The Consultant Pharmacist is published by the
American Society of Consultant Pharmacists.

Clinical Note
Nitrofurantoin-Induced Neuropathy and Muscle Weakness: A Case Report With Chronic Use Jeffrey Fudin
Jenny S. Allen
Objective: To describe a probable effect of iatrogenic neuropathy induced by nitrofurantoin.
Setting: An outpatient clinic at Samuel S. Stratton Veterans Affairs Medical Center, Albany, New York.
Practice Description: Two doctor of pharmacy practitioners at a pharmaceutical care and pain management clinic were involved.
Main Outcome Measurement: Probable adverse drug reaction.
Conclusion: Discontinuation of drug therapy, as recommended by clinical pharmacist, resulted in decreased pain and increased muscle strength.
Key Words: Nitrofurantoin, Peripheral neuropathy, Urinary tract infections, Long-term use.
Abbreviations: UTI = urinary tract infection; LS = lumbar spine; TURP = transurethral resection prostrate; CAT = computed axial tomography; CBC = complete blood count
    Consult Pharm 2000;15:77-82.
Nitrofurantoin is an antibacterial drug used for the treatment of acute and/or chronic urinary tract infections. Peripheral neuropathy and muscle weakness has been well documented with short-term use of nitrofurantoin; however, this complication is sparsely documented with long-term use. To date, there have been 58 articles published in worldwide literature describing nitrofurantoin-induced peripheral neuropathy, in which 137 cases were identified. All but six citations were for high doses used over short periods of time. The most recent publications addressing nitrofurantoin-induced peripheral neuropathy with chronic use were published in 1988. These were not published in English. We present a case of severe peripheral neuropathy and muscle weakness associated with chronic use of nitrofurantoin. Nitrofurantoin has been widely used since its availability in 1952 for the treatment of urinary tract infections (UTIs). It has activity against gram-negative bacilli and gram-positive cocci, both of which have been associated with UTIs. It is also active against gram-positive cocci, which are sometimes associated with UTIs. It is important to note that microorganisms rarely develop resistance to this medication.1

Peripheral neuropathy is a potential complication of nitrofurantoin generally seen with short-term use. There were several case reports in the 1970s and 1980s documenting nitrofurantoin-induced neuropathy. All but six citations are for high doses used over short periods of time. There were over 70 citations addressing the most common comorbidities associated with short-term nitrofurantoin use. These were renal, hepatic, and pulmonary toxicities. In addition, there were several general review articles addressing peripheral drug-induced neuropathy; all were published between 1960 and 1989. The only evidence-based publications attributing peripheral neuropathy to chronic nitrofurantoin use were published in Hebrew (1975),2 French (1988),3 Japanese (1975),4 Polish (1968),5 and German (1971, 1966).6,7 There have not been any case reports published in English concerning this drug-induced neuropathy. Below we present a case report of suspected nitrofurantoin-induced peripheral neuropathy associated with the long-term use of nitrofurantoin.1,8-18

Case Report

J.C. is a 77-year-old white man who presented to the Anesthesia Pain Management Clinic on 4 August 1997 for a second epidural injection of triamcinolone (80 mg) to the lumbar region of the back (L2–L3); the first had been given on 19 June 1997. Upon physical exam of the back, there was normal lordosis and alignment of the spine. He appeared healthy, ambulating without assisting devices, but he was in moderate distress and complained of pain to his lumbar spine, which he rated at 7–8 using a visual analog scale of 0–10. There was some tenderness noted on palpitation, but no trigger points. The patient complained of lower back pain for one year, which radiated to both legs and affected his right side predominately. He had obvious shingles on his right hip and was dragging his feet while walking. Steroid injections relieved the pain for about two weeks, which enabled this patient to ambulate without significant pain. At this visit, the pain was still present bilaterally with leg lifts done at 45 degrees. Current medications at the time were alprazolam, fluoxetine, docusate sodium, enteric-coated aspirin, chlorpheniramine maleate, diltiazem, and nitrofurantion. The patient’s past medical history was significant for reflux esophagitis, esophageal dysmotility, hypertension, panic disorder, Schatzki’s ring, peptic ulcer disease, status-post transurethral resection of the prostate, and chronic UTIs. His social history and family history were noncontributory. J.C. had a confirmed allergy to sulfa drugs, which resulted in exfoliative dermatitis as a result of sulfamethoxazole- trimethoprim.

A computed axial tomography (CAT) scan was done in June 1996, which revealed degenerative joint disease of the lower spine with moderate L3–L4, L4–L5 spinal stenosis. Disk desiccation was seen at all spinal levels, with disk space narrowing noted at L4–L5 and right-sided disc protrusion/herniation at L4–L5. There was moderate central stenosis at L3–L4 and L4–L5 secondary to hypertrophied facet disease, hypertrophied ligaments, and a right-sided disk protrusion/herniation. All laboratory parameters (blood chemistries and complete blood counts) were within normal limits, with the exception of elevated total cholesterol of 226 mg/dL. On the basis of the patient’s serum creatinine of 1.1mg/dL, he had an estimated creatinine clearance of 72 mL/min.

There was suspicion that the patient’s neuropathic pain and muscle weakness could perhaps be iatrogenic, induced by nitrofurantoin. The patient had been receiving nitrofurantoin (50 mg daily) for five consecutive years. On 4 August 1997, contact was made with the patient’s urologist regarding reassessment of his chronic UTI problem and chronic use of nitrofurantoin. We had particular concern, since no mechanical abnormalities were seen in this male patient that might result in a chronic urinary tract infection. A recommendation was made to the urologist to discontinue nitrofurantoin immediately until further urological work-up could be obtained. This recommendation was implemented and the nitrofurantoin discontinued immediately. After the discontinuation of nitrofurantoin, the patient’s pain decreased to 1–2 on the pain scale, with partial recovery of function occurring within four weeks. Muscle strength steadily increased, and within two months the only medication necessary for pain control was acetaminophen (500–1,000 mg orally, two to three times daily). We did not rechallenge this patient with nitrofurantoin.

Discussion

Nitrofurantoin neurotoxicity is associated with symmetric polyneuropathy. This category of neuropathy usually affects all extremities, with the longest neurons (i.e., those of legs and arms) being affected most severely. The neurons associated with nitrofurantoin-induced neuropathy are affected by both Wallarian degeneration and segmental demyelination. Wallerian degeneration is degeneration of the axon and myelin sheath in a uniform manner, distal to anatomic interruptions of the axon. This may be caused by trauma or disease. This effect is usually seen in the distal portion of the axon because it is located furthest from the cell body, which is responsible for protein synthesis. These proteins and other nutrients are vital to the growth and development of the axon and myelin sheath. Segmental demyelination occurs when the metabolic function of the neuron is changed by nutritional deficiency or various toxins, resulting in loss of myelin. These are shown in Figure 1.1

The exact mechanism by which polyneuropathy and antibacterial activity are produced by nitrofurantoin has not been well defined. It has been suggested that nitrofurantoin interferes with early stages of bacterial carbohydrate metabolism by inhibiting acetyl-coenzyme A. Inhibition of carbohydrate metabolism in human nerve tissue may be the mechanism responsible for nitrofurantoin neurotoxicity. Another hypothesis includes underlying comorbid diseases, which may contribute to subclinical nerve damage aggravated by nitrofurantoin. Nitrofurantoin may also cause neuropathy by acting as a folic acid antagonist, similar to other hydantoin derivatives.1

Figure 1
Patterns of nerve degeneration. B: Highly schematic diagram depicting the response to anatomic interruption of the axon, with degeneration of both axon and myelin sheath distally, and back to the first node of Ranvier proximally. Denervation phenomena are usually detectable in muscle within 10–14 days. C: When the metabolism of the neuron is disturbed, the distal axon may show segmental demyelination first, followed by Wallerian degeneration of the most distal portion. D: Another form of segmental demyelination is depicted, resulting from a direct assault on the myelin sheath, such as may occur with compression, ischemia, certain toxins, and, possibly, through immunological mechanisms. Originally published in Jacknowitz AI, Le-Frock JL, Prince RA. Nitrofurantoin polyneuropathy: report of two cases. American Society of Health-System Pharmacists, Inc. All rights reserved.

Irrespective of these hypotheses, there is enough evidence-based literature to support iatrogenic nitrofurantoin neuropathy with short-term use.1-18 The only case reports published with respect to this adverse effect with chronic nitrofurantoin use are non-English. A case report published in Harefuah by Grushka et al.2 described a woman who presented to the neurology department because of “strong” pains in her hands and legs. The patient had been receiving nitrofurantoin (50 mg once daily) for about 12 years, and she had normal renal function. The pain became so severe that she was bedridden, except for trips to the bathroom. Within three months of withdrawal of nitrofurantoin, the patient’s pain gradually decreased and her muscle strength gradually increased. The patient’s neurological studies that were completed after the three months indicated partial and full nerve regeneration.2

Another case report, published by Pages and Pages,3 presented a woman with normal renal function who had received about 45 g of nitrofurantoin over 18 months. The patient had paresthesias and difficulty ambulating. Nerve biopsy confirmed the density of the myelin fibers to be decreased. After discontinuation of nitrofurantoin, there was partial recovery of function within four weeks.3 We did not have access to translations of the Japanese,4 Polish,5 or German6,7 case reports.

Our suspicion of iatrogenic nitrofurantoin neuropathy is supported by earlier published case reports, as outlined above. It is unclear whether prolonged use would result in complete reversibility of neuropathy and muscle weakness.5 Because of this concern the patient was not rechallenged with nitrofurantoin. On the basis of Naranjo’s causality assessment of adverse drug reactions, we calculated a score that corresponded to a “probable” adverse drug reaction.19 As a result of our literature evaluation, we encourage practitioners to document and publish cases of neuropathy induced by chronic nitrofurantoin. There are a number of comorbid conditions that may contribute to neuropathy in patients who routinely receive nitrofurantoin. For example, consultant pharmacists cannot exclude nitrofurantoin as the causative agent in a patient presumed to have diabetic neuropathy. In addition, the literature is lacking reviews of contemporary drug therapies that may potentially induce peripheral neuropathy. We suggest that all patients receiving nitrofurantoin be carefully monitored and that perhaps an alternative therapy, such as trimethoprim-sulfamethoxazole or methenamine, be used where long-term therapy is indicated.

Acknowledgments
We acknowledge the assistance of Benoit Tonneau, MD, for his translation of the French journal article and Ruth Padan for her translation of the Hebrew journal article.

References

  1. Jacknowitz AI, Le-Frock JL, Prince RA. Nitrofurantoin polyneuropathy: report of two cases. Am J Hosp Pharm 1977;34:759–62.
  2. Grushka M, Tohechik M, Weiss S. Peripheral neuropathy due to prolonged treatment with nitrofurantoin (translated from Hebrew). Harefuah 1975;88:23–6.
  3. Pages M, Pages AM. Neuropathy during prolonged treatment with nitrofurantoin: study of a nerve biospy (translated from French). Arch Anat Cytol Path 1988;36:167–9.
  4. Hayabara T, Fukui H, Kuroda S, Tateishi J. Polyneuropathy due to prolonged administration of nitrofurantoin (Japanese). Rinsho Shinkeigaku (Clinical Neurology) 1975;15:465–71.
  5. Holyst M, Zachara E. A case of polyneuritis in the course of long-term treatment with nitrofurantoin (Polish). Polski Tygodnik Lekarski 1968;23:1978–9.
  6. Katschnig H, Weissenbacher G. Polyneuropathy following long-term treatment with nitrofurantoin in a child. (German) Monatsschrift fur Kinderheilkunde 1971;119:607–9.
  7. Lehmann W. Toxic polyneuritis in a female patient with chronic pyelonephritis after long-term treatment with nitrofurantoin (German). Deutsche Gesundheitsweses 1966;21:2338–43.
  8. Argov Z, Mastaglia FL. Neural effects of nitrofurantoin. Arch Neuro 1968;18:680–7.
  9. Argov Z, Mastaglia FL. Drug-induced peripheral neuropathies. BMJ 1979;1:663–6.
  10. Penn PG, Griffin JP. Adverse reactions to nitrofurantoin in the United Kingdom, Sweden, and Holland. BMJ Clin Res Educ 1982;284:1440–2.
  11. Yiannikas C, Pollard JD, McLeod JG. Nitrofurantoin neuropathy. Aust NZ J Med 1981;11:400–5.
  12. Holmberg L, Boman G, Bottiger LE et al. Adverse reactions to nitrofurantoin: Analysis of 921 reports. Am J Med 1980;69:733–8.
  13. McLeod JC. Peripheral neuropathy caused by drugs and toxic substances. Aust NZ J Med 1971;1:268–9.
  14. Thomas PK. Peripheral neuropathy. BMJ 1970;1:349–52.
  15. Honet JC. Electrodiagnostic study of a patient with peripheral neuropathy after nitrofurantoin therapy. Arch Phys Med Rehab 1967;48:209–12.
  16. Davey R. Macrodantin: A cautionary tale. Med J Aust 1986;145:476–7.
  17. Jacknowitz AI. Nitrofurantoin and peripheral neuropathy (Letter). Ann Intern Med 1985;102:138–9.
  18. White WT, Harrison L, Dumas J. Nitrofurantoin unmasking peripheral neuropathy in a type 2 diabetic patient. Arch Intern Med 1984;144:821.
  19. Naranjo CA, Busto U, Sellers EM et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981;30:239–45.

Jeffrey Fudin, PharmD, is Clinical Pharmacy Specialist in Pain Management, Samual S. Stratton Department of Veterans Affairs Medical Center, Albany, New York. Jenny S. Allen, PharmD, is Ambulatory Care Resident, Albany College of Pharmacy, Union University, Albany, New York.

Address for Correspondence: Jeffrey Fudin, PharmD, Samuel S. Stratton Department of Veterans Affairs Medical Center (119), 113 Holland Ave., Albany, NY 12208.

Copyright © 2000 The American Society of Consultant Pharmacists, Inc. All rights reserved.



The Consultant Pharmacist is published by the
American Society of Consultant Pharmacists.