One in 25 patients with very low kidney function were admitted to hospital with severe confusion and other cognitive-related symptoms a few days after being prescribed a common muscle relaxant.
A new study from ICES Western, Western University and Lawson Health Research Institute has shown that patients with kidney dysfunction who were prescribed a high dose of the drug baclofen, were more likely to be admitted to hospital for disorientation and confusion, than those who weren’t prescribed the drug.
Their results are being published on November 9 in the high impact journal, JAMA and are being presented at the same time at the American Society of Nephrology meeting in Washington, D.C.
“When we looked at people with low kidney function (30 per cent or less) who received a high dose of baclofen from their prescriber, approximately one in 25 were being admitted to hospital with severe confusion, typically over the next few days, ” said Dr. Amit Garg, Professor at Western’s Schulich School of Medicine & Dentistry and Scientist at ICES and Lawson.
“If you compare that to a group of people who had low kidney function who didn’t get baclofen, that risk is less than one in 500, so it’s quite a dramatic difference between the two groups.”
The research was initiated because of observations that nephrologists were noting in clinic at London Health Sciences Centre.
Dr. Peter Blake, Professor at Schulich Medicine & Dentistry, Lawson scientist and coauthor on the study says this drug is commonly prescribed for muscle spasms and muscle pain, and is also prescribed off-label for alcoholism, gastro-esophageal reflex disease, and trigeminal neuralgia. He says it is widely prescribed because it has not previously been associated with serious side-effects.
More than eight million prescriptions for the drug were handed out in the United States in 2016, and despite numerous case reports linking baclofen with cognitive symptoms in patients with kidney disease, this is the first population-based clinical study to look at the association between the two.
“It came to my clinical attention dealing with patients with advanced kidney failure, that this drug that is generally thought to be relatively harmless, appeared to be the precipitant of severe confusion,” said Dr. Blake.
“These are patients who had previously been very oriented, and they were suddenly extremely confused and when you took a history, we understood that they had recently started this drug, baclofen.”
Using ICES data, the research team looked at a group of approximately 16,000 people in Ontario with kidney disease who started a new dose of baclofen between 2007 and 2018.
They divided the patients into two groups, a group that received a high dose, and a group that received a low dose of the drug and compared both to a group of almost 300,000 kidney disease patients who were not prescribed the drug at all.
About 20 per cent of older adults live with kidney function of less than 60 per cent.
The research team found that 1.11 per cent of such patients (108/9707) who started a high dose of the drug baclofen were admitted to hospital with cognitive-related symptoms, versus 0.42 per cent (26/6235) with the low dose.
They found that the group most at risk had the lowest kidney function, 3.78 per cent of patients with kidney function less than 30 per cent were hospitalized with these symptoms after starting a high dose of baclofen (26/687).
“We found that in current practice most patients are getting a similar dose of baclofen no matter what the level their kidney function is,” said Dr. Garg who is concerned about this discrepancy in dosing because prescribing guidelines already suggest a lower dose for patients with kidney dysfunction that isn’t being followed.
“We also found that the risk for hospitalization for severe confusion was higher amongst patients who received doses that were higher versus doses that were lower.”
The authors hope this study will better inform physicians and pharmacists about the use of baclofen for patients with kidney disease. “This study shows quite clearly the potential harm of this drug.
When a patient with low kidney function presents to the hospital with confusion, when their medication list is reviewed baclofen should be considered as a potential culprit.
We’re hoping regulatory agencies will now take a look at this and perhaps add a new black box warning for baclofen.
With this new information prescribers should reconsider risk-benefit, and should be quite cautious before they prescribe this drug.
When they believe the drug is indicated, a low dose should be considered, and patients and their families should be warned about what to look out for in terms of side effects.”
The authors also say patients should not stop their prescription medications without talking to their doctor.
Baclofen is an oral derivative of gamma-aminobutyric acid (GABA) used to treat muscular spasticity from disorders of the central nervous system. However, it is also being used for a variety of other conditions such as musculoskeletal pain, myoclonus, and alcohol withdrawal.
The elimination of baclofen is heavily dependent on intact renal function, and the contraindication for use in patients with insufficient renal function is not well recognized by healthcare providers.
Here, the authors report a series of mild to severe cases of baclofen intoxication in patients with end-stage renal disease.
In all cases, baclofen was initiated by either inpatient or outpatient healthcare providers and the patients generally presented with altered mentation, somnolence, and/or respiratory depression.
All patients were treated with aggressive hemodialysis and made a full recovery. This paper will briefly review the literature regarding baclofen intoxication, safety of baclofen use in renal disease, and efficacy of extra-corporeal therapy in the treatment of baclofen intoxication.
Baclofen toxicity is an under-recognized and treatable cause of encephalopathy and respiratory failure among patients with acute kidney injury or chronic kidney disease.
Cases of baclofen neurotoxicity are frequently iatrogenic, poorly recognized, and result in significant mortality, morbidity, and hospital resource utilization. Here, we present five cases involving patients with end-stage renal disease who became symptomatic with low doses of baclofen administered for a variety of conditions.
All patients came to the attention of the nephrology hemodialysis service and were treated with daily hemodialysis or continuous renal replacement until resolution of symptoms. We suspect that a number of patients with milder presentations are not recognized in both the inpatient and outpatient settings.
Baclofen (β-4-chlorophenyl gamma-aminobutyric acid) is a synthetic derivative of the central, inhibitory neurotransmitter gamma-aminobutyric acid (GABA) (1). Baclofen acts as an agonist of GABAB receptors, which are G protein-coupled receptors that open nearby potassium channels, thereby increasing potassium membrane conductance (2). These actions promote cell membrane polarization, which decreases the likelihood of an action potential, and produces an overall inhibitory effect on central neurons.
After oral administration, baclofen is rapidly absorbed by the gastrointestinal tract. Peak concentrations are seen after 2 hours of ingestion (3).
Approximately 10–15% of the drug undergoes hepatic metabolism, while the remaining 85–90% is excreted unchanged by the kidneys (4). Drug clearance follows first-order elimination kinetics with a half-life around 3.5 hours (4). About 35% of serum baclofen is protein bound and it has an apparent volume of distribution of 0.8 l/kg in adults and 2.6 l/kg in children (3,5).
Baclofen distributes within the intravascular space and highly perfused organs such as the liver and kidney, but it slowly penetrates the CNS by directly crossing the blood–brain barrier (6,7). At usual doses, it primarily exerts its inhibitory effect on spinal motor neurons. Thus, it is most commonly prescribed to control spasticity associated with spinal cord disorders.
The adverse effects associated with baclofen are consistent with its inhibitory effect on the central nervous system. Common side effects at normal doses include transient drowsiness, lethargy, nausea, or orthostasis. Larger doses can cause CNS depression, which manifest as sedation, somnolence, and respiratory depression (8).
In patients with a history of seizure disorders, baclofen has been associated with increased seizure activity (8,10). It is hypothesized that there is greater inhibition of key inhibitory interneurons thus lowering the threshold for seizure activity (11).
With an acute overdose, profound CNS depression occurs. Case reports of severe baclofen overdoses (range 80–2500 mg) in the general population describe patients presenting with muscular hypotonia, areflexia, myoclonus, respiratory depression, bradycardia, and seizures (7,8). Severe baclofen intoxications can produce a profound comatose state with absent brain stem reflexes, mimicking brain death (12).
In one case, a patient with an acute baclofen intoxication and normal renal function was initially thought to have anoxic brain death and the treating physicians arranged for organ procurement.
By hospital day 5, the patient spontaneously regained purposeful movements, eventually leading to a full recovery (12). In the setting of large overdose like this, clearance appears to follow first-order elimination kinetics, but the half-life is significantly extended to 8 hours or even longer (4).
Case reports have noted that CNS depression persists despite plasma baclofen levels falling to the therapeutic range, suggesting that CNS clearance is significantly delayed compared to other body compartments (4). Thus, caution is warranted when interpreting serum baclofen levels.
Toxicity in Renal Failure
Because baclofen elimination is heavily dependent on renal clearance, patients with reduced kidney function are at high risk of baclofen intoxication. The earliest case reports noted that patients with ESRD developed altered mental status after taking small doses of baclofen for very short periods of time (13).
Case reports of baclofen toxicity in patients with renal insufficiency note that toxicity occurred primarily in patients with ESRD (27 cases, 68%) (14). Of the remainder, 10 patients had chronic kidney disease stage 3–5 (24%), and four had acute kidney injury (9%) (14).
Among those with ESRD, 68% were on hemodialysis and 32% were on continuous ambulatory peritoneal dialysis (CAPD). Symptoms often began 2–4 days after starting therapy. The mean daily dose was 20 mg/day with a wide range of doses reported (5–60 mg/day) (14). This is consistent with the findings in our series (see Table 1), where ESRD patient often developed symptoms within the first 24–48 hours on initial divided doses of 10–30 mg/day.
Confirmed baclofen toxicity cases from 2011 to 2013
|Case||Kidney function||Baclofen indication||Dose||Site of drug initiation||Presentation||Length of stay (days)||ICU admission||Mechanical ventilation||No. HD treatments required|
|1||ESRD||ETOH withdrawal||10 mg TID||Inpatient||AMS, coma, resp. failure||30||Yes||Yes||5|
|2a||ESRD||Leg pain||5 mg TID||Outpatient SNF||AMS, perseveration||2||No||No||2|
|2b||ESRD||Leg pain||5 mg TID||Outpatient SNF||AMS, perseveration||4||No||No||2|
|3||ESRD||Movement disorder||5 mg TID||Inpatient||AMS, seizure, resp. failure||27||Yes||Yes||CVVHDF|
|4||ESRD||Neck Pain||10 mg TID||Outpatient clinic||AMS, somnolence||4||No||No||2|
|5||ESRD||Muscle Spasm||5 mg BID||Outpatient clinic||AMS, somnolence||4||Yes||No||3|
AMS, Altered mental status; CVVHDF, Continuous veno-venous hemodiafiltration; SNF, Skilled nursing facility.
The package insert for baclofen tablets recommends a starting dose of 5 mg three times per day, titrated to effect, but not exceeding a total daily dose of 80 mg (15). Despite being primarily renally eliminated, the manufacturer’s label and available drug databases have no specific dosage adjustments for patients with renal insufficiency (15,16).
The package insert suggests that baclofen should be “given with caution, and it may be necessary to reduce the dosage,” with no mention of dosing adjustments for dialysis patients (15). Based on the pharmacokinetics of the drug, it is possible that appropriate dose reductions could allow the safe use of baclofen in patients with renal insufficiency.
he package insert suggests that baclofen should be “given with caution, and it may be necessary to reduce the dosage,” with no mention of dosing adjustments for dialysis patients (15). Based on the pharmacokinetics of the drug, it is possible that appropriate dose reductions could allow the safe use of baclofen in patients with renal insufficiency.
However, studies to determine these doses have not been performed, and baclofen is typically absent from comprehensive guidelines about drugs that require adjustment in renal failure (17,18). For these reasons, many practitioners are unaware of the need for dose adjustment as well as the increased risk of toxicity in patients with renal insufficiency.
More information: Flory T. Muanda et al, Association of Baclofen With Encephalopathy in Patients With Chronic Kidney Disease, JAMA (2019). DOI: 10.1001/jama.2019.17725
Journal information: Journal of the American Medical Association
Provided by University of Western Ontario