3 months leading up to conception may increase the likelihood of neurodevelopmental disorders in their children. Regulations and precautionary measures for female and male patients may vary between countries, with some countries taking a more heightened precautionary stance, and you should consult your local guidance for more information.

Selective serotonin-reuptake inhibitors (SSRIs)

SSRIs are not recommended by the AAN or the ADA for the management of painful DN.
May have some efficacy for painful DN.
Paroxetine has been found to reduce symptoms but is known to be associated with important harms and discontinuation problems.[155]
Fluoxetine was effective only in patients who were depressed.[156]
Sertraline reduced pain from DN in a small open-label study of 8 patients, but a placebo-controlled study has not yet been conducted.[157]

Combination treatment

A multicenter, double-blind, parallel-group study (COMBO-DN) in patients with DPN pain addressed whether, in patients not responding to monotherapy with standard doses of duloxetine or pregabalin, combining both medications was superior to increasing each drug to its maximum recommended dose. In an 8-week combination versus high-dose therapy period, nonresponders to monotherapy (n=339) received either maximum dose of duloxetine, a combination of standard doses of duloxetine and pregabalin, or a maximum dose of pregabalin. Both drugs and their combination were well tolerated. Although not significantly superior to high-dose monotherapy, combination therapy was considered to be effective, safe, and well tolerated.[158]
A further sub-analysis of COMBO-DN suggested that combination therapy with pregabalin and duloxetine is favored with moderate-intensity neuropathic pain, whereas high-dose monotherapy with either pregabalin or duloxetine favors higher-intensity neuropathic pain.[159]
In the OPTION-DM study, which was a multicenter, randomized, double-blind, crossover trial of 130 participants titrated to the maximum tolerated doses of amitriptyline supplemented with pregabalin, pregabalin supplemented with amitriptyline, and duloxetine supplemented with pregabalin were included in the primary analysis. Participants were assigned to test all three treatment pathways in a randomized order which included an initial titration period followed by 16 weeks of treatment.[160] Seven-day mean pain scores improved with monotherapy and were subsequently further improved when escalated to combination therapy. Combination treatment resulted in greater proportions with 50% pain relief and pain scores under 3. However, there were no differences between the treatment pathways.[160]
A combination of imipramine and pregabalin could be considered as an alternative to high-dose monotherapy. In one randomized controlled trial, combination therapy with imipramine and pregabalin significantly lowered pain scores compared with either agent alone, but was associated with a higher dropout rate and a higher rate and severity of side effects.[161]
The AAN recommends that for patients who achieve partial improvement with an initial therapeutic class, clinicians should offer a trial of a medication from a different effective class or offer combination therapy.[66]

Opioid analgesics

Opioids were previously used for the treatment of painful DN; however, the AAN and ADA now advise against the use of opioids for this indication due to the risk of addiction and the potential for adverse events.[39][66] Patients already receiving opioid treatment should be offered a safe taper off the medication, and nonopioid treatment strategies should be discussed.[66]
In the UK, NICE guidelines state that tramadol may be considered for acute rescue therapy only, in consultation with a pain specialist.[136]

Treatment of pain in peripheral neuropathy: other therapies

Some patients with painful DN may prefer the option of topical or nonpharmacologic interventions; evidence for these therapies remains limited.[66] Patients with more severe or refractory pain may benefit from interventions such as nerve or spinal cord stimulation.

Topical therapies

Capsaicin
- US guidelines advise that topical capsaicin may be effective in some patients when used alone or in combination with other therapies. In particular, it may be considered in patients with contraindications to oral medication, or in those who prefer topical treatments.[39][66]
- A capsaicin cutaneous patch is approved in the US for neuropathic pain associated with DPN of the feet, and in Europe for peripheral neuropathic pain.
- In the UK, NICE guidelines state that capsaicin cream may be considered in a specialist setting for patients with localized neuropathic pain who wish to avoid, or who cannot tolerate, oral treatments.[136]
- Believed to stimulate the release and depletion of substance P from sensory nerve fibers.
- Capsaicin cream (0.1%) has been shown to cause a loss of intraepidermal nerve fibers and thermal sensation, which does not recover for approximately 150 days.[162]
- A few small studies have demonstrated the effectiveness of topical capsaicin in control of pain and improvement in daily activities.[163] [ ]
- Poor adherence is common, due to the need for frequent applications, an initial exacerbation of symptoms, and frequent burning and redness at the application site.[147]
Nitroglycerin spray
- Included in the AAN guidelines as an option for topical treatment as it is possibly more likely than placebo to improve pain.[66]
- Evidence from one small randomized controlled trial suggested that nitroglycerin spray may have some efficacy when used alone and in combination with sodium valproate.[66][164]
Lidocaine topical patch
- A lidocaine topical patch is available in some countries for the management of postherpetic neuralgia. There are limited data supporting the off-label use of lidocaine topical patches in DPN. They may be considered in individuals with nocturnal neuropathic foot pain; however, they are not effective if there is a more widespread distribution of pain.[165]

Nonpharmacologic therapies

The AAN includes exercise, cognitive behavioral therapy (CBT), and mindfulness as potential options for patients with painful DN.[66]
Evidence for CBT in painful DN is currently limited, although CBT has been efficacious in other types of chronic pain.[66]

Transcutaneous electrical nerve stimulation (TENS), percutaneous electrical nerve stimulation (PENS), or acupuncture

May be added on to existing therapy or used alone, in refractory cases.[147][166]
In one controlled study, TENS was more effective than sham treatment in reducing pain in patients with DN.[167]
In uncontrolled studies, TENS and acupuncture have been reported to decrease pain in >75% of patients with DN.[168][169]
A report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology, based on a review of the literature up to April 2009, concluded that TENS may have some effectiveness for reducing pain caused by DPN.[166]
NICE found evidence of short-term efficacy of PENS for refractory neuropathic pain with no major safety concerns. Treatment with PENS should involve specialists in pain management.[170]

Spinal cord stimulation

Should be considered in patients refractory to all other treatment options for severe painful DN.[171][172]
One systematic review and meta-analysis found that spinal cord stimulation is an effective therapeutic adjunct to best medical therapy in reducing pain intensity and improving health-related quality of life in patients with painful DN.[173]
One systematic review and network meta-analysis found pain relief and health-related quality of life benefits of the addition of spinal cord stimulation to conventional medical management for patients with painful DN. Greater pain reductions were seen in those who received high-frequency spinal cord stimulation compared with those receiving low frequency.[174]

Cranial neuropathies, limb mononeuropathies, truncal mononeuropathy, diabetic amyotrophy

There is no specific treatment for cranial neuropathies, although gradual recovery typically occurs. There is also no specific treatment for abrupt limb neuropathies, though some have advocated immunomodulatory therapy when there is multinerve involvement.

Once structural abnormalities have been ruled out, treatment for diabetic truncal mononeuropathy consists of pain management. Improvement is generally gradual.

Typically, no treatment is given for diabetic amyotrophy, other than improving glycemic control. However, patients with inflammatory changes on biopsy may respond to immunomodulation.[175]

Autonomic neuropathy

Control of hyperglycemia has been shown to delay the onset and progression of autonomic neuropathy in type 1 diabetes and possibly in type 2 diabetes.[9][122][176][177] Studies have shown that implementing tight glucose control as early as possible in the treatment of type 1 diabetes prevents early development of CAN and promotes long-term protection for CAN, but the effects of glycemic control on CAN are less clear for type 2 diabetes.[63]

The following are various manifestations of autonomic neuropathy and the treatments are discussed.

Management of orthostatic hypotension

Simple lifestyle and supportive measures include:[23][68][69]

Avoiding sudden changes in body posture to the head-up position.
Avoiding medications that aggravate hypotension.[39]
Eating small, frequent meals; avoiding a low-salt diet; adequate fluid intake.[39]
Partaking in physical activity and exercise to avoid deconditioning.[39] However, activities that involve straining should be avoided.
Elevating the head of the bed 18 inches at night. This improved symptoms in a small series of patients with orthostatic hypotension from various causes.[178]
Using a compressive garment over the legs and abdomen.[39] Case reports suggest that this approach may be of benefit.[179][180][181][182]
Using an inflatable abdominal band. This was effective in a study of 6 patients with orthostatic hypotension.[183]
Using a low portable chair, as needed for symptoms. This was effective in one study.[184]

Several physical counter-maneuvers, such as leg crossing, squatting, and muscle pumping, can help maintain blood pressure (BP).[185]

Pharmacologic therapy is likely to be required. Midodrine is the only approved drug for the treatment of orthostatic hypotension in some countries, although in practice fludrocortisone is frequently used first.

Fludrocortisone

A synthetic mineralocorticoid, with a long duration of action, which induces plasma expansion. It may also enhance the sensitivity of blood vessels to circulating catecholamines.[186][187]
The earliest report described a single patient, and other case reports have followed.[188][189][190]
The effects are not immediate, but occur over a 1- to 2-week period.
Supine hypertension, hypokalemia, and hypomagnesemia may occur.
Caution must be used, particularly in patients with congestive heart failure, to avoid fluid overload.[191][192]

Midodrine[23][68][69]

A peripheral-selective direct alpha-1-adrenoreceptor agonist, and the only agent approved for the treatment of orthostatic hypotension in some countries.
Activates alpha-1 receptors on arterioles and veins, thereby increasing total peripheral resistance.[193][194]
Several double-blind, placebo-controlled studies have documented its efficacy in the treatment of orthostatic hypotension.[195][196][197]
Because it does not cross the blood-brain barrier, it has few central adverse effects. The main adverse effects are piloerection, pruritus, paresthesias, urinary retention, and supine hypertension.

Pseudoephedrine

Mixed alpha-adrenoreceptor agonists, which act directly on the alpha-adrenoreceptor and release norepinephrine from the postganglionic sympathetic neuron, include pseudoephedrine.[198]
Severe hypertension is an important adverse effect of all sympathomimetic agents. Other adverse effects, which may limit their use, are tremulousness, irritability, insomnia, tachycardia, reduced appetite, and, in men, urinary retention.[199]
Pseudoephedrine-containing medications are associated with a risk of posterior reversible encephalopathy syndrome (PRES) and reversible cerebral vasoconstriction syndrome (RCVS). These are rare conditions with potentially serious and life-threatening complications. Pseudoephedrine-containing medications should not be used in patients with severe or uncontrolled hypertension, or those with severe acute or chronic renal disease or failure.[200]

Erythropoietin[23][68][69]

Improves standing BP in patients with orthostatic hypotension.[67]
The mechanism of action for the pressor effect is still unresolved. Possibilities include increase in red cell mass and central blood volume; correction of the normochromic normocytic anemia that frequently accompanies diabetic autonomic neuropathy; alterations in blood viscosity; and a direct or indirect neurohumoral effect on the vascular wall and vascular tone regulation, which are mediated by the interaction between hemoglobin and the vasodilator nitric oxide.[201][202][203]

Clonidine

An alpha-2 antagonist that usually produces a central sympatholytic effect, and a consequent decrease in BP.
Patients with severe autonomic failure have little central sympathetic efferent activity, and clonidine may affect venous postsynaptic alpha-2 adrenoreceptors.
The use of this agent is limited by the inconsistent hypertensive effect, as well as serious adverse effects.
Clonidine could result in an increase in venous return without a significant increase in peripheral vascular resistance.

Octreotide[23][68][69]

May attenuate the postprandial BP fall, and reduce orthostatic hypotension in patients with autonomic failure.
Mechanisms of action include a local effect on splanchnic vasculature, by inhibiting the release of vasoactive gastrointestinal (GI) peptides; enhanced cardiac output; and an increase in forearm and splanchnic vascular resistance.

Management of diabetic gastroparesis

Some treatments for diabetic gastroparesis are based on commonly accepted clinical practices. These include:[100]

Eating multiple small meals.[39]
Changing diet, such as decreasing dietary fat and fiber.[39][204][205][206]

Drug therapy includes:

Erythromycin
Metoclopramide
Domperidone
OnabotulinumtoxinA (formerly known as botulinum toxin type A).

Erythromycin

Is effective in accelerating gastric emptying.
Is believed to act by stimulating motilin receptors in the gut.[207]
May be used orally, but intravenous administration has been found to be more effective.[208][209]

Metoclopramide

Has antiemetic properties, stimulates acetylcholine release in the myenteric plexus, and is a dopamine antagonist.[206]
Open, single-blind, and double-blind trials have shown mild benefit.[210]
Possible adverse effects include extrapyramidal symptoms, such as acute dystonic reactions; drug-induced parkinsonism; akathisia; and tardive dyskinesia. Galactorrhea, amenorrhea, gynecomastia, and hyperprolactinemia may also occur.
Metoclopramide should be used for up to 5 days only in order to minimize the risk of neurologic and other adverse effects.[211] Its use in the long-term treatment of gastroparesis is no longer recommended. It should be reserved for short-term use in severe cases that are unresponsive to other therapies.

Domperidone

Is a peripheral dopamine receptor antagonist.
Has been shown to stimulate gastric motility and to possess antiemetic properties. It acts as a prokinetic agent, increasing the number and/or the intensity of gastric contractions, and improves symptoms in patients with diabetic gastroparesis.
Stimulates both liquid- and solid-phase gastric emptying.[212]
Its major benefit results from its anti-emetic properties and, to a lesser extent, its motor stimulatory actions.[213]
A few open trials and double-blind trials have all demonstrated improvement in gastric emptying.[210][213]
A systematic review of all studies using oral domperidone for the treatment of diabetic gastroparesis clearly demonstrates the efficacy of domperidone in treating gastroparesis.[214]
The role of domperidone is controversial, due to safety concerns, and it has never been approved for marketing by the FDA.

Intrapyloric onabotulinumtoxinA injection

Several case reports of patients with severe diabetic gastroparesis, whose symptoms persisted despite dietary changes and the use of high-dose prokinetic agents, describe significant symptomatic improvement after intrapyloric injection, performed during upper GI endoscopy.[215][216][217]

Nonpharmacologic methods

Nonpharmacologic methods have been used to treat diabetic gastroparesis in patients unresponsive to pharmacotherapy:

Gastric pacing (stimulation)

Gastric electrical stimulation using a surgically implantable device is available in some locations.
Short-term it has been demonstrated that it is possible to entrain gastric slow waves and normalize myoelectrical activity with pacing.[218]
However, the evidence for gastric pacing in the management of diabetic gastroparesis is limited and does not allow for the identification of specific patient populations or the development of well-defined clinical criteria. It is, therefore, not used routinely in clinical practice and further research is needed.[39][219]

Surgery

Persistent vomiting may require placement of a feeding jejunostomy to bypass an atonic stomach.[206]
Radical surgery, consisting of resection of a large portion of the stomach, with performance of a Roux-en-Y loop was successful in a small series of patients.[220]

Management of diabetic diarrhea

Broad-spectrum antibiotics are commonly used to treat diabetic diarrhea, either when the hydrogen breath test is positive, or as an empiric trial.[100] An early double-blind study, involving a single patient, found that diarrhea subsided when the patient was treated with an oral antibiotic preparation, then recurred when placebo was substituted.[221] Several different regimens have been advocated.[204][205][206] Caution must be used because long-term use of metronidazole can lead to neuropathy.

Cholestyramine can be used in an attempt to chelate bile salts if the hydrogen breath test is normal, or if patients fail an empiric trial of broad-spectrum antibiotics.

Octreotide was effective in a case report of a single patient with diabetic diarrhea.[222] In healthy volunteers, octreotide improved gastric, small bowel, and colonic transit, and colonic motility and tone.[223] Octreotide may be considered for the management of diabetic diarrhea when other approaches have failed.

Management of diabetic bladder dysfunction

Bethanechol, a parasympathomimetic agent, may be helpful. Bladder training, such as scheduled voiding, may be used particularly for urge incontinence. The Crede maneuver may also be used. This method helps to empty the bladder if it is weak and flaccid. The patient pushes with a hand down on the abdomen from the umbilicus toward the bladder in a smooth, even manner.[100]

Management of diabetic erectile dysfunction

The first-line therapy for erectile dysfunction (ED) is a phosphodiesterase-5 (PDE-5) inhibitor.[224] PDE-5 inhibitors revolutionized the management of ED and are efficient and safe. Both sildenafil and tadalafil significantly increase erectile function and are generally well tolerated.[225][226] However, adverse effects may occur, with headache and flushing the most commonly reported. Flu-like syndromes, dyspepsia, myalgias, abnormal vision, and back pain may occur less frequently.

The second-line option for treatment of ED is intracavernosal injection with papaverine, an opioid alkaloid, or alprostadil, a synthetic analog of prostaglandin E1. The success rate of intracavernosal injections is high, with nearly 90% of patients achieving erection.[227][228]

A topically applied cream formulation of alprostadil is a third-line option for the treatment of diabetic ED in Europe and other countries including Canada. It is not available in the US. Alprostadil is delivered with a permeation enhancer to facilitate local absorption. Other benefits include avoidance of a contraindication with organic nitrates, fast onset of action, and minimal drug-drug interactions.[229]

Other options that may be considered include vacuum devices and penile prostheses.[39] Several case reports have described the use of vacuum devices, rigid penile implants, and inflatable prostheses for the treatment of ED.[228][230]

If suspected, hypogonadism should be investigated and treated as necessary.[39] Removal of medication exacerbating ED, management of associated comorbidities, and lifestyle modifications are essential in all patients.

As ED and diabetes can negatively impact male self-esteem and be associated with depression and anxiety, psychological assessment and appropriate treatment of patients affected is also likely to be beneficial.

Management of common comorbidities

Depression/mood disorders

Diabetic peripheral neuropathy is associated with comorbid mood disorders, particularly depression and anxiety.[24][66][102][103] The presence of mood disorders can affect perception of pain.
Treatment of comorbid mood disorders may help reduce pain and improve quality of life.[66] Antidepressant treatment options for painful neuropathy (tricyclic antidepressants and SNRIs) may also have beneficial effects on mood disorders. Presence of mood disorders should be taken into account when selecting regimens.

Sleep disorders

A high prevalence of sleep disorders is reported in patients with painful DN.[66][103][105][106]
Presence of sleep disorders can affect perception of pain.
Treatment of comorbid sleep disorders may help reduce pain and improve quality of life.[66]

For management of other diabetes-related complications, see separate topics:

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