Botulinum toxin type A (BoNT/A) is made naturally by certainbacteria. BoNT/A works by paralyzing specific kinds of nervecells. BoNT/A can be used to treat many illnesses that affecteither nerves or the muscles with which they communicate. Inthe article "Botulinum Toxin for Diabetic Neuropathic Pain:A Randomized Double-Blind Crossover Trial," Dr. Yuan and associatesdescribe how BoNT/A might be used to treat the kind of nervepain that develops in some people who have diabetes.1 The studycompares whether injecting BoNT/A into the skin is better atreducing neuropathic pain than injecting a placebo (saline,salt water) into the skin.
Dr. Yuan and colleagues looked carefully at 20 people who hadneuropathic pain due to type 2 diabetes. Each person had beendiagnosed with diabetes for at least 3 years. Patients withneuropathy experienced either paresthesias (prickling, tingling,or numbness) or a specific kind of pain (burning, itchy, shooting,etc.) in both of their feet up to the ankle or mid-shin. Doctorsassessed the pain by 1) physical examination, 2) a specificquestionnaire for pain, and 3) a specific test of nerve function.The nerve test is called a nerve conduction velocity test. Itis designed to see how well patients’ nerves can transmitelectrical signals. If the nerve is damaged, as happens in diabetes,the signals carried by the nerves are either slower or weakerthan normal.
As in all studies, there are reasons to include specific participants.This makes sure that the group is alike and that the resultsare solid. For instance, only people with proven polyneuropathydue to diabetes were included. Since a specific treatment wasbeing studied, only people who had not changed to other painmedications could be included. Otherwise, the doctors wouldnot have known whether the study treatment improved the painor if improvement was a result of changing to these other medications.Because alcoholism and kidney problems can both cause neuropathicpain, patients with these medical conditions could not be included.
Patients were randomly chosen to receive either BoNT/A or salineinjections. The injections were given at 12 evenly spaced sitesin the skin on the tops of their feet. A nurse prepared theneedles secretly in another room, so neither the patients northe doctors knew whether they were injecting the toxin or theplacebo. This is called a double-blind study. This was doneso that the results of the study would not be affected by eitherthe patients’ or the doctors’ expectations.
Three different tests of neuropathic pain symptoms were donebefore treatment. The tests were then repeated after the 1st,4th, 8th, and 12th weeks of the study. This was done to seehow well the treatments were working. The authors used a well-knownpain scale (visual analog scale) as one measure of improvement.They also used a Chinese version of the Pittsburgh Sleep QualityIndex, which is filled out by the patient. It is also filledout by the patient’s sleep partner. This provides theresearchers with a number representing sleep difficulty. A highernumber means worse sleep.
Third, the researchers used the Short Form-36, a questionnaireused to assess general quality of life. Another injection wasgiven after the 12th week. This time patients were given whichevertreatment—BoNT/A or saline—they had not been givenin the first injection. In other words, each patient receivedboth the treatment and the placebo. Called a crossover design,this allowed Dr. Yuan and colleagues to compare each patient’sresponse to both BoNT/A and placebo. Using this kind of study,they were able to show how the group did as a whole. Also, theycould see how well each person responded to the pain treatment.This is a common study design that improves the strength ofthe study’s conclusions.
At the end of the study, Dr. Yuan and colleagues compared thechange in scores between the treatment (BoNT/A) and placebogroups at the four time-points. After 4, 8, and 12 weeks, significantreductions in visual analog scale (pain) were seen in the BoNT/Agroup compared to the placebo group. Overall, 44.4% of the BoNT/Agroup vs 0% of the placebo group reported improved pain. Thesefindings support the theory that BoNT/A injections into theskin can help to relieve neuropathic pain in people with diabetes.However, the findings are not definite, and a larger study isneeded.2
In 2003, the National Center for Chronic Disease Preventionand Health Promotion predicted that one in three Americans bornafter the year 2000 would develop diabetes in their lifetime.3In general, more than 25% of people with diabetes are estimatedto suffer from diabetic neuropathy. This means there are manypeople who could benefit from new, effective treatments forneuropathic pain.
Diabetes prevents the body from processing sugars correctly.It leads to high levels of glucose (a sugar) in the blood. Highblood glucose levels and circulation problems (common in peoplewith diabetes) combine to damage nerves. The first nerves affectedby diabetic neuropathy are sensory nerves of the feet and ankles.Later, as the nerve problem gets worse, it may spread up thebody to involve the arms.
Unlike the pain felt when touching something very hot or sharp,which is triggered by tissue damage, neuropathic pain resultsdirectly from damage to the sensory nerves themselves. The damagednerves attempt to repair themselves, but uncontrolled diabetesinterferes with the repair system and the damage worsens. Asthis cycle continues, the nerves end up becoming overactiveand too easily stimulated. Neuropathy and neuropathic pain thenoccurs, as pain nerves fire even when there is no physical stress.
WHAT DO DIABETIC NEUROPATHY AND NEUROPATHIC PAIN FEEL LIKE?
Diabetic neuropathy changes the feeling in affected areas. Symptomsusually begin in the feet and go up the leg if the diabetesis not well-treated. As symptoms reach the mid-calf, they willoften also appear in the hands and begin moving up the arms.Sensory symptoms of diabetic neuropathy include less sensationof vibration, temperature, and touch. When a person developsnumbness, he or she may injure a foot and not realize it, leadingto untreated wounds that become infected.
Neuropathic pain occurs in the same area as the nerve damage.The pain has a shooting, sharp, or burning quality. Some peopledescribe a tingling or prickly feeling. Also, neuropathic painis very sensitive to things that would normally not be painful.For example, a breath of cool air or a brush with a feathermight trigger a stab of pain. Diabetic neuropathy often getsbetter with walking and worsens when the person is lying inbed or resting. Patients who suffer from this would benefitenormously from a successful treatment.
The single most important way to prevent diabetic neuropathyand the pain that goes with it is to control the blood sugar.People with diabetes should monitor their own blood sugar. Theyshould also talk with their doctor if they are not able to controlit. Hemoglobin A1c is a chemical marker in the blood that reflectshow well-controlled a patient’s blood sugar has been overthe past 3 months. It has been shown that a 1% rise in thischemical was associated with a slowing of nerve conduction,which is a sign of neuropathy.4 This result suggests that poorcontrol of blood sugar is directly associated with the developmentof neuropathy. This can lead to neuropathic pain. Proper diabetescare should include regular checks of blood sugar as well ashemoglobin A1c. Also, sensory examinations of the legs and feetto monitor for neuropathic changes are needed.
There are treatments for neuropathic pain, but none is perfectand many are associated with unpleasant side effects. Most studiesshow that fewer than 60% of people with this kind of pain experiencepartial improvement.2 The only FDA-approved drugs for treatingneuropathic pain are duloxetine (Cymbalta®), an antidepressant,and pregabalin (Lyrica®), an antiepileptic medication. Manypain specialists use drugs like oxycodone (an opioid, like morphine)and amitriptyline (a tricyclic antidepressant) with good results.
It is still unclear why some antidepressants and antiseizuremedications are helpful in treating neuropathic pain. In part,this is because we do not understand exactly how neuropathicpain develops. As our grasp of the causes of neuropathy improve,so will the available therapies. Careful studies, such as thisstudy of the use of BoNT/A, are critical in establishing whichtreatments work for this condition.
Yuan R-Y, Sheu J-J, Yu J-M, et al. Botulinum toxin for diabetic neuropathic pain: a randomized double-blind crossover trial. Neurology 2009;72:1473–1478.[Abstract/Free Full Text]
Apfel SC. Botulinum toxin for neuropathic pain? Neurology 2009;72:1456–1457.[Free Full Text]
Narayan KM, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF. Lifetime risk for diabetes mellitus in the United States. JAMA 2003;290:1884–1890.[Abstract/Free Full Text]
Amthor KF, Dahl-Jørgensen K, Berg TJ, et al. The effect of 8 years of strict glycaemic control on peripheral nerve function in IDDM patients: the Oslo Study. Diabetologia 1994;37:579–584.[Medline]
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