Perhexiline

General adverse effects and adverse reactions

Serious adverse effects of perhexiline include disorders affecting the nervous system and major metabolic disturbances. Minor adverse reactions include dizziness or unsteadiness, which occur in 20–25% of patients [ , ], nausea, vomiting, and abdominal pain, which are less frequent, and headache [ ]. Hepatotoxicity, polyneuropathy, papilledema with disturbed vision, and hypoglycemia are common and can be severe [ ]. The use of different dosage schedules probably accounts in part for the widely varying incidence reported in different studies. The incidence of hepatotoxicity and neuropathy seems to be in the order of about 10% [ , ], but minor disturbances in liver function occur with much higher frequencies. The pathogenesis of these adverse effects and reactions most probably involves altered lipid metabolism, with increased amounts of gangliosides in nerve biopsy specimens from 18 patients [ ].

Observational studies

Minor adverse reactions such as dizziness and nausea led to withdrawal of perhexiline in 49 of 363 patients in a cooperative trial [ ].

Cardiovascular

Electrocardiographic changes are seen in about a quarter of patients on long-term treatment with perhexiline; apart from a reduction in rate, the changes consist of prolongation of the QT interval and the appearance of an enlarged U wave or various abnormalities of the ST segment and T wave [ , ].

Two patients with perhexiline neuropathy and central nervous involvement (including raised intracranial pressure) had carotid arteriography using methylglucamine ioxitalamate to exclude an organic disorder and developed thrombosis of the ophthalmic veins with severe symptoms; the authors postulated a predisposing role of perhexiline, particularly since perhexiline produces polymorphous inclusion bodies not only in nerve cells but also in the vascular endothelial wall [ ].

Nervous system

Neurological symptoms, including dizziness, vertigo, disturbances of balance, difficulty in walking, and tremor or trunk incoordination, have been reported by 20–50% of patients taking perhexiline. Drowsiness and non-specific mental changes have been noted in older patients [ ].

Reported disorders take a number of forms [ ]. The commonest is a peripheral neuropathy that mainly affects the legs [ , ]. Proximal myopathies, ataxia [ ], and autonomic abnormalities [ ] have also been described [ ]. These adverse reactions occur after prolonged drug exposure and are reversible [ ]. Larger doses apparently produce symptoms more rapidly and slow metabolizers [by CYP2D6] may be more susceptible [ ]. The polyneuropathy is sensorimotor and is associated with a loss of ankle reflexes. Nerve conduction times are delayed [ ]. Sural nerve biopsies have demonstrated segmental demyelination, sometimes progressing to Wallerian degeneration [ , ]. Raised CSF protein has also been described [ ]. The polyneuropathy may affect autonomic functions such as sphincter innervation [ ] or maintenance of blood pressure. Reversible cerebellar ataxia, apparently related to perhexiline, has been reported [ ].

An electrophysiological study has suggested that many asymptomatic patients have changes in nerve conduction suggestive of latent neuropathy [ ].

Peripheral neuropathy has been reported in nine patients who had taken perhexiline 200–400 mg/day for 4 months to 2 years [ , ]. One patient was a chronic alcoholic and he developed Parkinsonian signs in addition to the neuropathy [ ]. Three patients had papilledema without impaired visual acuity [ ]. Velocity of conduction in peripheral nerves was reduced. In all cases, the condition slowly resolved when the drug was withdrawn.

In 35 patients taking perhexiline some two-thirds had electrophysiological changes in the peripheral nerves, irrespective of the dose or duration of treatment, and despite the fact that none of them had clinical signs of neuropathy [ ]. Although clinical recovery from perhexiline neuropathy may be complete within 3–8 months, electrophysiological changes can persist for much longer [ ]. Of a series of 20 patients 14 were poor metabolizers (CYP isoform not described) [ ].

A mixed sensory and motor peripheral neuropathy developed in 16 patients taking perhexiline in doses of 200–400 mg/day except for two patients who were taking 100 and 600 mg/day; the duration of treatment at the onset of symptoms varied from 3 weeks to 1 year; two patients were alcoholics and one had diabetes mellitus, which may possibly have been contributory factors [ ]. The typical presentation was with paresthesia in the hands or feet followed by sensory impairment in a glove and stocking distribution, then generalized weakness with muscle wasting and loss of tendon reflexes; one patient became deaf [ ]. Withdrawal of the drug is usually followed by gradual recovery over a period of months, although it can be slow and incomplete [ ]. The cerebrospinal fluid shows a modest increase in protein content and electromyography shows reduced conduction velocity [ , ]. Biopsy of the superficial peroneal nerve in some cases showed severe loss of myelinated fibers, with inclusion bodies in the cytoplasm of the Schwann and endothelial cells [ ]; in others there were predominantly Schwannian degeneration with mild Wallerian degeneration, and abundant polymorphous inclusion bodies in Schwann cells, fibrocytes, endothelial cells, and pericytes [ , ].

A detailed investigation of 61 patients who were taking perhexiline and complained of unsteadiness showed increased sensitivity to peripheral stimulation of the vestibular system in all those in whom objective abnormalities could be demonstrated [ ]. The authors suggested that the disturbance in function resulted from a fall in arterial pressure. However, it seems more likely that it resulted from a direct effect on the nervous system, since perhexiline has little or no effect on arterial pressure [ ], and vestibular symptoms are not a common accompaniment of treatment with drugs that lower blood pressure.

An extrapyramidal syndrome has been observed in a patient taking perhexiline, with akinesia and tremor [ ].

Aphonia was seen in two patients in poor general condition, but with no other signs of neuropathy [ ]. It was due to vocal cord atony, and the voice returned after withdrawal of perhexiline. A possible causal relation between perhexiline and parkinsonism has also been suggested [ ].