Unfortunately, there are no medicines at present with action on the pathogenetic mechanisms of neuropathy, which could effectively interfere with the natural history of the disease. Ongoing studies examine the effectiveness and safety of newer aldose reductase inhibitors (fidarestate). a-lipoic acid administration (an antioxidant factor) seems, in a series of studies, to be effective in improving the function of small unmyelinated nerve fibres. Small range studies have shown that g-linolenic acid may be effective in treating peripheral diabetic neuropathy. ACE inhibitor administration resulted in improvement of nerve conduction velocity in patients with mild peripheral neuropathy.
When symptoms of pain are mild, weak analgesics, like paracetamol, are indicated. Non-steroidal anti-inflammatory medicines are also effective, but their potential nephrotoxicity should be taken into consideration in patients with diabetic nephropathy.
Many randomized studies have documented the effectiveness of tricyclic antidepressants in treating neuropathic pain. They act by inhibiting norepinephrine re-uptake from presynaptic neurons. Amitrip-tyline, imipramine and desipramine have been studied more extensively and are considered medicines of first choice for treating painful symptoms of neuropathy. They are administered at a dose of 25-150 mg once a day, preferably at bedtime, so that side effects are minimized. Since small doses are effective in some patients, it is advised to start with small doses and gradually increase. Most frequent side effects are sleepiness and xerostomia.
Recent publications report a significant improvement of pain after administration of venlafaxine (a serotonin and norepinephrine re-uptake inhibitor) at a dose of 37.5-150mg/day. Compared to tricyclic antidepressants, venlafaxine has minimal anticholinergic action and no interactions with other medicines. Furthermore, recent studies show that duloxetine, another representative of this class of medicines (serotonin and norepinephrine re-uptake inhibitor), is effective and safe in painful diabetic neuropathy, at a dose of 60 mg/day.
Carbamazepine, essentially an anti-epileptic medicine, at a dose of 200 mg three times a day, was the first of its kind to be used for this condition with fairly good results. Principally, it helps patients with moderate intensity symptoms. It has many side effects as well as many interactions with other medicines. For this reason, carbamazepine is not a first choice medicine for treating neuropathic pain.
Gabapentin is a g-aminobutyric acid analogue and is used for treating focal convulsions. Administered at a dose of 900-3600 mg/day, it is quite effective in ameliorating neuropathic pain. It has the advantage of lacking side effects and interactions with other medicines and thus it has been extensively used in the symptomatic treatment of painful diabetic neuropathy. Furthermore, it is the only medicine of its class that has been officially approved for administration in this condition. In two recent randomized studies, gabapentin was compared to amitripty-line. The first study showed equal effectiveness in ameliorating pain, whereas the second displayed the superiority of gabapentin. Most frequent side effects are sleepiness and dizziness, with a feeling of tiredness less frequently reported. These side effects usually occur after initiation of therapy, but subside with its continuation.
The usual starting dose of gabapentin is 300-400 mg the first day, and then immediately from the second day a doubling of the dose (300400 mg twice a day). The dose can subsequently be increased up to 1800 mg/day, depending on the patient's responsiveness. Maximal therapeutic dose is 3600 mg/day. Pharmacokinetic properties are not affected by food intake. An advantage of the medicine is that it does not cause weight gain. Patients with renal insufficiency should receive a smaller dose (creatinine clearance > 60ml/min: 1200 mg/day; clearance 3060 ml/min: 600 mg/day; clearance 15-30 ml/min: 300 mg/day; and clearance < 10 ml/min: 300 mg every other day).
The newer antiepileptic medicines topiramate, lamotrigine, oxycarba-mazepine and zonisamide have been used in the treatment of painful diabetic neuropathy with variable results. For this reason, none has an official indication for this condition. Potentially these substances have a synergistic action with gabapentin and can be coadministered in resistant cases.
Clonazepam, at doses of 0.5-3 mg/day, is effective in patients with the restless leg syndrome when they do not respond to other medicines. There are no comparative studies of this medicine with others.
Mexiletine is an antiarrhythmic medicine (IB class), analogous to lidocaine. When administered at a relatively small dose (450 mg/day) it is effective in ameliorating pain. This dose does not require frequent electrocardiagraphic evaluation. Nevertheless, experience with long-term use of this medicine is limited and thus its use is recommended only for short periods. As regards lidocaine, although encouraging results have been reported after intravenous infusion, its use is not advocated.
192 Diabetes in Clinical Practice Table 15.2. Therapy of diabetic neuropathy
Systemically administered p.o. medicines Tricyclic antidepressants Imipramine 25-50 mg/day Amitriptyline 25-50 mg/day Selective serotonin norepinephrine re-uptake inhibitors Venlafaxine 37.5-150 mg/day Duloxetine 60 mg/day Antiepileptic Carbamazepine up to 800 mg/day Gabapentin 900-3600 mg/day Topical treatments Capsaicin
Newer aldose reductase inhibitors a-lipoic acid g-linolenic acid Angiotensin converting enzyme inhibitors
There is no consensus concerning the use of opiates in diabetic neuropathy. Many doctors think that they are effective when used at appropriate doses, whereas others that neuropathic pain is quite resistant to them. A recent study showed that the synthetic opioid, tramadole, was quite effective in treating severe neuropathic pain. This medicine has a central analgesic action and is not a member of narcotic analgesics.
Capsaicin is an alkaloid derived from red pepper. Topical application of this substance decreases peptide P concentrations at nerve endings. This peptide is involved in the causation of pain. Capsaicin use causes a temporary burning feeling, which disappears with continued use. It is used for short periods in patients with localized pain.
A concise description of the available medicines for treatment of neuropathic pain is shown in Table 15.2.
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