Diabetic neuropathy
Encyclopedia
Diabetic neuropathies are neuropathic disorders that are associated with diabetes mellitus
. These conditions are thought to result from diabetic microvascular injury
involving small blood vessel
s that supply nerves (vasa nervorum
) in addition to macrovascular conditions that can culminate in diabetic neuropathy. Relatively common conditions which may be associated with diabetic neuropathy include third nerve palsy
; mononeuropathy; mononeuropathy multiplex; diabetic amyotrophy
; a pain
ful polyneuropathy; autonomic neuropathy; and thoracoabdominal neuropathy.
s vary depending on the nerve(s) affected and may include symptoms other than those listed. Symptoms usually develop gradually over years.
Symptoms may include:
s depend on normal nerve function, and nerves depend on adequate blood flow
. The first pathological change in the microvasculature is vasoconstriction
. As the disease progresses, neuronal dysfunction correlates closely with the development of vascular abnormalities, such as capillary basement membrane thickening and endothelial hyperplasia, which contribute to diminished oxygen tension and hypoxia
. Neuronal ischemia is a well-established characteristic of diabetic neuropathy. Vasodilator agents (e.g., ACE inhibitor
s, α1-antagonists) can lead to substantial improvements in neuronal blood flow
, with corresponding improvements in nerve conduction velocities
. Thus, microvascular dysfunction occurs early in diabetes, parallels the progression of neural dysfunction, and may be sufficient to support the severity of structural, functional, and clinical changes observed in diabetic neuropathy.
cause a non-enzymatic covalent bond
ing with protein
s, which alters their structure and inhibits their function. Some of these glycosylated proteins have been implicated in the pathology of diabetic neuropathy and other long term complications of diabetes.
, which activates PKC. PKC inhibitors in animal model
s will increase nerve conduction velocity
by increasing neuronal blood flow.
Glucose is a highly reactive compound, and it must be metabolized or it will find tissues in the body to react with. Increased glucose levels, like those seen in diabetes, activates this alternative biochemical pathway, which in turn causes a decrease in glutathione
and an increase in reactive oxygen radicals. The pathway is dependent on the enzyme aldose reductase
. Inhibitors of this enzyme have demonstrated efficacy in animal models in preventing the development of neuropathy.
While most body cells require the action of insulin for glucose to gain entry into the cell, the cells of the retina, kidney and nervous tissues are insulin-independent. Therefore there is a free interchange of glucose from inside to outside of the cell, regardless of the action of insulin, in the eye, kidney and neurons. The cells will use glucose for energy as normal, and any glucose not used for energy will enter the polyol pathway and be converted into sorbitol. Under normal blood glucose levels, this interchange will cause no problems, as aldose reductase has a low affinity for glucose at normal concentrations.
However, in a hyperglycemic state, the affinity of aldose reductase for glucose rises, meaning much higher levels of sorbitol and much lower levels of NADPH
, a compound used up when this pathway is activated. The sorbitol can not cross cell membranes, and when it accumulates, it produces osmotic stresses on cells by drawing water into the cell. Fructose does essentially the same thing, and it is created even further on in the chemical pathway.
The NADPH, used up when the pathway is activated, acts to promote nitric oxide and glutathione production, and its conversion during the pathway leads to reactive oxygen molecules. Glutathione deficiencies can lead to hemolysis caused by oxidative stress, and we already know that nitric oxide is one of the important vasodilators in blood vessels. NAD+
, which is also used up, is necessary to keep reactive oxygen species from forming and damaging cells.
Furthermore, the high levels of sorbitol are believed to reduce the cellular uptake of another alcohol, myoinsitol, decreasing the activity of the plasma membrane Na+/K+ ATPase pump required for nerve function, further contributing to the neuropathy.
In summary, excessive activation of the polyol pathway leads to increased levels of sorbitol and reactive oxygen molecules and decreased levels of nitric oxide and glutathione, as well as increased osmotic stresses on the cell membrane. Any one of these elements alone can promote cell damage, but here we have several acting together.
and night time pain. The pain can feel like burning, pricking sensation, achy or dull. Pins and needles sensation is common. Loss of proprioception
, the sense of where a limb is in space, is affected early. These patients cannot feel when they are stepping on a foreign body, like a splinter, or when they are developing a callous from an ill-fitting shoe. Consequently, they are at risk of developing ulcers and infections on the feet and legs, which can lead to amputation
. Similarly, these patients can get multiple fractures of the knee, ankle or foot, and develop a Charcot joint. Loss of motor function results in dorsiflexion, contracture
s of the toes, loss of the interosseous muscle function and leads to contraction of the digits, so called hammer toe
s. These contractures occur not only in the foot but also in the hand where the loss of the musculature makes the hand appear gaunt and skeletal. The loss of muscular function is progressive.
is composed of nerves serving the heart
, lungs, blood vessels, bone
, adipose tissue
, sweat glands, gastrointestinal system and genitourinary system
. Autonomic neuropathy can affect any of these organ systems. The most commonly recognized autonomic dysfunction in diabetics is orthostatic hypotension
, or fainting when standing up. In the case of diabetic autonomic neuropathy, it is due to the failure of the heart and arteries to appropriately adjust heart rate and vascular tone to keep blood continually and fully flowing to the brain
. This symptom is usually accompanied by a loss of the usual change in heart rate seen with normal breathing. These two findings suggest autonomic neuropathy.
GI tract manifestations include gastroparesis
, nausea
, bloating
, and diarrhea
. Because many diabetics take oral medication for their diabetes, absorption of these medicines is greatly affected by the delayed gastric emptying. This can lead to hypoglycemia
when an oral diabetic agent is taken before a meal and does not get absorbed until hours, or sometimes days later, when there is normal or low blood sugar already. Sluggish movement of the small intestine
can cause bacteria
l overgrowth, made worse by the presence of hyperglycemia
. This leads to bloating
, gas and diarrhea
.
Urinary symptoms include urinary frequency, urgency, incontinence
and retention. Again, because of the retention of urine
, urinary tract infections are frequent. Urinary retention can lead to bladder diverticula, stones, reflux nephropathy
.
controls all of the muscles that move the eye
with the exception of the lateral rectus
and superior oblique muscle
s. It also serves to constrict the pupil
and open the eyelid. The onset of a diabetic third nerve palsy is usually abrupt, beginning with frontal or periorbital pain and then diplopia
. All of the oculomotor muscles innervated by the third nerve may be affected, but those that control pupil size are usually well-preserved early on. This is because the parasympathetic
nerve fibers within CNIII that influence pupillary size are found on the periphery of the nerve (in terms of a cross sectional view), which makes them less susceptible to ischemic damage (as they are closer to the vascular supply). The sixth nerve, the abducens nerve, which innervates the lateral rectus muscle of the eye (moves the eye laterally), is also commonly affected but fourth nerve, the trochlear nerve
, (innervates the superior oblique muscle, which moves the eye downward) involvement is unusual. Mononeuropathies of the thoracic or lumbar spinal nerve
s can occur and lead to painful syndromes that mimic myocardial infarction
, cholecystitis
or appendicitis
. Diabetics have a higher incidence of entrapment neuropathies, such as carpal tunnel syndrome
.
Options for pain control include tricyclic antidepressant
s (TCAs), serotonin reuptake inhibitors (SSRIs) and antiepileptic drugs (AEDs). A systematic review
concluded that "tricyclic antidepressants and traditional anticonvulsants are better for short term pain relief than newer generation anticonvulsants." A combination of these medication (gabapentin + nortriptyline) may also be superior to a single agent.
The only two drugs approved by the FDA for diabetic peripheral neuropathy are the antidepressant duloxetine
and the anticonvulsant pregabalin
. Before trying a systemic medication, some doctors recommend treating localized diabetic periperal neuropathy with lidocaine patches.
, amitriptyline
, desipramine
and nortriptyline
. These drugs are effective at decreasing painful symptoms but suffer from multiple side effects that are dosage dependent. One notable side effect is cardiac toxicity, which can lead to fatal arrhythmias. At low dosages used for neuropathy, toxicity
is rare, but if symptoms warrant higher doses, complications are more common. Among the TCAs, amitriptyline is most widely used for this condition, but desipramine and nortriptyline have fewer side effects
.
(Cymbalta) is approved for diabetic neuropathy, while venlafaxine
is also commonly used. By targeting both serotonin and norepinephrine, these drugs target the painful symptoms of diabetic neuropathy, and also treat depression if it exists. On the other hand, selective serotonin reuptake inhibitor
s are not useful.
, paroxetine
, sertraline
and citalopram
and are not recommended to treat painful neuropathy because they have been found to be no more efficacious than placebo in several controlled trials. Side effects are rarely serious, and do not cause any permanent disabilities. They cause sedation and weight gain, which can worsen a diabetic's glycemic control. They can be used at dosages that also relieve the symptoms of depression
, a common comorbidity of diabetic neuropathy.
and the related pregabalin
, are emerging as first line treatment for painful neuropathy. Gabapentin compares favorably with amitriptyline in terms of efficacy, and is clearly safer. Its main side effect is sedation, which does not diminish over time and may in fact worsen. It needs to be taken three times a day, and it sometimes causes weight gain, which can worsen glycemic control in diabetics. Carbamazepine
(Tegretol) is effective but not necessarily safe for diabetic neuropathy. Its first metabolite, oxcarbazepine
, is both safe and effective in other neuropathic disorders, but has not been studied in diabetic neuropathy. Topiramate
has not been studied in diabetic neuropathy, but has the beneficial side effect of causing mild anorexia
and weight loss
, and is anecdotally beneficial.
Duloxetine
+ extended release morphine
± naproxen
± hydroxyzine
(esp. with oxycodone
) ± morphine or hydromorphone
immediate release for breakthrough pain is a common recipe in cases where diabetic neuropathy is a complicating factor in a debilitating chronic pain condition — amitryptiline may be more effective than Duloxetine in some. Opioids requiring Cytochrome P-450 activation (e.g. codeine
, dihydrocodeine
) should perhaps be used with an agent not chemically related to the SSRIs; conversely, they may impact parts of the Liberation, Absorption, Distribution, Metabolism & Elimination profile for morphine, hydromorphone, oxymorphone
&c the other way.
can be an effective and alternative treatment option for patients with diabetes. This may help reduce dependency on pain relieving drug therapies. Certain physiotherapy techniques can help alleviate symptoms brought on from diabetic neuropathy such as deep pain
in the feet and legs, tingling or burning sensation in extremities, muscle cramps, muscle weakness
, sexual dysfunction
, and diabetic foot
.
Transcutaneous electrical nerve stimulation
(TENS) and interferential current (IFC) use a painless electric current and the physiological effects from low frequency electrical stimulation to relieve stiffness
, improve mobility, relieve neuropathic pain, reduce oedema, and heal resistant foot ulcers.
Gait training
, posture training, and teaching these patients the basic principles of off-loading can help prevent and/or stabilize foot complications such as foot ulcers. Off-loading techniques can include the use of mobility aids
(e.g. crutches) or foot splints. Gait re-training would also be beneficial for individuals who have lost limbs, due to diabetic neuropathy, and now wear a prosthesis
.
Exercise programs, along with manual therapy
, will help to prevent muscle contratures, spasms
and atrophy
. These programs may include general muscle stretching to maintain muscle length and a person’s range of motion. General muscle strengthening exercises will help to maintain muscle strength and reduce muscle wasting. Aerobic exercise such as swimming and using a stationary bicycle can help peripheral neuropathy, but activities that place excessive pressure on the feet (e.g. walking long distances, running) may be contraindicated.
Heat, therapeutic ultrasound
, hot wax and short wave diathermy are also useful for treating diabetic neuropathy. Pelvic floor muscle exercises can improve sexual dysfunction caused by neuropathy.
that compared once-daily oral doses of 600 mg to 1800 mg compared to placebo
, although nausea occurred in the higher doses.
Methylcobalamin, a specific form of Vitamin B-12 found in spinal fluid, has been studied and shown to have significant effect, taken orally or injected, in treating and improving diabetic neuropathy.
Though not yet commercially available, C-peptide
has shown promising results in treatment of diabetic complications, including neuropathies. Once thought to be a useless by-product of insulin production, it helps to ameliorate and reverse the major symptoms of diabetes.
In more recent years, Photo Energy Therapy devices are becoming more widely used to treat neuropathic symptoms. Photo Energy Therapy devices emit near infrared light (NIR Therapy) typically at a wavelength of 880 nm. This wavelength is believed to stimulate the release of Nitric Oxide
, an Endothelium-derived relaxing factor
into the bloodstream, thus vasodilating the capilaries and venuoles in the microcirculatory system. This increase in circulation has been shown effective in various clinical studies to decrease pain in diabetic and non-diabetic patients. Photo Energy Therapy devices seem to address the underlying problem of neuropathies, poor microcirculation
, which leads to pain and numbness in the extremities,.
Sativex
, a cannabis
based medicine has not been found to be effective for diabetic neuropathy.
There has been experimental work testing the efficacy of sildenafil
(Viagra) but this study described itself as an "isolated clinical report" and cited a need for further clinical investigation.
As a complication, there is an increased risk of injury to the feet because of loss of sensation (see diabetic foot
). Small infection
s can progress to ulceration and this may require amputation
.
in diabetes patients. It is estimated that the prevalence
of neuropathy in diabetes patients is approximately 20%. Diabetic neuropathy is implicated in 50–75% of nontraumatic amputation
s.
The main risk factor for diabetic neuropathy is hyperglycemia
. It is important to note that people with diabetes are more likely to develop symptoms relating to peripheral neuropathy
as the excess glucose in the blood results in a condition known as Glucojasinogen. This condition is affiliated with erectile dysfunction
and epigastric tenderness which in turn results in lack of blood flow to the peripheral intrapectine nerves which govern the movement of the arms and legs. In the DCCT (Diabetes Control and Complications Trial, 1995) study, the annual incidence of neuropathy was 2% per year, but dropped to 0.56% with intensive treatment of Type 1 diabetics. The progression of neuropathy is dependent on the degree of glycemic control in both Type 1 and Type 2 diabetes. Duration of diabetes, age
, cigarette
smoking, hypertension
, height and hyperlipidemia
are also risk factors for diabetic neuropathy.
Diabetes mellitus
Diabetes mellitus, often simply referred to as diabetes, is a group of metabolic diseases in which a person has high blood sugar, either because the body does not produce enough insulin, or because cells do not respond to the insulin that is produced...
. These conditions are thought to result from diabetic microvascular injury
Microvascular disease
Microangiopathy is an angiopathy affecting small blood vessels in the body. It can be contrasted to macroangiopathy....
involving small blood vessel
Blood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s that supply nerves (vasa nervorum
Vasa nervorum
Vasa nervorum are small arteries that provide blood supply to peripheral nerves. A decrease in blood flow through the vasa nervorum has been implicated in the development of diabetic neuropathy. Arteritis of the vasa nervorum leads to mononeuritis multiplex or polyneuropathy.The term is often...
) in addition to macrovascular conditions that can culminate in diabetic neuropathy. Relatively common conditions which may be associated with diabetic neuropathy include third nerve palsy
Oculomotor nerve palsy
Oculomotor nerve palsy is an eye condition resulting from damage to the third cranial nerve or a branch thereof. As the name suggests, the oculomotor nerve supplies the majority of the muscles controlling eye movements. Thus, damage to this nerve will result in the affected individual being unable...
; mononeuropathy; mononeuropathy multiplex; diabetic amyotrophy
Amyotrophy
Amyotrophy is progressive wasting of muscle tissues. Muscle pain is also a symptom. It can occur in middle age males with type 2 diabetes. It also occurs with Motor Neuron Disease.-See also:* Diabetic amyotrophy* Monomelic amyotrophy...
; a pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
ful polyneuropathy; autonomic neuropathy; and thoracoabdominal neuropathy.
Signs and symptoms
Diabetic neuropathy affects all peripheral nerves including pain fibers, motor neurons and the autonomic nervous system. It therefore can affect all organs and systems, as all are innervated. There are several distinct syndromes based upon the organ systems and members affected, but these are by no means exclusive. A patient can have sensorimotor and autonomic neuropathy or any other combination. SymptomSymptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s vary depending on the nerve(s) affected and may include symptoms other than those listed. Symptoms usually develop gradually over years.
Symptoms may include:
- Numbness and tingling of extremities
- DysesthesiaDysesthesiaDysesthesia comes from the Greek word "dys", meaning "not-normal" and "aesthesis", which means "sensation" . It is defined as an unpleasant, abnormal sense of touch, and it may be, or not be, considered as a kind of pain...
(abnormal sensation to a body part) - DiarrheaDiarrheaDiarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
- Erectile dysfunctionErectile dysfunctionErectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
- Urinary incontinenceUrinary incontinenceUrinary incontinence is any involuntary leakage of urine. It is a common and distressing problem, which may have a profound impact on quality of life. Urinary incontinence almost always results from an underlying treatable medical condition but is under-reported to medical practitioners...
(loss of bladder control) - Facial, mouth and eyelid drooping
- Vision changes
- DizzinessDizzinessDizziness refers to an impairment in spatial perception and stability. The term is somewhat imprecise. It can be used to mean vertigo, presyncope, disequilibrium, or a non-specific feeling such as giddiness or foolishness....
- Muscle weakness
- Difficulty swallowingDysphagiaDysphagia is the medical term for the symptom of difficulty in swallowing. Although classified under "symptoms and signs" in ICD-10, the term is sometimes used as a condition in its own right. Sufferers are sometimes unaware of their dysphagia....
- Speech impairment
- FasciculationFasciculationA fasciculation , or "muscle twitch", is a small, local, involuntary muscle contraction and relaxation visible under the skin arising from the spontaneous discharge of a bundle of skeletal muscle fibers...
(muscle contractions) - AnorgasmiaAnorgasmiaAnorgasmia, or Coughlan's syndrome, is a type of sexual dysfunction in which a person cannot achieve orgasm, even with adequate stimulation. In males the condition is often related to delayed ejaculation . Anorgasmia can often cause sexual frustration...
- Burning or electric pain
Pathogenesis
There are four factors thought to be involved in the development of diabetic neuropathy:Microvascular disease
Vascular and neural diseases are closely related and intertwined. Blood vesselBlood vessel
The blood vessels are the part of the circulatory system that transports blood throughout the body. There are three major types of blood vessels: the arteries, which carry the blood away from the heart; the capillaries, which enable the actual exchange of water and chemicals between the blood and...
s depend on normal nerve function, and nerves depend on adequate blood flow
Blood flow
Blood flow is the continuous running of blood in the cardiovascular system.The human body is made up of several processes all carrying out various functions. We have the gastrointestinal system which aids the digestion and the absorption of food...
. The first pathological change in the microvasculature is vasoconstriction
Vasoconstriction
Vasoconstriction is the narrowing of the blood vessels resulting from contraction of the muscular wall of the vessels, particularly the large arteries, small arterioles and veins. The process is the opposite of vasodilation, the widening of blood vessels. The process is particularly important in...
. As the disease progresses, neuronal dysfunction correlates closely with the development of vascular abnormalities, such as capillary basement membrane thickening and endothelial hyperplasia, which contribute to diminished oxygen tension and hypoxia
Hypoxia (medical)
Hypoxia, or hypoxiation, is a pathological condition in which the body as a whole or a region of the body is deprived of adequate oxygen supply. Variations in arterial oxygen concentrations can be part of the normal physiology, for example, during strenuous physical exercise...
. Neuronal ischemia is a well-established characteristic of diabetic neuropathy. Vasodilator agents (e.g., ACE inhibitor
ACE inhibitor
ACE inhibitors or angiotensin-converting enzyme inhibitors are a group of drugs used primarily for the treatment of hypertension and congestive heart failure...
s, α1-antagonists) can lead to substantial improvements in neuronal blood flow
Blood flow
Blood flow is the continuous running of blood in the cardiovascular system.The human body is made up of several processes all carrying out various functions. We have the gastrointestinal system which aids the digestion and the absorption of food...
, with corresponding improvements in nerve conduction velocities
Nerve conduction study
A nerve conduction study is a test commonly used to evaluate the function, especially the ability of electrical conduction, of the motor and sensory nerves of the human body.Nerve conduction velocity is a common measurement made during this test...
. Thus, microvascular dysfunction occurs early in diabetes, parallels the progression of neural dysfunction, and may be sufficient to support the severity of structural, functional, and clinical changes observed in diabetic neuropathy.
Advanced glycated end products
Elevated intracellular levels of glucoseGlucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
cause a non-enzymatic covalent bond
Covalent bond
A covalent bond is a form of chemical bonding that is characterized by the sharing of pairs of electrons between atoms. The stable balance of attractive and repulsive forces between atoms when they share electrons is known as covalent bonding....
ing with protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s, which alters their structure and inhibits their function. Some of these glycosylated proteins have been implicated in the pathology of diabetic neuropathy and other long term complications of diabetes.
Protein kinase C
PKC is implicated in the pathology of diabetic neuropathy. Increased levels of glucose cause an increase in intracellular diacylglycerolDiglyceride
A diglyceride, or a diacylglycerol , is a glyceride consisting of two fatty acid chains covalently bonded to a glycerol molecule through ester linkages....
, which activates PKC. PKC inhibitors in animal model
Animal model
An animal model is a living, non-human animal used during the research and investigation of human disease, for the purpose of better understanding the disease without the added risk of causing harm to an actual human being during the process...
s will increase nerve conduction velocity
Nerve conduction velocity
Nerve conduction velocity is the speed at which an electrochemical signal propagates down a neural pathway. Many things can affect this, including axon diameter, myelination, the internal resistance of the axon, and temperature. Nerve conduction velocity differs from species to species, and to a...
by increasing neuronal blood flow.
Polyol pathway
Also called the sorbitol/aldose reductase pathway, the polyol pathway may be implicated in diabetic complications that result in microvascular damage to nervous tissue, and also to the retina and kidney.Glucose is a highly reactive compound, and it must be metabolized or it will find tissues in the body to react with. Increased glucose levels, like those seen in diabetes, activates this alternative biochemical pathway, which in turn causes a decrease in glutathione
Glutathione
Glutathione is a tripeptide that contains an unusual peptide linkage between the amine group of cysteine and the carboxyl group of the glutamate side-chain...
and an increase in reactive oxygen radicals. The pathway is dependent on the enzyme aldose reductase
Aldose reductase
Aldose reductase is an NADPH-dependent oxidoreductase that catalyzes the reduction of a variety of aldehydes and carbonyls, including monosaccharides...
. Inhibitors of this enzyme have demonstrated efficacy in animal models in preventing the development of neuropathy.
While most body cells require the action of insulin for glucose to gain entry into the cell, the cells of the retina, kidney and nervous tissues are insulin-independent. Therefore there is a free interchange of glucose from inside to outside of the cell, regardless of the action of insulin, in the eye, kidney and neurons. The cells will use glucose for energy as normal, and any glucose not used for energy will enter the polyol pathway and be converted into sorbitol. Under normal blood glucose levels, this interchange will cause no problems, as aldose reductase has a low affinity for glucose at normal concentrations.
However, in a hyperglycemic state, the affinity of aldose reductase for glucose rises, meaning much higher levels of sorbitol and much lower levels of NADPH
Nicotinamide adenine dinucleotide phosphate
Nicotinamide adenine dinucleotide phosphate, abbreviated NADP or TPN in older notation , is a coenzyme used in anabolic reactions, such as lipid and nucleic acid synthesis, which require NADPH as a reducing agent....
, a compound used up when this pathway is activated. The sorbitol can not cross cell membranes, and when it accumulates, it produces osmotic stresses on cells by drawing water into the cell. Fructose does essentially the same thing, and it is created even further on in the chemical pathway.
The NADPH, used up when the pathway is activated, acts to promote nitric oxide and glutathione production, and its conversion during the pathway leads to reactive oxygen molecules. Glutathione deficiencies can lead to hemolysis caused by oxidative stress, and we already know that nitric oxide is one of the important vasodilators in blood vessels. NAD+
Nicotinamide adenine dinucleotide
Nicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...
, which is also used up, is necessary to keep reactive oxygen species from forming and damaging cells.
Furthermore, the high levels of sorbitol are believed to reduce the cellular uptake of another alcohol, myoinsitol, decreasing the activity of the plasma membrane Na+/K+ ATPase pump required for nerve function, further contributing to the neuropathy.
In summary, excessive activation of the polyol pathway leads to increased levels of sorbitol and reactive oxygen molecules and decreased levels of nitric oxide and glutathione, as well as increased osmotic stresses on the cell membrane. Any one of these elements alone can promote cell damage, but here we have several acting together.
Sensorimotor polyneuropathy
Longer nerve fibers are affected to a greater degree than shorter ones, because nerve conduction velocity is slowed in proportion to a nerve's length. In this syndrome, decreased sensation and loss of reflexes occurs first in the toes on each foot, then extends upward. It is usually described as glove-stocking distribution of numbness, sensory loss, dysesthesiaDysesthesia
Dysesthesia comes from the Greek word "dys", meaning "not-normal" and "aesthesis", which means "sensation" . It is defined as an unpleasant, abnormal sense of touch, and it may be, or not be, considered as a kind of pain...
and night time pain. The pain can feel like burning, pricking sensation, achy or dull. Pins and needles sensation is common. Loss of proprioception
Proprioception
Proprioception , from Latin proprius, meaning "one's own" and perception, is the sense of the relative position of neighbouring parts of the body and strength of effort being employed in movement...
, the sense of where a limb is in space, is affected early. These patients cannot feel when they are stepping on a foreign body, like a splinter, or when they are developing a callous from an ill-fitting shoe. Consequently, they are at risk of developing ulcers and infections on the feet and legs, which can lead to amputation
Amputation
Amputation is the removal of a body extremity by trauma, prolonged constriction, or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as malignancy or gangrene. In some cases, it is carried out on individuals as a preventative surgery for...
. Similarly, these patients can get multiple fractures of the knee, ankle or foot, and develop a Charcot joint. Loss of motor function results in dorsiflexion, contracture
Contracture
A muscle contracture is a permanent shortening of a muscle or joint.. It is usually in response to prolonged hypertonic spasticity in a concentrated muscle area, such as is seen in the tightest muscles of people with conditions like spastic cerebral palsy....
s of the toes, loss of the interosseous muscle function and leads to contraction of the digits, so called hammer toe
Hammer toe
A hammer toe or contracted toe is a deformity of the proximal interphalangeal joint of the second, third, or fourth toe causing it to be permanently bent, resembling a hammer...
s. These contractures occur not only in the foot but also in the hand where the loss of the musculature makes the hand appear gaunt and skeletal. The loss of muscular function is progressive.
Autonomic neuropathy
The autonomic nervous systemAutonomic nervous system
The autonomic nervous system is the part of the peripheral nervous system that acts as a control system functioning largely below the level of consciousness, and controls visceral functions. The ANS affects heart rate, digestion, respiration rate, salivation, perspiration, diameter of the pupils,...
is composed of nerves serving the heart
Heart
The heart is a myogenic muscular organ found in all animals with a circulatory system , that is responsible for pumping blood throughout the blood vessels by repeated, rhythmic contractions...
, lungs, blood vessels, bone
Bone
Bones are rigid organs that constitute part of the endoskeleton of vertebrates. They support, and protect the various organs of the body, produce red and white blood cells and store minerals. Bone tissue is a type of dense connective tissue...
, adipose tissue
Adipose tissue
In histology, adipose tissue or body fat or fat depot or just fat is loose connective tissue composed of adipocytes. It is technically composed of roughly only 80% fat; fat in its solitary state exists in the liver and muscles. Adipose tissue is derived from lipoblasts...
, sweat glands, gastrointestinal system and genitourinary system
Genitourinary system
In anatomy, the genitourinary system or urogenital system is the organ system of the reproductive organs and the urinary system. These are grouped together because of their proximity to each other, their common embryological origin and the use of common pathways, like the male urethra...
. Autonomic neuropathy can affect any of these organ systems. The most commonly recognized autonomic dysfunction in diabetics is orthostatic hypotension
Hypotension
In physiology and medicine, hypotension is abnormally low blood pressure, especially in the arteries of the systemic circulation. It is best understood as a physiologic state, rather than a disease. It is often associated with shock, though not necessarily indicative of it. Hypotension is the...
, or fainting when standing up. In the case of diabetic autonomic neuropathy, it is due to the failure of the heart and arteries to appropriately adjust heart rate and vascular tone to keep blood continually and fully flowing to the brain
Brain
The brain is the center of the nervous system in all vertebrate and most invertebrate animals—only a few primitive invertebrates such as sponges, jellyfish, sea squirts and starfishes do not have one. It is located in the head, usually close to primary sensory apparatus such as vision, hearing,...
. This symptom is usually accompanied by a loss of the usual change in heart rate seen with normal breathing. These two findings suggest autonomic neuropathy.
GI tract manifestations include gastroparesis
Gastroparesis
Gastroparesis, also called delayed gastric emptying, is a medical condition consisting of a paresis of the stomach, resulting in food remaining in the stomach for a longer period of time than normal. Normally, the stomach contracts to move food down into the small intestine for digestion. The...
, nausea
Nausea
Nausea , is a sensation of unease and discomfort in the upper stomach with an involuntary urge to vomit. It often, but not always, precedes vomiting...
, bloating
Bloating
Bloating is any abnormal general swelling, or increase in diameter of the abdominal area. As a symptom, the patient feels a full and tight abdomen, which may cause abdominal pain sometimes accompanied by increased borborygmus or more seriously the total lack of borborygmus.-Symptoms:The most common...
, and diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
. Because many diabetics take oral medication for their diabetes, absorption of these medicines is greatly affected by the delayed gastric emptying. This can lead to hypoglycemia
Hypoglycemia
Hypoglycemia or hypoglycæmia is the medical term for a state produced by a lower than normal level of blood glucose. The term literally means "under-sweet blood"...
when an oral diabetic agent is taken before a meal and does not get absorbed until hours, or sometimes days later, when there is normal or low blood sugar already. Sluggish movement of the small intestine
Small intestine
The small intestine is the part of the gastrointestinal tract following the stomach and followed by the large intestine, and is where much of the digestion and absorption of food takes place. In invertebrates such as worms, the terms "gastrointestinal tract" and "large intestine" are often used to...
can cause bacteria
Bacteria
Bacteria are a large domain of prokaryotic microorganisms. Typically a few micrometres in length, bacteria have a wide range of shapes, ranging from spheres to rods and spirals...
l overgrowth, made worse by the presence of hyperglycemia
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
. This leads to bloating
Bloating
Bloating is any abnormal general swelling, or increase in diameter of the abdominal area. As a symptom, the patient feels a full and tight abdomen, which may cause abdominal pain sometimes accompanied by increased borborygmus or more seriously the total lack of borborygmus.-Symptoms:The most common...
, gas and diarrhea
Diarrhea
Diarrhea , also spelled diarrhoea, is the condition of having three or more loose or liquid bowel movements per day. It is a common cause of death in developing countries and the second most common cause of infant deaths worldwide. The loss of fluids through diarrhea can cause dehydration and...
.
Urinary symptoms include urinary frequency, urgency, incontinence
Urinary incontinence
Urinary incontinence is any involuntary leakage of urine. It is a common and distressing problem, which may have a profound impact on quality of life. Urinary incontinence almost always results from an underlying treatable medical condition but is under-reported to medical practitioners...
and retention. Again, because of the retention of urine
Urine
Urine is a typically sterile liquid by-product of the body that is secreted by the kidneys through a process called urination and excreted through the urethra. Cellular metabolism generates numerous by-products, many rich in nitrogen, that require elimination from the bloodstream...
, urinary tract infections are frequent. Urinary retention can lead to bladder diverticula, stones, reflux nephropathy
Reflux nephropathy
Reflux nephropathy, RN is a term applied when small and scarred kidneys are associated with vesico-ureteric reflux . CPN being the most common cause, there are other causes including analgesic nephropathy and obstructive injury. Scarring is essential in developing RN and occurs almost during the...
.
Cranial neuropathy
When cranial nerves are affected, oculomotor (3rd) neuropathies are most common. The oculomotor nerveOculomotor nerve
The oculomotor nerve is the 3rd of 12 paired cranial nerves. It enters the orbit via the superior orbital fissure and controls most of the eye's movements, including constriction of the pupil and maintaining an open eyelid by innervating the Levator palpebrae superiors muscle. The optic nerve is...
controls all of the muscles that move the eye
Human eye
The human eye is an organ which reacts to light for several purposes. As a conscious sense organ, the eye allows vision. Rod and cone cells in the retina allow conscious light perception and vision including color differentiation and the perception of depth...
with the exception of the lateral rectus
Lateral rectus muscle
The lateral rectus muscle is a muscle in the orbit. It is one of six extraocular muscles that control the movements of the eye and the only muscle innervated by the abducens nerve, cranial nerve VI....
and superior oblique muscle
Superior oblique muscle
For the abdominal muscle see: Abdominal external oblique muscleThe superior oblique muscle, or obliquus oculi superior, is a fusiform muscle originating in the upper, medial side of the orbit which abducts, depresses and internally rotates the eye...
s. It also serves to constrict the pupil
Pupil
The pupil is a hole located in the center of the iris of the eye that allows light to enter the retina. It appears black because most of the light entering the pupil is absorbed by the tissues inside the eye. In humans the pupil is round, but other species, such as some cats, have slit pupils. In...
and open the eyelid. The onset of a diabetic third nerve palsy is usually abrupt, beginning with frontal or periorbital pain and then diplopia
Diplopia
Diplopia, commonly known as double vision, is the simultaneous perception of two images of a single object that may be displaced horizontally, vertically, or diagonally in relation to each other...
. All of the oculomotor muscles innervated by the third nerve may be affected, but those that control pupil size are usually well-preserved early on. This is because the parasympathetic
Parasympathetic nervous system
The parasympathetic nervous system is one of the two main divisions of the autonomic nervous system . The ANS is responsible for regulation of internal organs and glands, which occurs unconsciously...
nerve fibers within CNIII that influence pupillary size are found on the periphery of the nerve (in terms of a cross sectional view), which makes them less susceptible to ischemic damage (as they are closer to the vascular supply). The sixth nerve, the abducens nerve, which innervates the lateral rectus muscle of the eye (moves the eye laterally), is also commonly affected but fourth nerve, the trochlear nerve
Trochlear nerve
The trochlear nerve is a motor nerve that innervates a single muscle: the superior oblique muscle of the eye....
, (innervates the superior oblique muscle, which moves the eye downward) involvement is unusual. Mononeuropathies of the thoracic or lumbar spinal nerve
Spinal nerve
The term spinal nerve generally refers to a mixed spinal nerve, which carries motor, sensory, and autonomic signals between the spinal cord and the body...
s can occur and lead to painful syndromes that mimic myocardial infarction
Myocardial infarction
Myocardial infarction or acute myocardial infarction , commonly known as a heart attack, results from the interruption of blood supply to a part of the heart, causing heart cells to die...
, cholecystitis
Cholecystitis
-Signs and symptoms:Cholecystitis usually presents as a pain in the right upper quadrant. This is known as biliary colic. This is initially intermittent, but later usually presents as a constant, severe pain. During the initial stages, the pain may be felt in an area totally separate from the site...
or appendicitis
Appendicitis
Appendicitis is a condition characterized by inflammation of the appendix. It is classified as a medical emergency and many cases require removal of the inflamed appendix, either by laparotomy or laparoscopy. Untreated, mortality is high, mainly because of the risk of rupture leading to...
. Diabetics have a higher incidence of entrapment neuropathies, such as carpal tunnel syndrome
Carpal tunnel syndrome
Carpal Tunnel Syndrome is an entrapment idiopathic median neuropathy, causing paresthesia, pain, and other symptoms in the distribution of the median nerve due to its compression at the wrist in the carpal tunnel. The pathophysiology is not completely understood but can be considered compression...
.
Diagnosis
Diabetic peripheral neuropathy is the most likely diagnosis for someone with diabetes who has pain in a leg or foot, although it may also be caused by vitamin B12 deficiency or osteoarthritis. A recent review in the Journal of the American Medical Association's "Rational Clinical Examination Series" evaluated the usefulness of the clinical examination in diagnosing diabetic peripheral neuropathy. While the physician typically assesses the appearance of the feet, presence of ulceration, and ankle reflexes, the most useful physical examination findings for large fiber neuropathy are an abnormally decreased vibration perception to a 128-Hz tuning fork (likelihood ratio (LR) range, 16–35) or pressure sensation with a 5.07 Semmes-Weinstein monofilament (LR range, 11–16). Normal results on vibration testing (LR range, 0.33–0.51) or monofilament (LR range, 0.09–0.54) make large fiber peripheral neuropathy from diabetes less likely. Combinations of signs do not perform better than these 2 individual findings. Nerve conduction tests may show reduced functioning of the peripheral nerves, but seldom correlate with the severity of diabetic peripheral neuropathy and are not appropriate as routine tests for the condition.Treatment
Despite advances in the understanding of the metabolic causes of neuropathy, treatments aimed at interrupting these pathological processes have been limited. Thus, with the exception of tight glucose control, treatments are for reducing pain and other symptoms.Options for pain control include tricyclic antidepressant
Tricyclic antidepressant
Tricyclic antidepressants are heterocyclic chemical compounds used primarily as antidepressants. The TCAs were first discovered in the early 1950s and were subsequently introduced later in the decade; they are named after their chemical structure, which contains three rings of atoms...
s (TCAs), serotonin reuptake inhibitors (SSRIs) and antiepileptic drugs (AEDs). A systematic review
Systematic review
A systematic review is a literature review focused on a research question that tries to identify, appraise, select and synthesize all high quality research evidence relevant to that question. Systematic reviews of high-quality randomized controlled trials are crucial to evidence-based medicine...
concluded that "tricyclic antidepressants and traditional anticonvulsants are better for short term pain relief than newer generation anticonvulsants." A combination of these medication (gabapentin + nortriptyline) may also be superior to a single agent.
The only two drugs approved by the FDA for diabetic peripheral neuropathy are the antidepressant duloxetine
Duloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine for generalized anxiety disorder...
and the anticonvulsant pregabalin
Pregabalin
Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is approved for this use in the European Union. It was designed...
. Before trying a systemic medication, some doctors recommend treating localized diabetic periperal neuropathy with lidocaine patches.
Tricyclic antidepressants
TCAs include imipramineImipramine
Imipramine , also known as melipramine, is an antidepressant medication, a tricyclic antidepressant of the dibenzazepine group...
, amitriptyline
Amitriptyline
Amitriptyline is a tricyclic antidepressant . It is the most widely used TCA and has at least equal efficacy against depression as the newer class of SSRIs...
, desipramine
Desipramine
Desipramine is a tricyclic antidepressant . It inhibits the reuptake of norepinephrine and to a lesser extent serotonin. It is used to treat depression, but not considered a first line treatment since the introduction of SSRI antidepressants...
and nortriptyline
Nortriptyline
Nortriptyline is a second-generation tricyclic antidepressant marketed as the hydrochloride salt under the trade names Sensoval, Aventyl, Pamelor, Norpress, Allegron, Noritren and Nortrilen. It is used in the treatment of major depression and childhood nocturnal enuresis...
. These drugs are effective at decreasing painful symptoms but suffer from multiple side effects that are dosage dependent. One notable side effect is cardiac toxicity, which can lead to fatal arrhythmias. At low dosages used for neuropathy, toxicity
Toxicity
Toxicity is the degree to which a substance can damage a living or non-living organisms. Toxicity can refer to the effect on a whole organism, such as an animal, bacterium, or plant, as well as the effect on a substructure of the organism, such as a cell or an organ , such as the liver...
is rare, but if symptoms warrant higher doses, complications are more common. Among the TCAs, amitriptyline is most widely used for this condition, but desipramine and nortriptyline have fewer side effects
Adverse effect (medicine)
In medicine, an adverse effect is a harmful and undesired effect resulting from a medication or other intervention such as surgery.An adverse effect may be termed a "side effect", when judged to be secondary to a main or therapeutic effect. If it results from an unsuitable or incorrect dosage or...
.
Serotonin-Norepinephrine reuptake inhibitors
The SSNRI duloxetineDuloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine for generalized anxiety disorder...
(Cymbalta) is approved for diabetic neuropathy, while venlafaxine
Venlafaxine
Venlafaxine is an antidepressant of the serotonin-norepinephrine reuptake inhibitor class. First introduced by Wyeth in 1993, now marketed by Pfizer, it is licensed for the treatment of major depressive disorder , as a treatment for generalized anxiety disorder, and comorbid indications in...
is also commonly used. By targeting both serotonin and norepinephrine, these drugs target the painful symptoms of diabetic neuropathy, and also treat depression if it exists. On the other hand, selective serotonin reuptake inhibitor
Selective serotonin reuptake inhibitor
Selective serotonin re-uptake inhibitors or serotonin-specific reuptake inhibitor are a class of compounds typically used as antidepressants in the treatment of depression, anxiety disorders, and some personality disorders. The efficacy of SSRIs is disputed...
s are not useful.
Selective Serotonin reuptake inhibitor
SSRIs include fluoxetineFluoxetine
Fluoxetine is an antidepressant of the selective serotonin reuptake inhibitor class. It is manufactured and marketed by Eli Lilly and Company...
, paroxetine
Paroxetine
Paroxetine is an SSRI antidepressant. Marketing of the drug began in 1992 by the pharmaceutical company SmithKline Beecham, now GlaxoSmithKline...
, sertraline
Sertraline
Sertraline hydrochloride is an antidepressant of the selective serotonin reuptake inhibitor class. It was introduced to the market by Pfizer in 1991. Sertraline is primarily used to treat major depression in adult outpatients as well as obsessive–compulsive, panic, and social anxiety disorders in...
and citalopram
Citalopram
Citalopram brand names: Celexa, Cipramil) is an antidepressant drug of the selective serotonin reuptake inhibitor class. It has U.S...
and are not recommended to treat painful neuropathy because they have been found to be no more efficacious than placebo in several controlled trials. Side effects are rarely serious, and do not cause any permanent disabilities. They cause sedation and weight gain, which can worsen a diabetic's glycemic control. They can be used at dosages that also relieve the symptoms of depression
Clinical depression
Major depressive disorder is a mental disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities...
, a common comorbidity of diabetic neuropathy.
Antiepileptic drugs
AEDs, especially gabapentinGabapentin
Gabapentin is a pharmaceutical drug, specifically a GABA analogue. It was originally developed for the treatment of epilepsy, and currently is also used to relieve neuropathic pain...
and the related pregabalin
Pregabalin
Pregabalin is an anticonvulsant drug used for neuropathic pain and as an adjunct therapy for partial seizures with or without secondary generalization in adults. It has also been found effective for generalized anxiety disorder and is approved for this use in the European Union. It was designed...
, are emerging as first line treatment for painful neuropathy. Gabapentin compares favorably with amitriptyline in terms of efficacy, and is clearly safer. Its main side effect is sedation, which does not diminish over time and may in fact worsen. It needs to be taken three times a day, and it sometimes causes weight gain, which can worsen glycemic control in diabetics. Carbamazepine
Carbamazepine
Carbamazepine is an anticonvulsant and mood-stabilizing drug used primarily in the treatment of epilepsy and bipolar disorder, as well as trigeminal neuralgia...
(Tegretol) is effective but not necessarily safe for diabetic neuropathy. Its first metabolite, oxcarbazepine
Oxcarbazepine
Oxcarbazepine is a anticholinergic anticonvulsant and mood stabilizing drug, used primarily in the treatment of epilepsy. It is also used to treat anxiety and mood disorders, and benign motor tics...
, is both safe and effective in other neuropathic disorders, but has not been studied in diabetic neuropathy. Topiramate
Topiramate
Topiramate is an anticonvulsant drug. It was originally produced by Ortho-McNeil Neurologics and Noramco, Inc., both divisions of the Johnson & Johnson Corporation. This medication was discovered in 1979 by Bruce E. Maryanoff and Joseph F. Gardocki during their research work at McNeil...
has not been studied in diabetic neuropathy, but has the beneficial side effect of causing mild anorexia
Anorexia (symptom)
Anorexia is the decreased sensation of appetite...
and weight loss
Weight loss
Weight loss, in the context of medicine, health or physical fitness, is a reduction of the total body mass, due to a mean loss of fluid, body fat or adipose tissue and/or lean mass, namely bone mineral deposits, muscle, tendon and other connective tissue...
, and is anecdotally beneficial.
Classical Analgesics
The above three categories of drugs fall under the heading of Atypical, Adjuvant & Potentiators and are often combined with opioids and/or NSAIDs, usually having effects greater than the sum of their parts.Duloxetine
Duloxetine
Duloxetine is a serotonin-norepinephrine reuptake inhibitor manufactured and marketed by Eli Lilly. It is effective for major depressive disorder and has been shown to be as effective as venlafaxine for generalized anxiety disorder...
+ extended release morphine
Morphine
Morphine is a potent opiate analgesic medication and is considered to be the prototypical opioid. It was first isolated in 1804 by Friedrich Sertürner, first distributed by same in 1817, and first commercially sold by Merck in 1827, which at the time was a single small chemists' shop. It was more...
± naproxen
Naproxen
Naproxen sodium is a nonsteroidal anti-inflammatory drug commonly used for the reduction of pain, fever, inflammation and stiffness caused by conditions such as:...
± hydroxyzine
Hydroxyzine
Hydroxyzine is a first-generation antihistamine of the diphenylmethane and piperazine classes. It was first synthesized by Union Chimique Belge in 1956 and was marketed by Pfizer in the United States later the same year, and is still in widespread use today....
(esp. with oxycodone
Oxycodone
Oxycodone is an opioid analgesic medication synthesized from opium-derived thebaine. It was developed in 1916 in Germany, as one of several new semi-synthetic opioids in an attempt to improve on the existing opioids: morphine, diacetylmorphine , and codeine.Oxycodone oral medications are generally...
) ± morphine or hydromorphone
Hydromorphone
Hydromorphone, a more common synonym for dihydromorphinone, commonly a hydrochloride is a very potent centrally-acting analgesic drug of the opioid class. It is a derivative of morphine, to be specific, a hydrogenated ketone thereof and, therefore, a semi-synthetic drug...
immediate release for breakthrough pain is a common recipe in cases where diabetic neuropathy is a complicating factor in a debilitating chronic pain condition — amitryptiline may be more effective than Duloxetine in some. Opioids requiring Cytochrome P-450 activation (e.g. codeine
Codeine
Codeine or 3-methylmorphine is an opiate used for its analgesic, antitussive, and antidiarrheal properties...
, dihydrocodeine
Dihydrocodeine
Dihydrocodeine, also called DHC, Drocode, Paracodeine and Parzone and known by the brand names of Synalgos DC, Panlor DC, Panlor SS, Contugesic, New Bron Solution-ACE, Huscode, Drocode, Paracodin, Codidol, Didor Continus, Dicogesic, Codhydrine, Dekacodin, DH-Codeine,...
) should perhaps be used with an agent not chemically related to the SSRIs; conversely, they may impact parts of the Liberation, Absorption, Distribution, Metabolism & Elimination profile for morphine, hydromorphone, oxymorphone
Oxymorphone
Oxymorphone or 14-Hydroxydihydromorphinone is a powerful semi-synthetic opioid analgesic first developed in Germany circa 1914, patented in the USA by Endo Pharmaceuticals in 1955 and introduced to the United States market in January 1959 and other countries around the same time...
&c the other way.
Physical Therapy
Physical therapyPhysical therapy
Physical therapy , often abbreviated PT, is a health care profession. Physical therapy is concerned with identifying and maximizing quality of life and movement potential within the spheres of promotion, prevention, diagnosis, treatment/intervention,and rehabilitation...
can be an effective and alternative treatment option for patients with diabetes. This may help reduce dependency on pain relieving drug therapies. Certain physiotherapy techniques can help alleviate symptoms brought on from diabetic neuropathy such as deep pain
Pain
Pain is an unpleasant sensation often caused by intense or damaging stimuli such as stubbing a toe, burning a finger, putting iodine on a cut, and bumping the "funny bone."...
in the feet and legs, tingling or burning sensation in extremities, muscle cramps, muscle weakness
Muscle weakness
Muscle weakness or myasthenia is a lack of muscle strength. The causes are many and can be divided into conditions that have true or perceived muscle weakness...
, sexual dysfunction
Sexual dysfunction
Sexual dysfunction or sexual malfunction refers to a difficulty experienced by an individual or a couple during any stage of a normal sexual activity, including desire, arousal or orgasm....
, and diabetic foot
Diabetic foot
Diabetic foot ulcer is one of the major complications of diabetes mellitus, and probably the major component of the diabetic foot. It occurs in 15% of all patients with diabetes and precedes 84% of all lower leg amputations...
.
Transcutaneous electrical nerve stimulation
Transcutaneous electrical nerve stimulation
Transcutaneous electrical nerve stimulation is the use of electric current produced by a device to stimulate the nerves for therapeutic purposes...
(TENS) and interferential current (IFC) use a painless electric current and the physiological effects from low frequency electrical stimulation to relieve stiffness
Stiffness
Stiffness is the resistance of an elastic body to deformation by an applied force along a given degree of freedom when a set of loading points and boundary conditions are prescribed on the elastic body.-Calculations:...
, improve mobility, relieve neuropathic pain, reduce oedema, and heal resistant foot ulcers.
Gait training
Gait training
In its most general form, Gait training is the act of learning how to walk. However, the term is more often used in reference to a person learning how to walk again after injury or with a disability...
, posture training, and teaching these patients the basic principles of off-loading can help prevent and/or stabilize foot complications such as foot ulcers. Off-loading techniques can include the use of mobility aids
Mobility aids
Mobility aids are devices designed to assist walking or otherwise improve the mobility of people with a mobility impairment.There are various walking aids which can help with impaired ability to walk and wheelchairs or mobility scooters for more severe disability or longer journeys which would...
(e.g. crutches) or foot splints. Gait re-training would also be beneficial for individuals who have lost limbs, due to diabetic neuropathy, and now wear a prosthesis
Prosthesis
In medicine, a prosthesis, prosthetic, or prosthetic limb is an artificial device extension that replaces a missing body part. It is part of the field of biomechatronics, the science of using mechanical devices with human muscle, skeleton, and nervous systems to assist or enhance motor control...
.
Exercise programs, along with manual therapy
Manual therapy
Manual therapy, manipulative therapy, or manual & manipulative therapy is a physical treatment primarily used by physiotherapists, chiropractors, osteopaths to treat musculoskeletal pain and disability; it most commonly includes massage therapy, joint mobilization and joint...
, will help to prevent muscle contratures, spasms
Spasms
-Plot:Jason Kincaid has this massive serpent captured and brought to the US because it killed his brother and he now shares some kind of psychic link with it...
and atrophy
Atrophy
Atrophy is the partial or complete wasting away of a part of the body. Causes of atrophy include mutations , poor nourishment, poor circulation, loss of hormonal support, loss of nerve supply to the target organ, disuse or lack of exercise or disease intrinsic to the tissue itself...
. These programs may include general muscle stretching to maintain muscle length and a person’s range of motion. General muscle strengthening exercises will help to maintain muscle strength and reduce muscle wasting. Aerobic exercise such as swimming and using a stationary bicycle can help peripheral neuropathy, but activities that place excessive pressure on the feet (e.g. walking long distances, running) may be contraindicated.
Heat, therapeutic ultrasound
Therapeutic ultrasound
Therapeutic ultrasound refers generally to any type of procedure that uses ultrasound for therapeutic benefit. This includes HIFU, lithotripsy, targeted ultrasounddrug delivery, trans-dermal ultrasound drug delivery, ultrasound hemostasis, and ultrasound assisted thrombolysis.-Physical...
, hot wax and short wave diathermy are also useful for treating diabetic neuropathy. Pelvic floor muscle exercises can improve sexual dysfunction caused by neuropathy.
Other treatments
α-lipoic acid, an anti-oxidant that is a non-prescription dietary supplement has shown benefit in a randomized controlled trialRandomized controlled trial
A randomized controlled trial is a type of scientific experiment - a form of clinical trial - most commonly used in testing the safety and efficacy or effectiveness of healthcare services or health technologies A randomized controlled trial (RCT) is a type of scientific experiment - a form of...
that compared once-daily oral doses of 600 mg to 1800 mg compared to placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
, although nausea occurred in the higher doses.
Methylcobalamin, a specific form of Vitamin B-12 found in spinal fluid, has been studied and shown to have significant effect, taken orally or injected, in treating and improving diabetic neuropathy.
Though not yet commercially available, C-peptide
C-peptide
C-peptide is a protein that is produced in the body along with insulin. First preproinsulin is secreted with an A-chain, C-peptide, a B-chain, and a signal sequence. The signal sequence is cut off, leaving proinsulin...
has shown promising results in treatment of diabetic complications, including neuropathies. Once thought to be a useless by-product of insulin production, it helps to ameliorate and reverse the major symptoms of diabetes.
In more recent years, Photo Energy Therapy devices are becoming more widely used to treat neuropathic symptoms. Photo Energy Therapy devices emit near infrared light (NIR Therapy) typically at a wavelength of 880 nm. This wavelength is believed to stimulate the release of Nitric Oxide
Nitric oxide
Nitric oxide, also known as nitrogen monoxide, is a diatomic molecule with chemical formula NO. It is a free radical and is an important intermediate in the chemical industry...
, an Endothelium-derived relaxing factor
Endothelium-derived relaxing factor
Endothelium-derived relaxing factor is produced and released by the endothelium to promote smooth muscle relaxation. The best-characterized is nitric oxide . Some sources equate EDRF and nitric oxide....
into the bloodstream, thus vasodilating the capilaries and venuoles in the microcirculatory system. This increase in circulation has been shown effective in various clinical studies to decrease pain in diabetic and non-diabetic patients. Photo Energy Therapy devices seem to address the underlying problem of neuropathies, poor microcirculation
Microcirculation
The microcirculation is a term used to describe the small vessels in the vasculature which are embedded within organs and are responsible for the distribution of blood within tissues; as opposed to larger vessels in the macrocirculation which transport blood to and from the organs...
, which leads to pain and numbness in the extremities,.
Sativex
Sativex
Nabiximols is a cannabinoid oromucosal mouth spray developed by the UK company GW Pharmaceuticals for multiple sclerosis patients, who can use it to alleviate neuropathic pain, spasticity, overactive bladder, and other symptoms. Nabiximols is also being developed in Phase III trials as a...
, a cannabis
Cannabis
Cannabis is a genus of flowering plants that includes three putative species, Cannabis sativa, Cannabis indica, and Cannabis ruderalis. These three taxa are indigenous to Central Asia, and South Asia. Cannabis has long been used for fibre , for seed and seed oils, for medicinal purposes, and as a...
based medicine has not been found to be effective for diabetic neuropathy.
There has been experimental work testing the efficacy of sildenafil
Sildenafil
Sildenafil citrate, sold as Viagra, Revatio and under various other trade names, is a drug used to treat erectile dysfunction and pulmonary arterial hypertension . It was originally developed by British scientists and then brought to market by the US-based pharmaceutical company Pfizer...
(Viagra) but this study described itself as an "isolated clinical report" and cited a need for further clinical investigation.
Tight glucose control
Treatment of early manifestations of sensorimotor polyneuropathy involves improving glycemic control. Tight control of blood glucose can reverse the changes of diabetic neuropathy, but only if the neuropathy and diabetes is recent in onset. Conversely, painful symptoms of neuropathy in uncontrolled diabetics tend to subside as the disease and numbness progress.Prognosis
The mechanisms of diabetic neuropathy are poorly understood. At present, treatment alleviates pain and can control some associated symptoms, but the process is generally progressive.As a complication, there is an increased risk of injury to the feet because of loss of sensation (see diabetic foot
Diabetic foot
Diabetic foot ulcer is one of the major complications of diabetes mellitus, and probably the major component of the diabetic foot. It occurs in 15% of all patients with diabetes and precedes 84% of all lower leg amputations...
). Small infection
Infection
An infection is the colonization of a host organism by parasite species. Infecting parasites seek to use the host's resources to reproduce, often resulting in disease...
s can progress to ulceration and this may require amputation
Amputation
Amputation is the removal of a body extremity by trauma, prolonged constriction, or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as malignancy or gangrene. In some cases, it is carried out on individuals as a preventative surgery for...
.
Epidemiology
Diabetes is the leading known cause of neuropathy in developed countries, and neuropathy is the most common complication and greatest source of morbidity and mortalityDeath
Death is the permanent termination of the biological functions that sustain a living organism. Phenomena which commonly bring about death include old age, predation, malnutrition, disease, and accidents or trauma resulting in terminal injury....
in diabetes patients. It is estimated that the prevalence
Prevalence
In epidemiology, the prevalence of a health-related state in a statistical population is defined as the total number of cases of the risk factor in the population at a given time, or the total number of cases in the population, divided by the number of individuals in the population...
of neuropathy in diabetes patients is approximately 20%. Diabetic neuropathy is implicated in 50–75% of nontraumatic amputation
Amputation
Amputation is the removal of a body extremity by trauma, prolonged constriction, or surgery. As a surgical measure, it is used to control pain or a disease process in the affected limb, such as malignancy or gangrene. In some cases, it is carried out on individuals as a preventative surgery for...
s.
The main risk factor for diabetic neuropathy is hyperglycemia
Hyperglycemia
Hyperglycemia or Hyperglycæmia, or high blood sugar, is a condition in which an excessive amount of glucose circulates in the blood plasma. This is generally a glucose level higher than 13.5mmol/l , but symptoms may not start to become noticeable until even higher values such as 15-20 mmol/l...
. It is important to note that people with diabetes are more likely to develop symptoms relating to peripheral neuropathy
Peripheral neuropathy
Peripheral neuropathy is the term for damage to nerves of the peripheral nervous system, which may be caused either by diseases of or trauma to the nerve or the side-effects of systemic illness....
as the excess glucose in the blood results in a condition known as Glucojasinogen. This condition is affiliated with erectile dysfunction
Erectile dysfunction
Erectile dysfunction is sexual dysfunction characterized by the inability to develop or maintain an erection of the penis during sexual performance....
and epigastric tenderness which in turn results in lack of blood flow to the peripheral intrapectine nerves which govern the movement of the arms and legs. In the DCCT (Diabetes Control and Complications Trial, 1995) study, the annual incidence of neuropathy was 2% per year, but dropped to 0.56% with intensive treatment of Type 1 diabetics. The progression of neuropathy is dependent on the degree of glycemic control in both Type 1 and Type 2 diabetes. Duration of diabetes, age
Senescence
Senescence or biological aging is the change in the biology of an organism as it ages after its maturity. Such changes range from those affecting its cells and their function to those affecting the whole organism...
, cigarette
Cigarette
A cigarette is a small roll of finely cut tobacco leaves wrapped in a cylinder of thin paper for smoking. The cigarette is ignited at one end and allowed to smoulder; its smoke is inhaled from the other end, which is held in or to the mouth and in some cases a cigarette holder may be used as well...
smoking, hypertension
Hypertension
Hypertension or high blood pressure is a cardiac chronic medical condition in which the systemic arterial blood pressure is elevated. What that means is that the heart is having to work harder than it should to pump the blood around the body. Blood pressure involves two measurements, systolic and...
, height and hyperlipidemia
Hyperlipidemia
Hyperlipidemia, hyperlipoproteinemia, or hyperlipidaemia is the condition of abnormally elevated levels of any or all lipids and/or lipoproteins in the blood...
are also risk factors for diabetic neuropathy.
External links
- Diabetic Nerve Problems. MedlinePlus' extensive reference list of pertinent sites.
- Diagnosing Diabetic Autonomic Neuropathy (DAN)