Local anaesthetics are of course, well known for their properties in numbing local areas to allow procedures to be carried out (minor surgery, dentistry, setting fractures etc.)

For the purposes of this article, we will be briefly looking at other ways in which these drugs can be used in chronic pain. The use of local anaesthetic agents in spinal injections will not be included here, but will be covered in a future article on invasive procedures.

Firstly, we can look at EMLA, a topical preparation "Eutectic Mixture of Local Anaesthetics". It is a mixture of 2.5% lidocaine and 2.5% prilocaine. It is thought to act by blocking damaged nerve endings. It is well tolerated and therefore may be worth trying in those who cannot tolerate systemic drugs or who experience severe allodynia (pain triggered by non-painful stimuli such as light touch or change in temperature). Another topical preparation is less widely known: lidocaine tape (contains 60% lidocaine)also, a lidocaine patch(5% lidocaine) has been reported as effective in treating pain due to postherpetic neuralgia(shingles).

The use of intravenous infusions dates back many years: the analgesic properties of iv novocaine were described in 1943 by Gordon. Various authors have written about intravenous lidocaine but there are few statistically significant studies available. Most of the studies have used slow iv infusion, usually with lidocaine 100-300mg or 4-5mg/kg over 20-30 minutes. One study() found iv lidocaine to result in analgesia in diabetic peripheral neuropathy lasting between 3 and 21 days. In another, lidocaine was administered at 8.35mg/min (500mg in 250ml saline over 60 minutes). 10 of the 13 patients studied achieved complete pain relief. However, the author remarks that "a significant analgesic effect was not seen at one week and 2 weeks post-infusion." A further similar study showed a duration of 2-25 days.

Subcutaneous infusion of lidocaine() has been found to provide effective relief for patients with Complex Regional Pain Syndrome (CRPS or Reflex sympathetic dystrophy: RSD).

ORAL LAs:

Response to intravenous lidocaine is a useful tool for selecting patients who will respond to oral local anaesthetics.

MEXILETINE:

Mexiletine is a local anaesthetic that has been used to treat heart rhythm disorders.

Unlike externally used local anesthetics, mexiletine only appears to affect the painful nerves and thus neither numbs nor desensitizes the patient. It is sometimes used to treat diabetic neuropathy.

In 1997, The Mexiletine Study Group conducted a study on the safety and efficacy of mexiletine .() They found "A significant reduction in sleep disturbances and pain during nighttime was observed in the group of patients taking the highest dosage (675 mg/day) of mexiletine compared with the other groups." They concluded that "Mexiletine in a dosage of 675 mg daily can reduce pain caused by diabetic neuropathy, and the effect of this drug appears to have a rapid onset." No serious adverse effects were seen. Mexiletine has now become widely used to combat cancer-related neuropathic pain. Mexiletine is the preferred drug as it has a favourable side-effect profile () It may be considered as a second-line agent in treating refractory neuropathic pain.(of any origin). It could be used if, say, an antidepressant or anticonvulsant drug fails to be effective. The starting dose should be low, at 100- 150mg/day and be increased gradually until effective or side-effects become troublesome. (max. dose 900mg/day i.e. 300 mg tds.). ECG readings should be monitored during dose escalation and plasma levels should be measured at higher doses.

ADVERSE EFFECTS: generally well tolerated. Adverse effects may include gastrointestinal distress, dizziness or lightheadedness, tremor, and coordination difficulties. Mexiletine may worsen pre-existing cardiac arrhythmias and is contraindicated in patients with pre-existing second- or third-degree atrioventricular blockade.

Tocainide is one of the other alternatives. It has been found to be useful in treating trigeminal neuralgia.() NOTE: up to 12% of patients on tocainide may experience hallucinations as a side effect.

Flecainide is absorbed well when administered rectally and may have a potential indication in terminal cancer patients when oral drugs cannot be administered.()

INTRASPINAL LAs:

Bupivicaine has been found to be effective in reducing neuropathic pain when given as an intrathecal infusion. Dahn et al() described its use in a patient with multiple sclerosis. This method of administration will be addressed in a future article.

KETAMINE

This dissociative anaesthetic is an NMDA (N-methyl D-aspartate) receptor antagonist. NMDA is implicated in the centralisation of pain and sensitisation of the central nervous system via the "wind-up" mechanism. It has been used as an anaesthetic for many years and only recently has its application as an analgesic been explored. In 1994, studies() found ketamine to be effective in treating post-herpetic neuralgia(PHN).

Mercadante et al ()recommended a starting dose of 150 mg/day, which they stated would allow the dose of opiate medication to be significantly decreased. In one patient whose case they presented, the treatment was effective over a studied period of 13 months.

Various other authors have described ketamine's properties in combating centralised pain( ) but there have been no large studies of its use in chronic pain.

Backonja et al () evaluated three patients with chronic peripheral pain(of traumatic origin) and three with central pain,by administering intravenous ketamine 250 g/kg . Patients with peripheral neuropathic pain presented partial pain relief, which lasted 2-3 hours. 2 patients with central pain showed pain relief lasting 2-3 hours or reduction of symptoms. In one patient the relief lasted for 2 weeks. However, moderate adverse effects appeared in all patients (sedation, nystagmus, diplopia(double vision), increased heart rate and blood pressure, dreams). They went on to treat two patients, who had had initial good response, with a subcutaneous perfusion (10-14 mg/hr) maintained for 2 /4 days.

* NB.In fact, there is evidence that ketamine reverses morphine tolerance which may result in the reappearance of morphine sensitivity. This means that the morphine dose should be reduced as ketamine is introduced, to avoid the problems associated with morphine toxicity. It may need to be reduced by 30-50%.

Well-known side-effects seen after anaesthesia using ketamine include confusion, delirium, vivid dreams, hallucinations and feelings of detachment from the body. Haloperidol or a benzodiazepine may be used to alleviate these distressing symptoms.

Ketamine has been used long-term in a few small studies. Klepstad et al() treated a patient with PHN using a combination of ketamine and dextromethorphan(another NMDA antagonist) administered via various routes, without serious side-effects for 4 years.

ORAL KETAMINE:

Oye et al () reported the case of a patient with severe post-traumatic neuropathic pain and fibromyalgia, who responded well to a regime of 250 mg/kg ketamine hydrochloride taken orally in the form of capsules every night at bedtime, which was initiated after a test dose of intramuscular ketamine and remained successful for some months. More recently, the authors and other colleagues conducted a study() of patients with trigeminal neuralgia treated with an i.m. injection of ketamine 0.4 mg/kg combined with midazolam 0.05 mg/kg. They reported that "Ketamine caused a long-term (6-24 h) analgesic effect partly dissociated from the mental side effects in 8 of the 26 patients," "in nine patients, ketamine caused a short-lasting (<2 h) analgesic effect closely associated with the mental side effects" and in the remaining nine, no analgesic effect was seen.

Enarson et al () published a study of 21 patients with chronic neuropathic pain were treated with oral ketamine starting at a divided dose of 100 mg/day and titrating upwards by 40 mg/day until efficacy was reached, or until side effects became limiting. Nine patients discontinued the regime due to intolerable side effects and four patients went on to use oral ketamine for "long periods." The authors suggested, on the basis of their clinical experience, that ketamine is of most benefit in patients who have pain of less than 5 years' duration.

PRESERVATIVES IN SPINAL KETAMINE PREPARATIONS:

Animal studies have shown that chlorobutanol, a preservative in the ketamine injectate, is neurotoxic() The authors made the following statement: "The appearance of spinal cord lesions after intrathecal chlorobutanol strongly suggests that this preservative is responsible for apparent toxicity of ketamine and therefore should not be used in any solution intrathecally injected into humans." A more recent study in pigs() has found that clinically, in swine, subarachnoid ketamine without preservative is a safe and effective anesthetic and did not show significant neurotoxic effects

OTHER NMDA RECEPTOR ANTAGONISTS

It has been postulated that NMDA antagonists are most beneficial in conditions involving ongoing nerve damage, such as diabetic neuropathy, as compared with their effect on fixed lesions such as those seen in post-herpetic neuralgia.

Dextromethorphan: available OTC as a cough suppressant, it is a low-affinity NMDA receptor antagonist; it is rapidly metabolised to dextrorphan, which is an active metabolite that also has NMDA receptor activity. Various studies have had mixed results, but Nelson's study() of dextromethorphan in diabetic neuropathy and post-herpetic neuralgia (using an initial dose of 120mg per day increasing up to maximum dose of 960mg per day) found significant improvement in pain.

Memantine : investigational agent that significantly decreased nighttime neuropathic pain in a large study of patients with diabetic peripheral neuropathy(). However, a previous study() found it ineffective in treating postherpetic neuralgia.

Amantadine : generally used to treat symptoms of Parkinson's disease, it has also been reported () to be effective in managing neuropathic pain(in three patients, acute administration resulted in complete resolution of symptoms, which was attributed to termination of the "wind-up" mechanism). Pud et al() looked at intravenous administration of amantadine for relief of cancer-related neuropathic pain and found that there are indications that suggest it may be of benefit, but they recommend further trials. It is, in fact, also an antiviral agent; it is known to be helpful in relieving muscle stiffness and tremor in neurological conditions such as Parkinson's. It is also well established to treat fatigue and reduced exercise tolerance in Multiple Sclerosis.

Dr. S. A. Andreae-Jones MB BS

Patron of the Arachnoiditis Trust

July 2000