Mythbusters: Neurology and Pharmaceuticals Edition

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By Jennifer Michaels, DVM, DACVIM (Neurology)
angell.org/neurology
neurology@angell.org
617-541-5140
October 2024

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There are many common misconceptions regarding the use of certain pharmaceuticals in neurological patients, which result in the use of some medications that should not be used or the refusal to use medications that are actually safe. This could potentially be detrimental to patients. This article aims to highlight some of these common misconceptions, review where the misinformation originated from, and clarify what the recent data actually reports.

Ketamine and Intracranial Pressure

Myth

Ketamine causes an increase in intracranial pressure (IPC) and, therefore, should not be used in patients with intracranial disease.

Background

Ketamine is an NMDA receptor (NMDAR). The NMDAR are the most ubiquitous excitatory receptors in the central nervous system (CNS). When glutamate, the NMDAR ligand, is released from the pre-synaptic nerve terminal, it binds to the NMDAR, resulting in an influx of calcium ions into the post-synaptic neuron, thus triggering an action potential and many other intracellular processes. Classical uses of ketamine include as a sedative/anesthesia and for pain management. The benefit of ketamine over other sedatives/anesthetic drugs is its relative lack of hemodynamic and respiratory depression. For pain management, the beneficial effects of ketamine far outlast the actual drug levels in the system.

Origin of the Myth

A collection of approximately six case reports and case cohorts from the 1970s. These publications described increasing ICP in patients with intracranial disease receiving ketamine.

Problems with the original data

The reports were all low-patient volume, non-controlled, descriptive papers, including patients with abnormal CSF pathways (e.g., patients with hydrocephalus). In addition, given the time at which these papers were published, the ICP monitoring techniques are very outdated, and there was no assessment of the clinical impact of the documented ICP changes.

New Data

A plethora of more recent data, including controlled studies, systematic reviews, and meta-analyses, document the safety of ketamine in patients with intracranial disease.

• Most of these studies document no impact on ICP
• A few studies even show a decrease in ICP
• The few studies that show an increase in ICP associated with ketamine administration fail to demonstrate any negative clinical impact

In addition, many of these studies have also documented potentially beneficial effects of ketamine, including an increase in cerebral perfusion pressure and mean arterial pressure, which are essential for maintaining cerebral blood flow. The use of ketamine in patients with intracranial disease also allowed for a reduction in the requirement of other medications, including other sedatives, vasopressors, and pain medications such as opioids.

Not only is this a misconception, but withholding ketamine in this subset of patients potentially results in missing out on some particular benefits of ketamine that could be useful for patients with intracranial disease. Modern uses of ketamine, including its use for the management of chronic pain, depression, seizures, and migraines, are important to acknowledge. There is also promising research regarding the neuro-protective effect of ketamine in post-trauma or post-stroke patients, given its action against NMDAR, the activation of which can lead to neuronal excitotoxicity and neuronal necrosis.

Conclusion

Ketamine is overall safe to use in patients with neurological disease without fear of significantly increasing ICP. In addition, there are many mechanisms and secondary uses for ketamine that may make it beneficial in neurological patients.

Acepromazine and the Seizure Patient

Myth

Acepromazine causes seizures and, therefore, should not be given to any patient with a history of seizures or one who is at risk for seizures.

Background

Acepromazine is one of the phenothiazine medications, a group which also includes chlorpromazine. Phenothiazines are neuroleptic drugs that suppress spontaneous movements and complex behavior while leaving spinal reflexes and unconditioned behaviors intact. Acepromazine is commonly used to reduce anxiety and for sedation/anesthesia.

Origin of the Myth

The potential risk of seizures with phenothiazines was originally documented in human medicine in the 1950s. The first veterinary paper documenting a connection between phenothiazines and seizures was published in the 1970s. The purpose of this study was to describe clinical and EEG observations in dogs with seizures and to relate these findings to human epileptic conditions. The researchers rapidly administered high doses of chlorpromazine and monitored EEG. One-half of dogs had EEG changes consistent with epileptiform activity, and 5% had clinical signs consistent with a seizure. This study formed the basis of the concern surrounding acepromazine and seizures.

Problems with the original data

The study used chlorpromazine, which is known to be more epileptogenic than acepromazine in people. The dogs were also administered 5 to 50 times the recommended dose of chlorpromazine; the risk of seizures with phenothiazines in people is dose-dependent. Lastly, this effect was seen in an experimental setting where the authors intentionally tried to elicit seizure activity.

New Data

In the last 20 years, three studies have been published documenting the safety of acepromazine in seizure patients.

1. Two retrospective studies evaluated the use of acepromazine for sedation or as part of an anesthesia protocol in patients with a history of seizures. There was no observed correlation between ACE administration in dogs with a seizure history and the recurrence of seizure activity during hospitalization.
2. A retrospective study comparing the incidence of seizures in patients undergoing myelography with one group receiving acepromazine as part of the anesthetic protocol and one group not receiving acepromazine. There was no reported difference in seizure incidence between groups.

Conclusion

The lack of correlation between the original data regarding chlorpromazine and seizures and the clinical use of acepromazine, as well as the newer data documenting no increased incidence of seizures in at-risk patients receiving acepromazine, suggest that acepromazine is safe to use in patients with a history of seizures.

Potassium Bromide (KBr) and Pancreatitis

Myth

KBr causes pancreatitis. If a patient on KBr develops pancreatitis, the medication must be discontinued.

Background

KBr is an anti-seizure medication primarily used as an adjunct therapy in refractory patients. A halide salt increases negative ion transmission across the neuronal cell membranes, resulting in hyperpolarization and reduced membrane excitability. This results in an increase in the seizure threshold and stabilization of the neurons against excitatory inputs.

Origin of the Myth

The first mention of a connection between bromide and pancreatitis was in the early 1990s in two papers evaluating the use of KBr in epileptic dogs. These studies mentioned a few dogs that developed pancreatitis after initiating KBr therapy. Of note, all of the affected dogs were also receiving phenobarbital, and two had a history of dietary indiscretion. A subsequent letter to the editor published in 2000 described a subpopulation of six dogs included in a study evaluating the efficacy of phenobarbital, half of which developed pancreatitis when KBr was added to their treatment protocols.

As a result of these reported cases, several additional studies in the 2000s to 2010s evaluated various laboratory values, including cPLI, C-reactive protein (CRP), amylase, lipase, lipids, and liver values in patients receiving KBr. While bromide-treated dogs did have relatively higher liver values, amylase and lipase values, and triglycerides, only one study showed a difference in cPLI values, and there was no difference in CRP.

Problems with the original data

All prior studies utilized data collected from diagnostic lab submissions to reference laboratories. As such, there was limited to no correlation to clinical disease or clinical status of the patients. In addition, by including only those patients with diagnostic lab submissions, there is an inherent bias toward sick patients. Second, there was no assessment of any lab values or clinical history before initiating KBr therapy. In addition, a vast majority of the patients with abnormal laboratory values were not receiving KBr alone; rather, they were receiving polytherapy, including phenobarbital. Lastly, there was no assessment of other factors that could potentially predispose patients to pancreatitis, including diet, dietary indiscretion, breed predispositions, or comorbidities.

New Data

In 2012, a systematic review evaluating the safety of KBr in dogs reported that the association between GI side effects, including pancreatitis, and using KBr was one of the least well-supported. The review concluded that there was “not enough evidence to determine whether dogs receiving KBr were at a higher risk of developing pancreatitis.”

Conclusion

Given the paucity of data to support an association between KBr and pancreatitis, it is important not to withhold this highly effective anti-seizure drug from patients who may benefit from its use nor to discontinue this treatment in patients who are currently receiving it. This is especially true given the use of KBr primarily as an adjunct therapy for refractory patients, as they are unlikely to have many other treatment options available for seizure control.

In the author’s experience, the acute medical management and long-term lifestyle and diet changes that would be recommended for any patient with pancreatitis have been equally effective for patients on KBr without necessitating discontinuation of this therapy.

Psychotropic Medications and the Seizure Patient

Myth

Psychotropic medications cause seizures and, therefore, should not be used in patients with a history of seizures or at risk of seizures.

Background

Psychotropic medications are medications used for the treatment and management of depression and anxiety. In general, these medications work by increasing certain neurotransmitters, including serotonin, norepinephrine, and dopamine. Commonly used psychotropic medications include:

• Selective Serotonin Reuptake Inhibitors (fluoxetine, sertraline)
• Tri-Cyclic Antidepressants (amitriptyline, clomipramine, imipramine)
• Serotonin-Norepinephrine Reuptake Inhibitors (venlafaxine, duloxetine)
• Serotonin Antagonist and Reuptake Inhibitors (trazodone)

Behavioral comorbidities are common in people with epilepsy (PWE). About 1/3 of PWE develop mood or anxiety disorders (MAD), with depression and anxiety being the most common. Cognitive impairment and ADHD are also described. Interestingly, there is a well-documented bidirectional effect between MAD and epilepsy in both adult and pediatric patients. Not only are PWE more likely to develop MAD, but people with MAD are more likely to develop epilepsy. If one condition is poorly controlled, the presence or severity of the other may increase, suggesting a potential common etiology. In addition, anti-seizure drugs can impact behavior with polytherapy linked to more severe MAD.

Behavioral comorbidities are also documented in dogs with epilepsy, with about 2/3 of epileptic dogs showing behavioral changes, including fear, anxiety, cognitive impairment, and ADHD-like behaviors. While medications can impact the severity of behavioral comorbidities, they have been documented in drug naïve epileptic dogs, thus proving a direct connection between the two conditions. In addition, these comorbidities are more severe in refractory epileptics, suggesting a possible similar connection between epilepsy and behavioral disorders as that which is described in people.

The identification and management of behavioral comorbidities in epileptic patients is critical due to the impact on quality of life. In PWE, psychological comorbidities are significantly associated with poorer health-related quality of life. In fact, the negative impact of MAD on health-related quality of life is often found to be greater than the impact of epilepsy-related factors, including seizure frequency and seizure severity. In veterinary medicine, behavioral comorbidities, including reduced trainability, altered reactions to daily situations, and fear-related behavior, have been documented to affect daily life and quality of life for both patients and owners.

Origin of the Myth and Problems with the Data

While both human and veterinary papers report seizures in patients administered various psychotropic medications, many of these in people and all in veterinary medicine are in the setting of misuse, overdose, or toxicity. In addition, clinical trials performed in humans do document increased seizures in people receiving psychotropic medications compared to the general population but fail to show a significant difference compared to people receiving placebos. Therefore, it is likely that the increased seizures noted in this population of patients are more a result of the established connection between MAD and epilepsy rather than an effect of the medications themselves.

New Data

There are numerous studies, systematic reviews, and meta-analyses evaluating the risk of psychotropic medications in seizure patients, the majority of which show no negative effect. In fact, a small number report an improvement in seizure control in patients receiving psychotropic medications.

Although a majority of the commonly used psychotropic medications have been determined to be safe for seizure patients, four medications have been associated with an increased risk of seizures: bupropion, clomipramine, amoxapine, and maprotiline. Only clomipramine is used in veterinary medicine.

Conclusion

In summary, all commonly used psychotropic medications in veterinary medicine, with the exception of clomipramine, are safe to use at therapeutic doses in pets with seizures. In addition, evidence shows that managing primary behavioral disorders or behavioral comorbidities in epileptic patients is important for improvement in the quality of life of both pets and their owners.

References

Ketamine

1. Laws JC, Vance EH, Betters KA, et al. Acute Effects of Ketamine on Intracranial Pressure in Children With Severe Traumatic Brain Injury. Crit Care Med. 2023;51(5):563-572. doi:10.1097/CCM.0000000000005806
2. Kumar A, Kohli A. Comeback of ketamine: resurfacing facts and dispelling myths. Korean J Anesthesiol. 2021;74(2):103-114. doi:10.4097/kja.20663
3. Rueda Carrillo L, Garcia KA, Yalcin N, Shah M. Ketamine and Its Emergence in the Field of Neurology. Cureus. 2022;14(7):e27389. doi:10.7759/cureus.27389
4. Dengler BA, Karam O, Barthol CA, et al. Ketamine Boluses Are Associated with a Reduction in Intracranial Pressure and an Increase in Cerebral Perfusion Pressure: A Retrospective Observational Study of Patients with Severe Traumatic Brain Injury. Crit Care Res Pract. 2022;2022:3834165. doi:10.1155/2022/3834165
5. Godoy DA, Badenes R, Pelosi P, Robba C. Ketamine in acute phase of severe traumatic brain injury “an old drug for new uses?” Crit Care. 2021;25(1):19. doi:10.1186/s13054-020-03452-x
6. Cohen L, Athaide V, Wickham ME, Doyle-Waters MM, Rose NGW, Hohl CM. The Effect of Ketamine on Intracranial and Cerebral Perfusion Pressure and Health Outcomes: A Systematic Review. Annals of Emergency Medicine. 2015;65(1):43-51.e2. doi:10.1016/j.annemergmed.2014.06.018
7. Zeiler FA, Teitelbaum J, West M, Gillman LM. The Ketamine Effect on ICP in Traumatic Brain Injury. Neurocrit Care. 2014;21(1):163-173. doi:10.1007/s12028-013-9950-y
8. Zeiler FA, Teitelbaum J, West M, Gillman LM. The ketamine effect on intracranial pressure in nontraumatic neurological illness. Journal of Critical Care. 2014;29(6):1096-1106. doi:10.1016/j.jcrc.2014.05.024

Acepromazine

1. Tobias KM, Marioni-Henry K, Wagner R. A retrospective study on the use of acepromazine maleate in dogs with seizures. J Am Anim Hosp Assoc. 2006;42(4):283-289. doi:10.5326/0420283
2. McConnell J, Kirby R, Rudloff E. Administration of acepromazine maleate to 31 dogs with a history of seizures. Journal of Veterinary Emergency and Critical Care. 2007;17(3):262-267. doi:10.1111/j.1476-4431.2007.00231.x
3. Drynan EA, Gray P, Raisis AL. Incidence of seizures associated with the use of acepromazine in dogs undergoing myelography. J Vet Emerg Crit Care (San Antonio). 2012;22(2):262-266. doi:10.1111/j.1476-4431.2012.00721.x
4. Redman HC, Wilson GL, Hogan JE. The effect of chlorpromazine combined with intermittent light stimulation on the electroencephalogram and clinical response of the beagle dog. Am J Vet Res 1973;34:929-936.
   

Potassium Bromide:

1. Baird-Heinz HE, Van Schoick AL, Pelsor FR, Ranivand L, Hungerford LL. A systematic review of the safety of potassium bromide in dogs. J Am Vet Med Assoc. 2012;240(6):705-715. doi:10.2460/javma.240.6.705
2. Albarracín V, Teles M, Meléndez-Lazo A, Rodón J, Pastor J. Canine Pancreas-Specific Lipase and C-reactive Protein in Dogs Treated With Anticonvulsants (Phenobarbital and Potassium Bromide). Top Companion Anim Med. 2015;30(2):57-61. doi:10.1053/j.tcam.2015.07.007
3. Gaskill CL, Cribb AE. Pancreatitis associated with potassium bromide/phenobarbital combination therapy in epileptic dogs. Can Vet J. 2000;41(7):555-558.
4. Steiner JM, Xenoulis PG, Anderson JA, Barr AC, Williams DA. Serum pancreatic lipase immunoreactivity concentrations in dogs treated with potassium bromide and/or phenobarbital. Vet Ther. 2008;9(1):37-44.

Psychotropic Medications:

1. Maguire MJ, Marson AG, Nevitt SJ. Antidepressants for people with epilepsy and depression. Cochrane Database Syst Rev. 2021;4(4):CD010682. doi:10.1002/14651858.CD010682.pub3
2. Centre (UK) NG. Evidence Review: Psychological Treatments for People with Epilepsies. National Institute for Health and Care Excellence (NICE); 2022.
3. Neveu J, Villeneuve N, Milh M, Desnous B. Fluoxetine as adjunctive therapy in pediatric patients with refractory epilepsy: A retrospective analysis. Epilepsy Res. 2021;177:106780. doi:10.1016/j.eplepsyres.2021.106780
4. Kanner AM. Most antidepressant drugs are safe for patients with epilepsy at therapeutic doses: A review of the evidence. Epilepsy Behav. 2016;61:282-286. doi:10.1016/j.yebeh.2016.03.022
5. Taylor RS, Sander JW, Taylor RJ, Baker GA. Predictors of health-related quality of life and costs in adults with epilepsy: A systematic review: Quality of Life and Costs in Epilepsy. Epilepsia. 2011;52(12):2168-2180. doi:10.1111/j.1528-1167.2011.03213.x
6. Thomas DE, Lee JA, Hovda LR. Retrospective evaluation of toxicosis from selective serotonin reuptake inhibitor antidepressants: 313 dogs (2005-2010). J Vet Emerg Crit Care (San Antonio). 2012;22(6):674-681. doi:10.1111/j.1476-4431.2012.00805.x
7. Fitzgerald KT, Bronstein AC. Selective serotonin reuptake inhibitor exposure. Top Companion Anim Med. 2013;28(1):13-17. doi:10.1053/j.tcam.2013.03.003
8. Ribot R, Ouyang B, Kanner AM. The impact of antidepressants on seizure frequency and depressive and anxiety disorders of patients with epilepsy: Is it worth investigating? Epilepsy Behav. 2017;70(Pt A):5-9. doi:10.1016/j.yebeh.2017.02.032
9. Johnson EK, Jones JE, Seidenberg M, Hermann BP. The relative impact of anxiety, depression, and clinical seizure features on health-related quality of life in epilepsy. Epilepsia. 2004;45(5):544-550. doi:10.1111/j.0013-9580.2004.47003.x