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Republished: Severe hyperthermia due to oral baclofen withdrawal
  1. Vishesh Paul1,
  2. Kari Righter2,
  3. Elise Kim2,
  4. Weston Nadherny3
  1. 1 Pulmonary & Critical Care Medicine, Carle Foundation Hospital, Urbana, Illinois, USA
  2. 2 Pharmacology, Carle Foundation Hospital, Urbana, Illinois, USA
  3. 3 Internal Medicine, Carle Foundation Hospital, Urbana, Illinois, USA
  1. Correspondence to Dr Vishesh Paul; visheshpaul{at}gmail.com

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In conjunction with BMJ Case Reports, DTB will feature occasional drug-related cases that are likely to be of interest to readers. These will include cases that involve recently marketed drugs for which there is limited knowledge of adverse effects and cases that highlight unusual reactions to drugs that have been marketed for several years.

SUMMARY

We report a case of a 53-year-old woman who presented initially with sepsis and later in her stay developed a severe and rapidly progressing hyperthermia after a decrease in oral baclofen dosage. Her fever peaked at 42.5C (108.5F), creating a broad differential diagnosis and complicating her initial sepsis diagnosis. When the oral baclofen dose was increased, the fevers resolved which confirmed the clinical diagnosis of baclofen withdrawal. Dose reductions of oral baclofen should be made gradually and with caution, and patients should be monitored for fevers as a possible symptom of baclofen withdrawal.

Background

Baclofen, a centrally acting gamma-aminobutyric acid (GABA) derivative, reduces endogenous neurotransmitter release by binding to the GABA (b) receptors at the presynaptic terminals.1 Its clinical effect is the prevention of hyperreflexia, involuntary muscle movement and decreased muscle tone.2 Hence, baclofen is one of the most frequently used agents to control the spasticity in spinal cord injury.1 Oral baclofen does not readily cross the blood-brain barrier, which is why its benefits in spinal cord injury are typically attained through high oral doses averaging from 60 mg/day to 300 mg/day, or through intrathecal administration where it is directed at the site of action.3–5

Withdrawal of intrathecal baclofen is a well-documented medical emergency. Oral baclofen withdrawal can also lead to significant side effects such as agitation, delirium, altered mental status, dyskinesia, tachycardia and seizures.6 Few case reports link oral baclofen to high fevers and autonomic dysfunction.5–7 We report a case of baclofen withdrawal syndrome characterised by severe hyperthermia with temperatures peaking at 42.5C (108.5F) after a significant decrease in the patient’s usual total daily dose.

Case presentation

A 53-year-old woman with a medical history significant for paraplegia due to a previous traumatic C6 spinal cord injury was brought to the emergency room with respiratory distress and lethargy for a day. Additional history included neurogenic bowel and bladder with a suprapubic catheter in place. At baseline, the patient was awake, alert, and oriented x3, wheelchair-bound and could feed herself. Her initial vital signs were: temperature-36.8°C (98.4F), pulse rate—94/min, respiratory rate—15/min and blood pressure of 78/50 mm Hg. Initial laboratory testing showed leucocytosis (19.5×109/L) with left shift, hypokalaemia (3.2 mEq/L) and elevated procalcitonin levels (3.19 ng/mL). Kidney and liver function tests were within normal limits.

The clinical examination was significant for lethargy, dyspnoea and cold-clammy extremities. Her neck was supple, and pupils were equal in size and reactive to light. Rhonchi were heard diffusely on the left side on lung auscultation. Cardiac and abdominal examinations were unremarkable. The suprapubic catheter had urine, which was turbulent with a substantial amount of sediment. She was intubated because of her respiratory distress and lethargy. Propofol drip and as needed fentanyl pushes were initiated and continued for sedation and pain control. Chest imaging showed air space disease at the left base. CT scan of the brain did not show any acute processes. She was diagnosed with acute encephalopathy and septic shock secondary to aspiration pneumonia and possible urinary tract infection, and admitted to the intensive care unit (ICU). Vancomycin, metronidazole and cefepime were empirically started after blood, urine and endotracheal secretions were sent for microbiology testing. Her home medications included baclofen 40 mg four times per day, amitriptyline 100 mg daily and pregabalin 300 mg three times per day, and all were resumed through the orogastric tube.

During the initial 24 hours, she required a significant amount of vasopressor support (norepinephrine drip 0.4–0.6 µg/kg/min). The clinical condition slowly started to improve as the vasopressor requirement decreased over the next 48 hours. Microbiology resulted back positive for methicillin-susceptible Staphylococcus aureus in the respiratory tract and Escherichia coli in the urine. Vancomycin was stopped, and cefepime and metronidazole were continued. On day 4, the patient was afebrile, with minimal norepinephrine requirement, and she was moving around more but was not waking up enough to follow commands despite sedation vacation.

Assuming an exaggerated somnolent effect of baclofen in this time of critical illness, the baclofen dose was cut down from 40 mg four times per day to 20 mg three times per day (on day 4 of hospitalisation). She developed a low-grade fever with a temperature of 38C (100.4F) approximately 12 hours after the baclofen dose change. On the morning of day 5, her temperature was 39.4C (102.9F) and then increased rapidly to 42.5C (108.5F) in the next 3 hours (figure 1). She became unresponsive and tachycardic with a heart rate of up to 150/min. On examination, there was no nuchal rigidity, muscle spasticity/rigidity, and tendon reflexes were hypoactive as before. The eye examination did not reveal any abnormalities. The rest of the examination was also unchanged except for apparent tachypnea and tachycardia. Tylenol was given a couple of times without any observed benefit.

Figure 1

Maximum temperatures reached on each hospital day and corresponding baclofen dose adjustments. (QID, four times per day; TID, three times per day.)

Investigations

Her white blood cell (WBC) count was stable at 9.5×109/L, and procalcitonin levels were decreasing (0.67 ng/mL). Lumbar puncture was obtained to rule out meningitis and showed 0 WBC count, normal glucose and low-normal protein. An electroencephalogram (EEG) was obtained to look for seizures but instead showed a toxic encephalopathy pattern. Other infectious work-up was done, including repeating blood cultures and chest imaging. Chest X-ray showed improving airspace disease at the left base, and there were no new infiltrates identified. MRI of the brain was done later on after the patient was deemed medically stable and did not show any acute pathology.

Differential diagnosis

With the sudden onset of such high fevers, broad differential diagnosis was considered, including sepsis, meningitis, neuroleptic malignant syndrome (NMS), propofol infusion syndrome, serotonin syndrome and drug-induced fever.

Meningitis was ruled out with the results of the lumbar puncture. Worsening sepsis was unlikely given the patient already was on broad-spectrum antibiotics, had stable WBC count, clearing lung infiltrates, and improving procalcitonin levels.

EEG pattern was consistent with toxic encephalopathy and did not show any epileptiform activity. There was no hyper-reflexia, ocular clonus on any medication interaction that would suggest serotonin syndrome. NMS was ruled out as the patient did not receive antipsychotics, had normal muscle tone and stable PaCO2 (arterial carbon dioxide pressure). Propofol infusion syndrome was unlikely due to the lack of metabolic and electrolyte derangements. All the patient’s current medications were checked, and the likelihood of drug-induced fever to present in such a way was considered very low.

Treatment

Active external cooling (Arctic Sun) was initiated because of severe hyperthermia, and the patient’s temperature was successfully brought down to 37.7C (100F) in the next 3–4 hours. The antibiotic regimen was not changed as infectious aetiology was less likely.

ICU pharmacy team suggested that this could be a manifestation of baclofen withdrawal. Considering that no clear aetiology for such hyperthermia was identified, and with suspicion for drug withdrawal, the baclofen dose was increased that evening from 20 mg three times per day to 40 mg three times per day (75% of her home dose). The clinical diagnosis of baclofen withdrawal was confirmed when the patient became normothermic after the baclofen dose was increased.

Outcome and follow-up

The morning after the baclofen dose increase, the maximum temperature decreased to 37.9C (100.2°F) with discontinuation of external cooling. After 48 hours, the patient started to become more responsive on sedation vacation, and vasopressors were weaned off on day 8. She was successfully extubated on day 12 of hospital stay and transferred to the medical floor.

Discussion

Unlike intrathecal baclofen, oral baclofen doses can lead to central nervous system depression, making it a target for dose adjustments in the setting of encephalopathy6 While small dose adjustments are typically well tolerated, one must be cognisant of the possibility of severe withdrawal. The half-life of baclofen in unimpaired kidneys is 3–4 hours, explaining part of the pathophysiology and rapid symptom onset of withdrawal.4 Research from mouse hemisected spinal cord reveals that baclofen causes GABA (b) receptor hyperactivity, and sudden disruption of this medication can cause a ‘rebound enhancement’ of the spinal transmission, ultimately leading to autonomic instability and severe withdrawal effects.8

Fevers and autonomic instability of varying severity have been described in a few case reports in literature5–7 (table 1). Richter et al reported a case of fever of 40C (104F) and neurological symptoms such as confusion and head tremors after discontinuing oral baclofen.5 In their case, while neurological symptoms manifested after 24 hours, fevers did not present until day 4 of the patient’s hospital stay. Similar to our case, their patient’s symptoms were resolved within 48 hours of reinstating baclofen. Cunningham et al reported a case of a 24-year-old woman who developed fevers up to 40.5C (104.9F) after a day of discontinuing baclofen.7 Fevers also coincided with autonomic instability in their patient. Once they resumed the patient’s original baclofen dose, fever and autonomic instability were resolved within 24 hours. This is similar to our case, in which the withdrawal symptoms began 12 hours after baclofen dosage was significantly reduced and near-complete resolution within 24 hours after increasing the dose. Risk factors for baclofen withdrawal include long duration of therapy, high dose, and brevity of taper.1 In our case, all three risk factors were present, which led to severe hyperthermia of 42.5C (108.5F). This emphasises the dangers of making abrupt dose adjustments with baclofen and the severity of possible withdrawal syndrome. As seen in our case and echoed in others, the rapid recognition and reintroduction of medication is the only effective approach to management.3 5–7

Table 1

Reports of hyperthermia after baclofen discontinuation/dose reduction5–7

However, baclofen withdrawal should always be a diagnosis of exclusion, and appropriate differential diagnoses should be considered each time. The diagnosis should be based on the temporal relationship of symptoms onset after the discontinuation or dose reduction, improvement after resuming or increasing the dose, and most importantly, ruling out other differential diagnoses.

In conclusion, baclofen is a widely prescribed antispastic drug, even used in the elderly.9 Close attention should be paid to baclofen dosing on admission and throughout the course of stay. Those patients with risk factors for developing a withdrawal should avoid abrupt dose reduction and be closely monitored for withdrawal symptoms including high temperature. If discontinuation is necessary, it should be done gradually. And if withdrawal syndrome occurs, dose increase or the reinstitution of the original baclofen dose is advised.

Patient’s perspective

The intensive care unit (ICU) team did a great job of taking care of me. They explained to my daughter about my very high fever due to decreasing my baclofen dose. I was on a ventilator and was unconscious at that time, and have no memory of it. The ICU team was communicating with my daughter who was at the bedside. I got to know about all these many days later. They instructed me and my daughter to make sure that my baclofen dose should not be changed significantly by anyone unless it is approved by my neurologist. I feel happy that my medical history is being used for educating other people, and hopefully they find this useful.

Learning points

  • Baclofen withdrawal can present as severe hyperthermia which can complicate patient diagnosis and prolong treatment if not suspected and recognised.

  • Risk factors for baclofen withdrawal include dose intensity, length of use, and the brevity of taper.

  • Caution should be used when decreasing baclofen doses and, if necessary, should be done in a slow taper.

Ethics statements

Patient consent for publication

References

Footnotes

  • Twitter @visheshpaul83

  • Contributors KR: wrote the initial manuscript. VP: edited the manuscript and took care of the patient. EK: took care of the patient and edited the manuscript. WN: took care of the patient and edited the manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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