The baclofen withdrawal syndrome

Long-term administration of baclofen is widely used in patients with muscle spasticity resulting from a variety of cerebral and spinal chord lesions. As with other GABA receptor agonists, withdrawal reactions will occur if it is stopped abruptly. Patients can present with different symptoms, not all ofwhich would be considered classical of drug withdrawal. Some interesting aspects of withdrawal symptoms after baclofen administration have been highlighted in three recent reports.

Clinical presentation There is a proposed similarity between baclofen withdrawal and the neuroleptic malignant syndrome.

• A 36-year-old man with paraplegia after a spinal cord injury became disoriented (23A). He had been taking baclofen 10 mg at night for several years. He had marked rigidity in both arms and legs, he was sweating and pyrexial (38° C), and his heart rate was 112 beats/min. His serum creatine kinase was raised at 2668 U/l and rose to 2982 U/l on day 3. At that time, baclofen was restarted. Within 3 days he was fully oriented. Over 2 weeks his cre-atine kinase activity gradually fell to normal and his temperature settled. It turned out that he had neglected to take any medication for several days before admission.

The authors believed that symptoms in this case resembled the neuroleptic malignant syndrome, based on the combination of muscle rigidity, pyrexia, signs of autonomic disturbance, and altered consciousness. They did not think that the raised serum creatine kinase activity was associated with rhabdomyolysis, stating that there was no evidence from uri-nalysis to suggest this. Unfortunately, they did not specify whether there was myoglobin in the urine or not. Creatine kinase activities up to 40 000 U/l have been noted during baclofen withdrawal (24c ), compared with which crea-tine kinase activity in this case was much lower, suggesting only moderate muscle damage. One might assume that muscle damage after ba-clofen withdrawal correlates with the duration and intensity of muscular hyperactivity. In addition, prolonged muscular hyperactivity may be expected to be followed by an increase in both body temperature and heart rate, owing to hypermetabolism and sympathetic activation. Sweating will result from sympathetic activation and a thermoregulatory response to hyper-thermia and is not necessarily an autonomic disturbance. Disorientation is also an expected symptom of baclofen withdrawal. In conclusion, this patient's combination of symptoms could have been explained by baclofen withdrawal alone. Assuming that disturbances in central dopaminergic systems could have been involved, as in neuroleptic malignant syndrome, is speculative.

This is not the first report of similarities between the neuroleptic malignant syndrome and baclofen withdrawal (24c, 25cr, 26c). In addition, hyperthermia seems to be common in baclofen withdrawal (25cr).

If a patient stops taking baclofen, a blood sample for baclofen serum concentration measurement should be taken ifpossible, to confirm the diagnosis post hoc if hyperthermia occurs. If a patient taking long-term baclofen presents with similar symptoms, baclofen withdrawal should be considered and baclofen should be given. If this is not effective and the patient deteriorates, with hyperthermia, increasing creatine kinase activity, and metabolic sequelae, dantrolene can be given. Dantrolene is life-saving in malignant hyperthermia associated with volatile anesthetics and succinylcholine and is also the drug of choice for the treatment of neuroleptic malignant syndrome. In one case of baclofen withdrawal, dantrolene was given with success (24c).

It should be stressed that baclofen withdrawal is a potentially fatal emergency requiring intensive care.

The effects of renal impairment Baclofen is cleared predominantly by renal excretion. Thus, if a patient taking baclofen has deteriorating renal function one would expect relative baclofen overdose and would reduce the dosage.

• An 82-year-old man with left ventricular dysfunction and gout had worsening renal function (27A). He was taking lisinopril, furosemide, naproxen, al-lopurinol, and baclofen 20 mg tds. As no reason could be found for the use ofbaclofen the dose was halved and then stopped 10 days later. The next day he had visual hallucinations, confusion, and agitation, and required sedation with diazepam. He was afebrile, with normal inflammatory markers, and a CT scan ofthe brain showed only cerebral atrophy. Baclofen was reintroduced, with complete resolution ofneuropsychiatric symptoms within 48 hours.

A reduced dosage of baclofen may be necessary in patients with renal insufficiency. On the other hand underdosing can result in withdrawal symptoms and an inadequate therapeutic effect. Both overdosing and underdosing will cause significant morbidity and a prolonged hospital stay. Measuring baclofen serum concentrations in problem patients could be helpful for dosage adjustments and might be cost effective. Withdrawal from baclofen should be performed with extreme caution. In selected patients, hospital admission for this purpose may be justified, for example in elderly patients who live on their own without someone looking after them.

Fetotoxicity Convulsions have been attributed to baclofen withdrawal after in utero exposure (28A).

• A 7-day-old baby was admitted to hospital with generalized convulsions, which did not respond to phenobarbital, phenytoin, clonazepam, lidocaine, or pyridoxine. A variety of investigations all gave negative results. Electroencephalography 4 days later showed prolonged episodes of epileptic activity. At that time baclofen withdrawal was suspected, as the paraplegic mother had been taking baclofen 20 mg tds throughout pregnancy. The baby was given baclofen 0.25 mg/kg qds and 30 minutes after the first dose the convulsions stopped. The baclofen was then slowly withdrawn over 2 weeks. An MRI scan ofthe brain on day 17 suggested a hypoxic ischemic insult in the perinatal period, which was considered to have been secondary to convulsions.

This is the first published case of baclofen withdrawal after intrauterine exposure. As convincingly presented by the authors, baclofen withdrawal was the most likely explanation for the convulsions. In discussing the possible mechanisms of the delayed onset of convulsions the authors assumed that a secondary increase in baclofen serum concentration due to redistribution might have prevented earlier onset of the withdrawal symptoms. This is of course speculative; nothing is known about baclofen phar-macokinetics in neonates. On the other hand, the authors stated that the mother had noted some abnormal movements starting on the second day post-partum, which might have represented the first signs of withdrawal. The half-life of baclofen in adults is 3-6 hours, and adults usually become symptomatic 24-72 hours after baclofen is reduced or withdrawn (25cr). In conclusion, baclofen withdrawal should be suspected if postnatal convulsions occur after intrauterine exposure. The first priority in such a case is to rule out other causes, such as infections, electrolyte disturbances, and in-tracranial pathology, and to prevent secondary brain damage due to prolonged convulsions. Baclofen should probably be considered at an early stage, as it might be the most effective an-ticonvulsant in such cases.

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