Tramadol (Ultram) for Painful Diabetic Neuropathy
ABSTRACT & COMMENTARY
Source: Harati Y, et al. Double blind randomized trial of tramadol for the treatment of the pain of diabetic neuropathy. Neurology 1998;50:1842-1846.
In this multi-center, double-blind, placebo-controlled, parallel-group study, 131 patients with painful diabetic neuropathy were randomized to receive oral tramadol (Ultram) starting at 50 mg/d up to a maximum of 400 mg/d (n = 65), or placebo (n = 66) in a four-times-per-day dosage. Neuropathy was documented by clinical, electrophysiologic, and quantitative sensory testing, and patients had to be experiencing daily neuropathic leg pain for at least three months prior to enrollment. Exclusionary criteria consisted of other possible causes of neuropathy, including brittle diabetes, other clinically significant medical conditions, alcohol or drug abuse, severe depression, and prior use of tramadol. All patients underwent a washout period of 1-3 weeks depending on medication history, and no other pain medications were permitted during the study period. Diabetic therapy remained unchanged, and patients were evaluated every two weeks during the double-blind phase. Patient-rated pain intensity score after six weeks of therapy, or at the time when treatment was discontinued, provided the primary efficacy end point. Secondary end point measures included patient-rated pain relief score and the Medical Outcomes Study (MOS) measures of daily activities and sleep (Stuart AR, Ware JE. Durham NC: Duke University Press, 1992). Data were analyzed by an intent-to-treat approach, and all statistical tests were two-tailed at the 0.05 level of significance.
Tramadol significantly reduced pain compared to placebo (P < 0.001), but no difference was appreciated for overall daily behavior, psychological stress, current health perception, or sleep. Nine patients discontinued tramadol vs. one placebo drop-out. Associated reasons included adverse effects that were generally benign and included nausea (23%), constipation (22%), headache (17%), somnolence (12%), dyspepsia (9%), and flu-like symptoms, pruritis, or rash (6% each). No significant effects on serum chemistries were noted in either group. Tramadol appears to be safe and efficacious for treatment of painful diabetic neuropathy.
COMMENTARY
Polyneuropathy affects up to 93% of diabetics (Brown MJ. Ann Neurol 1984;15:2-12) who possess small fiber involvement that underlies painful forms. Objective documentation is difficult and encompasses quantitative sensory testing and autonomic studies, including sweat testing by the quantitative sudomotor axon reflex test (QSART) or thermoregulatory sweat test (TST). No confirmatory test, however, is universally accepted as correct. Quantification of unmyelinated intraepidermal nerve fibers (IENF) on punch skin biopsy is an easy, repeatable, and minimally invasive technique that can overcome this difficulty. Twenty healthy controls and 20 patients with painful sensory neuropathy (2 with diabetes, 8 with HIV, and 10 idiopathic) underwent 3 mm punch skin biopsy from the distal calf and proximal lateral thigh under local anesthetic (Holland, et al. Neurology 1997;48:708-711). Mean IENF density was significantly reduced at both sites in patients compared to controls (P < 0.0001 at the calf; P < 0.001 at the thigh). The degree of fiber loss correlated with the severity of painful neuropathy. Also, as would be predicted, fiber density was lower distally than proximally, underscoring the length dependency of these neuropathies. Interestingly, fiber density was decreased even in proximal regions as yet clinically unaffected. Quantitative sensory thresholds correlated neither with IENF density, clinical severity of neuropathy, or sural sensory nerve action potential amplitude on routine nerve conduction study (the latter being a large diameter fiber measurement).
Among 32 patients with idiopathic small fiber sensory neuropathy (SFSN) evidenced by burning feet, no significant weakness, small fiber sensory abnormalities on neurological examination, normal nerve conduction studies, and no identifiable cause for neuropathy, two clinical patterns emerged (Holland NR, et al. Ann Neurol 1998;44:47-59). Most (n = 28, 88%) had a "chronic progressive SFSN" with initial involvement of toes and feet that, over time, spread proximally to affect legs and hands. Infrequently (n = 4, 12%), abrupt onset of generalized cutaneous pain and hypersensitivity was the presenting complaint, and this slowly improved with time ("acute generalized SFSN"). IENF density was severely reduced distally but less so proximally than the former, whereas IENF density was significantly reduced both proximally and distally. Skin punch biopsy and IENF density studies are simple and safe techniques that are useful for the diagnosis and staging of painful sensory neuropathy. They also may be important as an outcome measure in clinical trials of nerve growth factors for small fiber neuropathy. -MR
You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
- Award-winning Medical Content
- Latest Advances & Development in Medicine
- Unbiased Content