Parenteral Antiepileptics

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Those involved in neurology and neurosurgical practice will be familiar with the use of intramuscular and intravenous (IV) anti-epileptic drugs (AEDs) for the treatment and prevention of epileptic seizures. Their use by those in purely pain practice is much less common.

Historically the first AED to be used in the treatment of pain was when phenytoin was used in the treatment of facial neuralgia in the early 1940s. Since that time oral phenytoin has been shown to be effective for the treatment of, among other conditions, painful diabetic neuropathy and so it is likely that it may be effective for other neuropathic pain conditions as well. Some concern must exist about the long-term use of oral phenytoin in view of its enzyme inducing, tachyphylactic, and gingival hyperplastic effects. With the advent of newer generation AEDs the long-term oral use of phenytoin must be questionable.

On the other hand, one is left with the problem of how to treat a patient with a flare-up of neuropathic pain, in whom a quick onset of treatment is desirable, or in whom the oral route is unavailable. What drugs can we use? Logically one would assume that if an oral formulation of a drug can be effective then the IV or intramuscular use of that same drug should have the same effect, and yet it was almost 60 years after the original description of the use of an AED in a patient with neuropathic pain before a study was published showing that IV infusion of phenytoin could also reduce neuropathic pain. Phenytoin was chosen as the parenteral AED as none of the newer AEDs were available in a parenteral formulation at that time. In this case the study compared the effect of a 2-h infusion of either phenytoin (15 mg Kg-1) or placebo in patients with neuropathic pain of mixed etiology. The interesting aspect of this study was not only that the IV phenytoin was effective, but also that after a 2-h infusion the duration of pain relief persisted for many days. Therefore the period of relief was longer than the duration of infusion and the half-life of the drug.

A further report of the successful use of IV phenytoin relates to its use in a patient with rapidly progressive neuropathic pain as a result of cancer.

However, while the parenteral formulation of phenytoin is a cheap and widely available drug, there are problems specific to the IV use of the drug. When diluted phenytoin is infused through a vein, should the cannula displace out of the vein then the spilt phenytoin can cause tissue ischemia and even skin necrosis. This can be of a severity to require surgical repair by debridement and skin-grafting. The reason for this toxicity is because of the very alkaline pH of the diluents accompanying phenytoin in the injectable form. These include potassium hydroxide and ethylene glycol.

With this in mind attention was focused on the manufacture of a safer version of phenytoin. This resulted in the marketing of fosphenytoin, a water soluble, ester pro-drug of phenytoin with near normal pH. When injected or infused, it requires activation by endogenous phosphatases before a therapeutic effect may be produced. While this increases markedly the safety of fosphenytoin, it does contribute to its major side effect. When injected, a burning sensation is produced in those areas of the body where phosphatases are found in the greatest concentration. In the male these are particularly prevalent in the groin and perineal areas and so an intense burning in that area often accompanies injection.

Perhaps the other very major drawback of fosphenytoin use is its expense. In the UK this amounts to about £40 (~$75) per ampoule.

Again, unsurprisingly, both the intramuscular and IV administration of fosphenytoin can produce pain relief in those with neuropathic pain. After intramuscular injection in patients with neuropathic pain of mixed etiology, pain relief of up to 48 h can be produced. When given by IV infusion over 24 h, again in patients with neuropathic pain of mixed etiology, pain relief is apparent with this relief extending to weeks. Indeed, a case report of a patient with neuropathic pain from operative intervention for a pelvic malignancy reports consistent pain relief of between 3 and 14 weeks after repeated 24-h infusions of fosphenytoin. The need for oral medication was significantly reduced during these periods of relief, and although infusion of phenytoin and fosphenytoin can both produce dizziness, nausea, and light-headedness, these persist for the infusion period and shortly after, whereas the side effects of oral medication, taken day-in, day-out, persist for the entire treatment period.

A further case report relates the successful alleviation of an acute flare-up of trigeminal neuralgia in three patients who had been refractory to other therapeutic interventions. In these three patients, relief persisted for several days after fosphenytoin use and allowed time for other oral pharmacotherapeutic strategies to be instituted. This exemplifies the potential benefit of parenteral AED in bringing about a rapid diminution of otherwise intractable pain.

Since fosphenytoin is a pro-drug of phenytoin, it would be expected that those who respond to phenytoin would respond to fosphenytoin and vice versa. In order not to confuse practitioners too much, a novel measurement unit is used for fosphenytoin. This is the "phenytoin equivalent unit" or PE unit, one of which is equal to 1 mg of phenytoin. The use of this was thought necessary since phenytoin and fosphenytoin are not milligram to milligram equal. Fosphenytoin is presented in vials of 500 PE in a volume of 10 ml. In the study examining intramuscular use, a dose of 500 PE was used, whereas in the IV study 1,500 PE diluted to 50 ml infused over 24 h was used.

It is likely that phenytoin and fosphenytoin achieve their analgesic effect by having sodium channel blocking actions. This they share with many other drugs used in pain practice such as carbamazepine, lidocaine, and mexiletine. It could therefore be argued that these other drugs could be used in place of phenytoin or fosphenytoin. However, clinical experience shows that phenytoin/fosphenytoin can be effective when these others drugs are ineffective: this may be because they target different sodium channels.

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