Metronidazole: high dose and long duration risks peripheral neuropathy

Metronidazole — a member of the nitroimidazole class of antibiotics — provides potent bactericidal action against anaerobic bacterial and protozoal infections. It is commonly used across all healthcare settings for common infections and plays an important role in treating both suspected and confirmed anaerobic bacterial infections; it is typically associated with deep-seated infections. Combination therapy with penicillin is common and is likely to feature more prominently in hospital formularies as part of efforts to reduce the use of broader spectrum antimicrobials such as co-amoxiclav and piperacillin/tazobactam.

The side effects of metronidazole are usually mild and predominantly present as gastrointestinal disturbances such as nausea, abdominal pain and diarrhoea. However, there is a well-established link between the use of metronidazole and peripheral neuropathy, which can be irreversible and even fatal. Peripheral neuropathy is characterised by symptoms such as numbness, loss of sensation and neuropathic pain of the lower extremities, which is often worse at night. The manufacturer’s datasheet suggests that early identification of metronidazole-induced peripheral neuropathy, followed by cessation of therapy, commonly leads to full reversibility of symptoms and no long-term complications^[1]
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The duration and total dosage of metronidazole received is the primary determinant for patients developing peripheral neuropathy. Prescribers are advised to assess the need for prolonged courses of metronidazole over three months in duration owing to this established risk. The manufacturers and the British National Formulary (BNF) advise that all patients receiving treatment in excess of three months should receive counselling on the risks of peripheral neuropathy^[2]
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A recent systematic review assesses the long-term safety of metronidazole therapy^[3]
. The review investigates the impact of duration and total dosing of metronidazole on the risk of symptoms of peripheral neuropathy. A total of 54 relevant publications including clinical studies and case reports were included. The review found a higher incidence of peripheral neuropathy in patients receiving a higher dose (>42g total) or at a longer duration (>4 weeks) compared with those receiving ≤42g total (17.9% vs 1.7%). Resolution or improvement of symptoms was evident in the majority of patients followed up; only 10% of patients experienced continuation of symptoms beyond medicine termination or dose reduction. Out of 40 case reports studied, 21 patients experienced central neurotoxicity, notably ataxia, dysphagia, dysarthria and encephalopathy, but these conditions were resolved in all patients on withdrawal or dose reduction. This can be investigated further in the future.

It is difficult to differentiate whether the high dose or duration of metronidazole is causing the adverse reaction, owing to the overlap of study groups. Dosing in many of the studies was 500mg, orally, three times a day, based on the available licensed preparation; in the UK, 400mg, orally, three times a day, is more frequently prescribed. Doses less than 1.2g/day are unlikely to be used for active bacterial infections owing to the risk of treatment failure. Suppressive therapy or symptom control in inflammatory bowel disease may see some local use of lower dosing (400mg twice daily, or 200mg three times daily) depending on clinician preference, but this approach is not routinely practised.

There are limitations of this retrospective study. The time to complete or partial resolution of symptoms was not well defined in the studies or reported cases. The clinical studies and patient cases did not include patients taking other antimicrobial agents in combination with metronidazole. Metronidazole is commonly used in combination with other antibiotics in long treatment courses, particularly for infections such as osteomyelitis and diabetic foot ulcers. Although the effect of metronidazole in combination with other antibiotics was not investigated in the study, it is indicated that the rates of peripheral neuropathy in these patients will be similar to those of the reported patient populations.

This review makes a compelling case for the risk of peripheral neuropathy secondary to metronidazole treatment, when the treatment exceeds four weeks or >42g total dose. A number needed to harm of 6 is evident at doses exceeding this limit. This exposure limit is shorter than the three-month threshold proposed by the BNF and will affect many patients under our care. Efforts should be taken by pharmacists to review prolonged treatment courses for appropriateness. Patients for whom metronidazole is deemed necessary for four weeks or more (for example, for deep-seated infections such as osteomyelitis, intra-abdominal infection, or for symptom control in inflammatory bowel disease) should receive appropriate counselling on the increased risk of peripheral neuropathy.

We propose the following recommendations for healthcare professionals using metronidazole:

• The 12-week warning for metronidazole treatment durations proposed by the BNF should be revised to 4 weeks (or >42g), owing to a recent update to the evidence base;
• Healthcare professionals considering long-term prescription of metronidazole (>4 weeks or >42g) should be able to justify its use against the risk of peripheral neuropathy;
• Patients who are on long-term treatment with metronidazole (>4 weeks or >42g) should have given consent and be counselled on regular monitoring;
• Metronidazole should be used with caution in patients with active or chronic severe peripheral and central nervous system disease, as recommended by manufacturers;
• Patients should be monitored for adverse effects such as peripheral or central neuropathy (such as paraesthesia, ataxia, dizziness, convulsive seizures), particularly if metronidazole has been prescribed for long-term use.

Hui Yin Chin, pharmacy student, University College London

Stephen Hughes, antimicrobial pharmacist, Chelwest