Baclofen overdose mimicking anoxic encephalopathy: a case report and review of the literature

Abstract

A patient who has overdosed on baclofen can present with significant neurological symptoms suggestive of a serious brain insult, but with appropriate diagnosis and treatment they often fully recover within 72 h. If the patient had been maintained on chronic baclofen therapy prior to the overdose, one must be watchful for signs of baclofen withdrawal as recovery from the overdose occurs.

Case

A 48-year-old white female was brought to our Emergency Room by Emergency Medical Services (EMS) after a family member found her unresponsive and in respiratory distress. EMS administered IV naloxone and flumazenil at the scene with minimal response, and this was the only administration of these drugs. Upon arrival at the hospital she was intubated. A head computerized tomograph scan was negative. Her urine toxicology screen was positive only for benzodiazepines. Her family reported that she took no medications, and there was no significant medical, psychiatric or substance abuse history, although they did report she occasionally took one of her husband’s diazepam tablets when she had insomnia.

Her electrocardiogram (ECG) showed sinus bradycardia with a rate of 45. Blood pressure was 134/66 mmHg. Body temperature was 95.7°F. Neurological consultation revealed unresponsiveness to verbal commands, and decorticate posturing with deep pressure stimulation. Corneal reflexes were absent. Her pupils were symmetrical at 2.5 mm, and nonreactive. She had a negative horizontal and vertical oculocephalic response. There was no gag reflex. Deep tendon reflexes were diffusely trace, her plantars were flexor and there was diffuse hypotonia. She was diagnosed as comatose with a Glasgow Coma Scale of 5, with the putative etiology as hypoxia.

Within 24 h of admission she had a spontaneous breathing trial and was able to be extubated. Her neurological condition continued to improve. Although initially confused, she did acknowledge having taken pills in an intentional overdose. Within 48 h of admission her neurological symptoms had fully resolved, and she was alert, well oriented, and cognitively intact. Her family confirmed that her mental status was back at her baseline. She reported she had been feeling emotionally overwhelmed, and had intentionally ingested a handful of baclofen (from a family member’s old prescription bottle) and a few diazepam tablets approximately 18 h before she was discovered by her family in an unresponsive state. By 72 h following admission she was completely back to her baseline and had been cleared for discharge by psychiatry with a plan for out-patient psychotherapy to address the psychosocial issues.

The patient discussed in this case provided written informed consent consistent with the Committee on Publication Ethics Best Practice Guidelines published on 25 February 2016.

Discussion

Baclofen is a gamma-aminobutyric acid derivative that functions as an agonist of GABA-B receptors. It is used in the treatment of muscle spasticity and as a skeletal muscle relaxant. Common clinical usage is for muscle spasticity resulting from multiple sclerosis, cerebral palsy and spinal cord injury. Baclofen primarily reduces excitatory neurotransmission, with activity at both spinal and supraspinal sites. ¹ Baclofen differs from diazepam as it is an agonist at the GABA-B receptor, which is a metabotropic (G-protein coupled) receptor. Diazepam is an agonist at the benzodiazepine site on the ionotropic GABA-A receptor. ² However, both agents can cause respiratory depression. The primary treatment for baclofen overdose is mechanical ventilation. Renal excretion accounts for 70% of baclofen’s removal from the body. Hence, individuals with renal disease will likely have a longer time to recovery. There is a case report of a 70-year-old female with end-stage renal disease who was prescribed oral baclofen 5 mg orally three times daily for leg soreness. She developed baclofen-associated encephalopathy, and completely recovered after 8 h of emergency haemodialysis. ³

In the decades following the introduction of oral baclofen as a medical treatment in 1977, there were a series of case reports on the clinical presentation of baclofen overdose.^4-11 Common manifestations of a baclofen overdose include: respiratory depression, lack of tendon reflexes, hypotonia, coma, hypothermia, bradycardia and possible seizures and cardiac conduction abnormalities. In most cases, with assisted ventilation and supportive treatment, patients fully recover within 48–72 h. This case is presented to highlight the features of the initial presentation of a baclofen overdose, as what initially looks like a serious brain insult in the emergency room with a grim prognosis can ultimately result in full patient recovery in <72 h.

One significant limitation of this case is that no quantification of the presence of baclofen in the patient’s serum was obtained during this hospitalization. However, the discovery that baclofen was the likely primary etiological agent to this patient’s serious neurological presentation occurred approximately 50 h after the overdose. Given the 4 h half-life of baclofen, and its Cmax of 1 h, ² at 50 h post overdose it would be unlikely that any baclofen would have been detected. Supporting baclofen as the causative agent is the patient’s clinical presentation and time course which follows the description in the clinical literature of baclofen overdoses. Additionally, the family reported that the patient was on no prescription medications, and when they searched the home for possible drugs taken in the overdose, the only candidates were baclofen (“a handful” from an old prescription bottle) and diazepam (“a few” from the husband’s prescription, which he confirmed). It is possible that the diazepam contributed to this clinical picture, as it is a central nervous system depressant that has been causal to serious respiratory depression and death in overdose. However, the information available supports the ingestion of a small number of diazepam tablets. Additionally, the administration of flumazenil at the scene produced no clinical improvement. Supporting the minimal role of the diazepam in this patient’s clinical course, in the context of her rapid recovery, is the half-life difference between baclofen and diazepam (baclofen T1/2 = 4 h; diazepam T1/2 = 1–2 days and its active metabolite N-desmethyldiazepam T1/2 = 60 h).

Also of related interest is the phenomenon of baclofen acute withdrawal symptoms after baclofen overdose in a patient who was being treated with baclofen chronically. Many patients do not respond to oral baclofen for treatment of their muscle spasticity, and as a result intrathecal baclofen treatment has become popular. In fact, as recently as November 2010 the United States Food and Drug Administration granted approval of Gablofen (baclofen injection) for use in the management of severe spasticity with intrathecal baclofen treatment. There are case reports of accidental intrathecal baclofen overdose with presentations identical to oral overdoses.^12-14 An initial report that use of intravenous physostigmine could reverse the respiratory depression and coma resulting from baclofen overdose was later called into question.^12,15 Patients who have been receiving baclofen chronically are at risk of serious baclofen withdrawal symptoms if their clinical status is not monitored, and the baclofen is not reinstated once the overdose symptoms resolve.^9,14 Baclofen withdrawal symptoms can include: confusion, hallucinations, delirium, seizures, muscle rigidity and fever.

Baclofen, a commonly prescribed medication, should be considered in the differential of a patient who presents with unresponsiveness and respiratory distress. In patients who have been treated with baclofen chronically, the clinician should also monitor for baclofen acute withdrawal symptoms.