Baclofen is a gamma-aminobutyric acid (GABA) derivative that is a specific agonist for the receptor type B. It is widely used in the treatment of patients with muscle spasticity, specifically those with etiologies such as spinal cord injury, multiple sclerosis, and cerebral injuries.1 It is also used off-label for the treatment of alcohol use disorder, but the higher dosages required for this have the potential for abuse.2 It generally works by reducing excitatory transmission in the spinal cord and other sites; however, its exact mechanism of action in the central nervous system (CNS) by which it reduces spasticity is unclear. It is known, however, that the drug binds to the GABA-B receptor on the presynaptic terminal of type Ia muscle spindle afferents, activating a G-protein–linked cascade.3 This causes synaptic inhibition by increasing potassium ion conductance while decreasing calcium ion conductance into the presynaptic terminal, hyperpolarizing the cell and decreasing the amplitude of excitatory postsynaptic potentials of the alpha-motor neuron.3 The result is a counteraction to the loss of tonic inhibition.3 Baclofen can be administered orally or intrathecally. The average recommended oral dose is 40 to 80 mg daily.4 It has a half-life of 3 to 5 hours and is primarily eliminated renally, which accounts for its rapid withdrawal.5
A review of the literature shows a temporal relationship between psychiatric symptoms and baclofen cessation. Baclofen withdrawal may present with altered mental status, insomnia, anxiety, depersonalization, thought disorder, delusions, and hallucinations. Delirium caused by baclofen withdrawal can be difficult to distinguish from delirium due to other etiologies and, when unrecognized and inadequately treated, it is associated with significant morbidity and mortality. The differential diagnosis of baclofen-withdrawal delirium includes autonomic dysreflexia, illicit drug abuse, alcohol withdrawal, benzodiazepine withdrawal, serotonin syndrome, neuroleptic malignant syndrome (NMS), and sepsis. Neuropsychiatric effects of abrupt baclofen withdrawal are thought to invoke the GABA system. Baclofen, like GABA, inhibits CNS pathways involving monoamine neurotransmitter systems.6 Sudden withdrawal of baclofen causes a disinhibition of monoamine pathways (ie, a release of norepinephrine and dopamine onto super-sensitized receptors), leading to autonomic arousal (eg, tachycardia, hypertension, agitation, restlessness), delusions, hallucinations, and delirium.6 As the management of baclofen-withdrawal delirium differs from other etiologies, its early detection is imperative to begin adequate treatment. Complete resolution of baclofen-withdrawal delirium is possible after restarting the medication.6
A 46-year-old woman with a past medical history of intracranial hemorrhage (ICH) and hypertension was seen in the emergency department for disorganized behavior and hallucinations. On initial evaluation, she was markedly disoriented, cursing at imaginary people, and making bizarre hand gestures. She reported not sleeping for the past 3 days, claimed she saw her mother-in-law behind the nursing station, reported that people were trying to have sex with her, and stated that her incarcerated husband was having an affair with a hospital nurse. The patient's past psychiatric history included major depressive disorder, anxiety disorder, and alcohol and prescription opioid use disorder. She admitted to prior cannabinoid use but no current alcohol or recreational drug use. Collateral history from her mother-in-law, with whom the patient resided, confirmed that the patient had not been using alcohol or drugs and that her husband was incarcerated. Current medications included sertraline, gabapentin, buprenorphine/naloxone, and propranolol of unknown dosages. The mental status examination showed a disheveled woman with psychomotor agitation, slurred speech, anxious mood, constricted affect with auditory and visual hallucinations, and persecutory delusions of being the subject of a plot by her mother-in-law, husband, and hospital staff. There was no suicidal/homicidal ideation, intent, or plan. Insight, judgment, and impulse control were poor. Urine toxicology and ethanol levels were negative. A computed tomography scan of the patient's head showed stable right posterior encephalomalacia secondary to the history of ICH. The patient was given 5 mg of haloperidone and 2 mg of lorazepam intramuscularly to decrease agitation, and she was admitted to the hospital for altered mental status. A psychiatry consult was called for evaluation of the patient's agitation.
During the second day of hospitalization, the patient reported to the consulting psychiatry team that she ran away from home due to her paranoia regarding her in-laws and husband plotting against her, seeing her husband kissing and undressing himself with his new, younger girlfriend who worked in the hospital. She reported visual hallucinations of masked faces at home and of men signaling her to pack her belongings and leave. She also had auditory hallucinations of conversations between her in-laws and husband plotting against her. She admitted she was recovering from alcohol abuse but had consumed one beer prior to admission and denied any other drug use. The patient became irritable, restless, and combative. She complained of feeling “very hot” and was given 2 mg of lorazepam intramuscularly for agitation. Buprenorphine/naloxone was not available, so a methadone taper was recommended to prevent opioid withdrawal. She was placed on close observation for safety and a lorazepam taper was recommended due to observed autonomic instability.
During the third day of her hospitalization, the patient recalled using 60 mg/day of baclofen for back pain and abusing her prescription 3 days prior to admission. The lorazepam taper was continued as the psychiatry consultation team suspected baclofen withdrawal. Over the next 3 days, the patient gradually improved and her close observation was discontinued. The patient's altered mental status improved, the methadone protocol was completed, and she eventually returned to baseline, apologizing to her in-laws for her accusations. The delirium resolved and the patient was discharged to follow-up with her outpatient psychiatrist.
Management of Acute Baclofen Withdrawal
Management of baclofen withdrawal includes early recognition of symptoms and a prompt diagnosis. Presenting features such as fever, myalgias, spasticity, confusion, altered mental status, and visual and auditory hallucinations, and physical examination findings such as tachycardia, hypertension, hyperthermia, muscle rigidity, and seizures are frequently seen.6 There should be an index of suspicion if symptoms began within a few hours after cessation of baclofen.6 However, withdrawal symptoms can appear from 2 days to weeks after cessation. Most often, the full set of withdrawal symptoms occurs at 72 hours. Airway, breathing, and circulation must be assessed, and a systemic examination should be done to rule out other possible etiologies.
Management includes initial supportive measures such as oxygen if hypoxic, and cardiac monitoring. It also includes seizure prevention and management with CNS-sedating agents such as benzodiazepines, external cooling for hyperthermia, and prevention of rhabdomyolysis.6 Further management may also include intravenous fluids to maintain kidney perfusion and adequate urine output while monitoring electrolyte abnormalities, especially hyperkalemia.6 Baclofen itself can be given for symptoms of withdrawal or benzodiazepines can be used, as they act on GABA-A receptors and are not affected by GABA-B receptor down-regulation caused by chronic baclofen use.6
A continuous intravenous infusion of propofol, another GABA-A receptor agonist, has been shown to have positive effects when titrated to the withdrawal symptoms. Also, due to the similarities of baclofen-withdrawal delirium and serotonin syndrome, the antiserotonergic drug cyproheptadine has been used with positive effects in a recent case series.7 It was proposed that intrathecal baclofen withdrawal, specifically when GABA-B receptor-directed presynaptic inhibition of serotonin is lost, might lead to excessive serotonin activity.3,8 Continued observation and supportive care are important to avoid more serious complications such as rhabdomyolysis and disseminated intervascular coagulation.
Baclofen is an analog of GABA that acts on GABA-B receptors. Abrupt withdrawal can cause altered mental status, insomnia, anxiety, depersonalization, thought disorder, delusions, and hallucinations.6 More severe cases of baclofen withdrawal present with an agitated delirium and can have new-onset seizures.9 Supratherapeutic baclofen has been associated with mania and psychosis.10 Rapid withdrawal of baclofen can cause delirium, as seen in the patient in this report, which can result in severe morbidity. Several case reports of adverse effects after sudden cessation of intrathecal baclofen have been published; however, reports of withdrawal after sudden cessation from oral use of baclofen are not as widely recognized.11,12 A differential diagnosis of baclofen withdrawal includes autonomic dysreflexia, illicit drug abuse, alcohol withdrawal, benzodiazepine withdrawal, serotonin syndrome, NMS, and sepsis. It is important to be aware that a routine toxicology screen does not include baclofen; therefore, its withdrawal should be considered in the differential diagnosis of a confused patient with autonomic instability, especially if culprits such as NMS, alcohol withdrawal, and benzodiazepine withdrawal are ruled out.6,10,13 This case emphasizes the importance of considering and recognizing baclofen withdrawal in the differential diagnosis for delirium as well as its timely management.
- Meythaler JM, Steers WD, Tuel SM, Cross LL, Haworth CS. Continuous intrathecal baclofen in spinal cord spasticity. Am J Phys Med Rehabil. 1992;71(6):321–327. doi:10.1097/00002060-199212000-00003 [CrossRef] PMID: doi:10.1097/00002060-199212000-00003 [CrossRef]1466869
- Agabio R, Colombo G. GABAB receptor ligands for the treatment of alcohol use disorder: preclinical and clinical evidence. Front Neurosci. 2014;8:140. https://doi.org/10.3389/fnins.2014.00140 PMID: doi:10.3389/fnins.2014.00140 [CrossRef]24936171
- Douglas AF, Weiner HL, Schwartz DR. Prolonged intrathecal baclofen withdrawal syndrome. Case report and discussion of current therapeutic management. J Neurosurg. 2005;102(6):1133–1136. https://doi.org/10.3171/jns.2005.102.6.1133 PMID: doi:10.3171/jns.2005.102.6.1133 [CrossRef]16028775
- Baclofen: drug information. UpToDate. https://www.uptodate.com/contents/baclofen-drug-information?search=baclofen&source=panel_search_result&selectedTitle=1~81&usage_type=panel&kp_tab=drug_general&display_rank=1. Accessed November 14, 2019.
- Roberts JK, Westphal S, Sparks MA. Iatrogenic baclofen neurotoxicity in ESRD: recognition and management. Semin Dial.2015;28(5):525–529. https://doi.org/10.1111/sdi.12400 PMID: doi:10.1111/sdi.12400 [CrossRef]26096760
- Leo RJ, Baer D. Delirium associated with baclofen withdrawal: a review of common presentations and management strategies. Psychosomatics. 2005;46(6):503–507. https://doi.org/10.1176/appi.psy.46.6.503 PMID: doi:10.1176/appi.psy.46.6.503 [CrossRef]16288128
- Meythaler JM, Roper JF, Brunner RC. Cyproheptadine for intrathecal baclofen withdrawal. Arch Phys Med Rehabil. 2003;84(5):638–642. doi:10.1016/s0003-9993(03)00105-9 [CrossRef] PMID: doi:10.1016/S0003-9993(03)00105-9 [CrossRef]12736874
- Green LB, Nelson VS. Death after acute withdrawal of intrathecal baclofen: case report and literature review. Arch Phys Med Rehabil. 1999;80(12):1600–1604. https://doi.org/10.1016/S0003-9993(99)90337-4 PMID: doi:10.1016/S0003-9993(99)90337-4 [CrossRef]10597813
- Mohammed I, Hussain A. Intrathecal baclofen withdrawal syndrome—a life-threatening complication of baclofen pump: a case report. BMC Clin Pharmacol. 2004;4(1):6. https://doi.org/10.1186/1472-6904-4-6 PMID: doi:10.1186/1472-6904-4-6 [CrossRef]
- Geoffroy PA, Auffret M, Deheul S, Bordet R, Cottencin O, Rolland B. Baclofen-induced manic symptoms: case report and systematic review. Psychosomatics. 2014;55(4):326–332. https://doi.org/10.1016/j.psym.2014.02.003 PMID: doi:10.1016/j.psym.2014.02.003 [CrossRef]24751117
- Chong C-F, Wang TL. An unusual presentation of baclofen overdose. Emerg Med J.2005;22(9):673–674. https://doi.org/10.1136/emj.2003.011908 PMID: doi:10.1136/emj.2003.011908 [CrossRef]16113202
- Greenberg MI, Hendrickson RG. Baclofen withdrawal following removal of an intrathecal baclofen pump despite oral baclofen replacement. J Toxicol Clin Toxicol.2003;41(1):83–85. https://doi.org/10.1081/CLT-120018277 PMID: doi:10.1081/CLT-120018277 [CrossRef]12645974
- Chawla JM, Sagar R. Baclofen-induced psychosis. Ann Pharmacother.2006;40(11):2071–2073. https://doi.org/10.1345/aph.1H202 PMID: doi:10.1345/aph.1H202 [CrossRef]17047139