Paradoxical reaction

Paradoxical reaction is when medical treatment, usually a drug, has an opposite effect to an effect normally expected. An example of a paradoxical reaction is when a pain relief medication causes an increase in pain. Some sedatives prescribed for adults, actually cause hyperactivity in children. For example, paradoxical reaction to benadryl or diphenhydramine, which is used to relieve red, irritated, itchy, watery eyes; sneezing; and runny nose caused by hay fever, allergies, or the common cold. Due to its sedating properties, benadryl (diphenhydramine) is used in some hypnotic preparations. Occasionally, patients respond to benadryl (diphenhydramine) with paradoxical excitation ¹.

• Amphetamines: Amphetamines a class of psychoactive drugs that are stimulants. Paradoxical drowsiness can sometimes occur in adults ².
• Antibiotics: The paradoxical effect or Eagle effect (named after H. Eagle who first described it) refers to an observation of an increase in survivors, seen when testing the activity of an antimicrobial agent ³. Initially when an antibiotic agent is added to a culture media, the number of bacteria that survive drops, as one would expect. But after increasing the concentration beyond a certain point, the number of bacteria that survive, paradoxically, increases.
• Antidepressants: In rare cases antidepressants can make users obsessively violent or have suicidal compulsions, which is in marked contrast to their intended effect. This can be regarded as a paradoxical reaction but, especially in the case of suicide, may in at least some cases be merely due to differing rates of effect with respect to different symptoms of depression: If generalized overinhibition of a patient’s actions enters remission before that patient’s dysphoria does and if the patient was already suicidal but too depressed to act on his/her inclinations, the patient may find him/herself in the situation of being both still dysphoric enough to want to commit suicide but newly free of endogenous barriers against doing so ⁴. Children and adolescents are more sensitive to paradoxical reactions of self-harm and suicidal ideation while taking antidepressants but cases are still very rare ⁵.
• Antipsychotics: Chlorpromazine, an antipsychotic and antiemetic drug, which is classed as a “major” tranquilizer may cause paradoxical effects such as agitation, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms and toxic confusional states.
• Barbiturates: Phenobarbital can cause hyperactivity in children ⁶.

Paradoxical reaction to benzodiazepines

Benzodiazepines a class of psychoactive drugs called the “minor” tranquilizers, frequently are administered to patients to induce sedation. Paradoxical reactions to benzodiazepines, characterized by increased talkativeness, agitation, emotional release, excitement, excessive movement, confusion, disinhibition, aggression, violent behavior, convulsions and loss of impulse control are relatively uncommon and occur in less than 1% of patients ⁷. Paradoxical adverse effects may even lead to criminal behavior ⁸. Severe behavioral changes resulting from benzodiazepines have been reported including mania, schizophrenia, anger, impulsivity, and hypomania ⁹. The exact mechanism of paradoxical reactions remains unclear; however, several predisposing risk factors have been identified. Most cases are idiosyncratic; however, some evidence suggests that these reactions may occur secondary to young and advanced age, a genetic link, history of alcohol abuse or alcoholism and psychiatric and/or personality disorders ⁷. Paradoxical effects of benzodiazepines appear to be dose related, that is, likelier to occur with higher doses ⁷.

Children and elderly patients may be more predisposed than other patients to paradoxical reactions with benzodiazepines. It has been theorized that these subgroups of patients have alterations in the pharmacodynamic response to benzodiazepines; however, the exact differences have not been specifically characterized in the literature ¹⁰. Some patients may have a genetic variability in the benzodiazepine-GABA-chloride receptor that results in an abnormal pharmacodynamic response ¹¹. Multiple allelic forms of genetically determined benzodiazepine receptors exist, resulting in differing affinity for benzodiazepines among patients.

Patients who are alcoholic may be at increased risk of adverse reactions from benzodiazepines due to an alteration of the neuroregulatory mechanisms of the brain ¹². Alcoholics are believed to have decreased synthesis and functioning of GABA, resulting in less inhibitory action of the neurotransmitter. Finally, patients with psychiatric and/or personality disorders have an increased risk of paradoxical reactions to benzodiazepines.[5,6,7] In this group of patients, the highest risk is experienced by those with psychiatric histories of anger and aggressive behavior. The exact mechanism of paradoxical reaction development in these patients is unclear ¹².

The medical literature contains a multitude of reports of paradoxical reactions to benzodiazepines in adults. The first such report, published in 1960, involved a patient receiving chlordiazepoxide ¹³. Since then, several reports have described these reactions in association with more commonly used agents from the benzodiazepine class.

Paradoxical rage reactions due to benzodiazepines occur as a result of an altered level of consciousness, which generates automatic behaviors, anterograde amnesia and uninhibited aggression. These aggressive reactions may be caused by a disinhibiting serotonergic mechanism ¹⁴.

In a letter to the British Medical Journal, it was reported that a high proportion of parents referred for actual or threatened child abuse were taking drugs at the time, often a combination of benzodiazepines and tricyclic antidepressants. Many mothers described that instead of feeling less anxious or depressed, they became more hostile and openly aggressive towards the child as well as to other family members while consuming tranquilizers. The author warned that environmental or social stresses such as difficulty coping with a crying baby combined with the effects of tranquilizers may precipitate a child abuse event ¹⁵.

Self aggression has been reported and also demonstrated in laboratory conditions in a clinical study. Diazepam was found to increase people’s willingness to harm themselves ¹⁶.

Benzodiazepines can sometimes cause a paradoxical worsening of EEG readings in patients with seizure disorders ¹⁷.

Lorazepam

Paradoxical reactions to lorazepam were described in a 22-year-old, healthy woman with a fear of elevators and escalators ¹³. To help overcome this phobia, the patient was prescribed oral lorazepam 3 mg/day for 1 week followed by dosage titrations until the fear was resolved. After receiving the first dose, the woman’s anxiety ceased and she experienced no fear of the elevator. However, hours later, she reported feelings of distress and uncontrollable anger. She was unable to perform her functions at work and responded to a situation with a coworker by yelling and screaming, acts which were out of character. The paradoxical reactions subsided within 24 hours. Subsequently, her fear of elevators was treated successfully with chlordiazepoxide with no adverse effects. This case report illustrates that paradoxical reactions may occur with lorazepam and may be precipitated by a frustrating stimulus, such as the situation with a coworker.

Diazepam

Dose-dependent, paradoxical reactions to diazepam have been reported ¹⁸. A 28-year-old woman with a medical history significant for depression sought medical attention for frequent crying spells, diminished libido, and irritability, which had persisted for several months. She was prescribed an antidepressant and had minimal response. Six weeks after starting therapy, she requested an anxiolytic. Oral diazepam 5 mg was started with directions to take every 6 hours as needed. As the dose of diazepam was titrated over the next month, the patient began to experience sexual and aggressive fantasies. The woman was physically abusive to her daughter, hostile to her therapist, and became self-destructive and reported repeatedly banging her head against the wall. Her behavior improved within 2-3 days of discontinuing diazepam.

Alprazolam

Manic types of symptoms, including increased energy, racing thoughts, and insomnia, were reported in three patients treated with alprazolam ¹⁹. The first patient, a 32-year-old woman, had an 8-year history of depressive bipolar disease, which was well controlled by drugs. She experienced manic types of symptoms after receiving alprazolam 0.5 mg 3 times/day as needed for anxiety. In the second case, a 34-year-old man with a 5-year history of anxiety sought medical attention for increased panic attacks. Alprazolam was started and titrated to 1 mg 3 times/day. The man had no relief of anxiety; however, he experienced irritable behavior and insomnia. The third patient was a 32-year-old woman with a history of panic attacks due to heights and elevators. After taking alprazolam 1 mg/day, she reported feeling agitated, irritable, and restless. In all three cases, alprazolam was discontinued and the paradoxical reactions ceased within 48-72 hours. The authors concluded that alprazolam may induce symptoms resembling mania in patients with no history of affective disorder. They also noted that no specific characteristics define patients at risk for these adverse reactions.

Temazepam

Uncharacteristic agitation and angry behavior were described in four patients treated for insomnia with temazepam ²⁰. The first patient, a 30-year-old woman with a medical history of manic depressive symptoms, became enraged after taking temazepam 30 mg at bedtime for 4 days. The second patient was a 30-year-old man who became agitated with temperamental outbursts after receiving temazepam 30 mg at bedtime for 6 days. The man had broken dishes in the middle of the night but had no recollection of that event. In the third case, a 37-year-old man with a medical history of schizophrenia awoke from sleep with much anger after taking temazepam 30 mg. In the final case, a 39-year-old woman experienced sleeplessness and agitation when taking temazepam. These problems occurred while she received temazepam 15 mg and 30 mg at bedtime. In the first and third patients described above, temazepam was stopped and reinitiated with the same response. In all four patients, once temazepam was discontinued, the anger and agitation ceased.

Triazolam

Six cases of paradoxical reactions to triazolam were reported in patients being treated for chronic insomnia ²⁰. The patients, of whom five were women, ranged in age from 29-75 years and had failed earlier therapies, including treatment with other benzodiazepines. Triazolam was prescribed at dosages ranging from 0.5 mg every other night to 1.5 mg/day at bedtime. Although this treatment effectively controlled the patients’ insomnia, all patients experienced an increased level of anger and agitation. In addition, the man developed visual hallucinations, and one of the women had three incidents of bizarre behavior. Neither of the patients remembered these events. In all six patients, the paradoxical reactions ceased after discontinuing triazolam. Three of the patients were given temazepam after triazolam was stopped, and no adverse effects were reported.

Clonazepam

During the late 1980s, several cases of paradoxical reactions were reported with clonazepam. One report described paradoxical reactions to clonazepam in three acutely psychotic patients ²¹. A 37-year-old man with a 3-year history of poorly controlled bipolar affective disorder was readmitted to the hospital for increasing manic symptoms. Clonazepam was administered to control his anxiety, and the dosage was increased gradually from 1 mg/day to 12 mg/day. After receiving the drug for a few days, the patient became verbally and physically violent and attacked a fellow patient. Clonazepam was gradually tapered off, and the patient displayed the same manic behaviors he had shown on admission to the hospital.

In the second case, a 25-year-old man with a 1-year history of bipolar affective disorder was hospitalized due to two episodes of acute manic behavior and delusional thoughts. He began treatment with clonazepam, which was titrated to 4.5 mg/day over 3 days. During the dosage titration, the man became increasingly hyperactive and hyperverbal, making verbal threats to staff and fellow inpatients. Clonazepam was tapered and discontinued over the next 48 hours, and the manic symptoms ceased.

The third case concerned a 19-year-old man with borderline personality disorder, seizure disorder, and admitted use of alcohol and intravenous drugs. He was hospitalized for self-destructive behavior, as well as reported delusions and auditory hallucinations. After admission, the patient received a total of clonazepam 4 mg, and his behavior became more agitated and bizarre, requiring physical restraint. Clonazepam was discontinued, and the remaining hospital course was free of severely agitated episodes.

These case reports demonstrate that paradoxical reactions involving manic types of behavior may occur in patients who are not schizophrenic and may worsen with dose escalations.

Another account describes a 37-year-old man with a medical history significant for psychiatric manic episodes who was hospitalized for a 3-year history of recurrent panic attacks, which had been treated with alprazolam ²². After admission, alprazolam was stopped and clonazepam was started. During the first 3 days of therapy, the patient displayed manic behaviors consisting of hyperactivity, racing thoughts, and insomnia. The clinical picture worsened when the clonazepam dosage was increased to 8 mg/day; therefore, the drug was discontinued. The patient’s manic behaviors ceased, and he was treated successfully with clonazepam 2 mg/day as an outpatient. This case report demonstrates that paradoxical reactions may be a dose-related phenomenon.

Midazolam

Reports of paradoxical reactions to midazolam are a recent development in the medical literature. Midazolam, which has sedative effects, is commonly prescribed before short surgical procedures.

While participating in a study to evaluate benzodiazepine potency, 28-year-old healthy, identical twin men experienced similar paradoxical reactions ¹¹. On three separate occasions, the men received various dosages of midazolam and diazepam. After receiving intravenous midazolam 5 mg, one of the twins became sedated with restlessness and heightened motor responses of his extremities. An additional dose of midazolam 5 mg heightened these responses. On the second occasion, one of the men became unconscious after receiving intravenous midazolam 12 mg. When he awoke, he was extremely restless and agitated. Administration of intravenous diazepam 10 mg resulted in similar but less intensive sedation and motor responses. The second twin displayed the same responses. Neither man had any recollection of the events. The authors stated that the intensity of the behaviors was so strong that if this had been an actual procedure and not an experiment, the procedure would have had to be discontinued. These cases demonstrate that paradoxical reactions to benzodiazepines may be genetically linked.

Another case report describes aggressive behaviors in a patient with anger management difficulties ²³. A 31-year-old man was hospitalized for an endogastric-duodenoscopy to evaluate recent complaints of epigastric pain with fever. Before the procedure, the man received midazolam 5 mg intravenously. Soon thereafter, he became verbally and physically threatening to an extent that necessitated restraint. The behaviors ceased after he received an intramuscular injection of sodium amobarbital 200 mg. The authors did not mention if the procedure was reattempted at a later time.

Paradoxical reactions to midazolam occurred during surgical removal of impacted molars in a 22-year-old woman with a history of anger management problems and alcohol abuse sufficient to require rehabilitation ¹². The patient was enrolled in a multicenter clinical trial to evaluate the safety and efficacy of intravenous sedatives. The study protocol randomly assigned participants to one of five groups to receive various combinations of midazolam, fentanyl, and methohexital. The dosage of midazolam was titrated to slurred speech and ptosis, with a maximum dose not to exceed 25 mg. After receiving midazolam 18 mg over 18 minutes, the woman became belligerent and verbally abusive, with disruptive movement of her extremities. The dental procedure was terminated due to these extreme behaviors, which continued for the next 24 hours. Afterward, the woman had no recollection of the events. Based on this case, the authors suggested that a history of alcohol abuse may predispose patients to paradoxical reactions with benzodiazepines.

Other authors described a case of agitation secondary to midazolam successfully managed with haloperidol ²⁴. A 50-year-old man with a medical history of hypercholesterolemia was hospitalized for coronary artery bypass grafting (CABG) surgery after presenting with chest pain consistent with myocardial infarction and 90% occlusion of the coronary artery. The patient received intravenous midazolam before placement of the arterial catheter. After a total dose of 6 mg was administered, the man developed worsening anxiety and agitation. The physician chose to treat the paradoxical reaction with haloperidol 10 mg delivered intravenously over 2 minutes. The patient calmed, the CABG procedure was completed, and amnesia was retained. The authors concluded that haloperidol may be a safe and effective agent for treating paradoxical reactions of benzodiazepines.

Several reports indicate that the benzodiazepine antagonist flumazenil may be useful in the treatment of paradoxical reactions to midazolam. Flumazenil should be considered if these types of reactions are suspected.

A 49-year-old healthy woman experienced a paradoxical reaction while under conscious sedation during insertion of breast implants ²⁵. Midazolam was started before the procedure and administered throughout the procedure, in varying doses as needed, until adequate sedation was attained. Vital signs were monitored and remained within normal limits during the surgery. In general, every time the woman moved during the procedure, additional midazolam was delivered. This pattern was repeated several times, and she received a total dose of midazolam 12 mg intravenously over 70 minutes. Fluma-zenil 0.5 mg was administered intravenously when her movements became very aggressive and required force to control. Her aggressiveness ceased after receiving flumazenil; however, she remained sedated and amnesia was retained.

In another report, a 71-year-old man with a 1-year history of episodes of increased anger, jealousy, and paranoid ideation, experienced paradoxical reactions to midazolam before an endoscopy ²⁶. One month earlier, the patient had undergone an uneventful endoscopy procedure. On this occasion, after receiving midazolam 4 mg intravenously over 14 minutes, he became sedated and delirious, requiring restraint for increased movement of his extremities. The behaviors were reversed after administration of intravenous flumazenil 0.2 mg. The man did not remember the events. This case illustrates that elderly patients, as well as those with psychiatric disturbances, may be at increased risk for paradoxical reactions to benzodiazepines.

One case report indicated that patients without psychiatric disorders also may experience paradoxical reactions with benzodiazepines ²⁷. A 27-year-old man received a total dose of midazolam 7 mg intravenously before cystoscopy and laser ablation of a meatal condyloma. The surgery was completed despite his agitated and restless behavior. Vital signs remained within normal limits and the patient denied pain. Postoperatively, he received lorazepam 4 mg intravenously with no change in behavior. The agitation ceased after administration of flumazenil 0.3 mg (total dose), and amnesia was retained.

Flumazenil effectively reversed paradoxical reactions of midazolam in three patients undergoing endoscopy procedures ²⁸. The first patient, a 62-year old man with a long history of alcohol abuse, experienced movement of the extremities with head shaking after receiving midazolam 5 mg intravenously. The second patient, a 58-year-old woman, also with a history of alcohol abuse, became restless and agitated after receiving midazolam 7.5 mg intravenously. The last patient, a healthy 26-year-old man, had violent movements after receiving midazolam 10 mg intravenously. In all three patients, the paradoxical reactions were reversed by intravenous flumazenil 0.5 mg. Sedation was maintained, the procedures were completed, and no patient had any recollection of the unusual behaviors.

A case series of patients who underwent minor to medium lower body surgical procedures addressed the development of paradoxical reactions to midazolam ¹⁰. All patients were given spinal or epidural anesthesia and incremental injections of midazolam 1.5 mg intravenously to induce sedation. Six of 58 patients experienced paradoxical reactions to midazolam. The authors compared these patients with six matched control subjects who received midazolam uneventfully. The paradoxical reactions were characterized as flailing of the arms, writhing on the examination table, and attempting to speak during the surgical procedures. All six patients were delirious and needed to be physically restrained due to their aggressive behavior. The mean ± SD total dose of midazolam was 7.3 ± 2.8 mg, which was similar in the six matched controls (8.8 ± 3.2 mg). Flumazenil was administered in all six patients, with total doses ranging from 0.3-0.5 mg. The paradoxical reactions ceased after administration of flumazenil, and all patients completed the surgical procedure and were discharged successfully.

The most recent report described two cases of paradoxical reactions in patients given midazolam for dental procedures ²⁹. An anxious 19-year-old woman requested sedation before molar extraction. After receiving midazolam 5 mg intravenously over 7 minutes, she became uncooperative and began crying, yet denied pain. A 21-year-old woman displayed a similar response after receiving midazolam 7 mg intravenously over 10 minutes. In both cases, the women calmed and ceased crying after receiving flumazenil 0.2-0.4 mg intravenously. Neither patient had any memory of the events.

Paradoxical reactions to benzodiazepines in children have been described in both case reports and in clinical trials involving midazolam ³⁰.

A randomized, double-blind, placebo-controlled study assessed the efficacy of rectal midazolam for sedation in children undergoing dental surgery ³¹. Participants were 80 healthy children, aged 2-7 years. Exclusion criteria were past hypersensitivity to benzodiazepines, current treatment with psychotropic agents, and diagnosis of myasthenia gravis. Each child was assigned to one of four treatment groups: placebo or rectal midazolam 0.25 mg/kg, 0.35 mg/kg, or 0.45 mg/kg. The drug was administered 30 minutes before the procedure. Vital signs, hemodynamic parameters, sedation, and pain levels were assessed at various intervals during surgery. Adverse effects were observed in 14 children in the groups receiving the highest doses of midazolam: 0.35 mg/kg and 0.45 mg/kg. Of these reactions, agitation, restlessness, and excitement were the most common. This study illustrates that paradoxical reactions to benzodiazepines in children may be dose related.

A case report described unusual behavior in a healthy 26-month-old girl who was brought to the emergency department after suffering a facial dog bite ³². Before suture placement, the girl was playful yet anxious. Therefore, oral midazolam 0.5 mg/kg was administered and the sutures were placed uneventfully. During the procedure, vital signs were monitored and remained within normal limits. After discharge to home, the child became agitated and upset. Her parents brought her back to the emergency department to be reevaluated. Mental evaluation showed no evidence of head trauma, but the child remained in the fetal position, crying and screaming. She calmed and ceased crying after receiving morphine sulfate 0.1 mg/kg intravenously; after leaving the hospital she was playful and interactive. The authors of the report eliminated other possible causes of delirium in this patient, such as administration of other drugs or the possibility of an illicit drug ingestion.

In another case report, flumazenil was effective in reversing a paradoxical reaction in a normally quiet 11-year-old boy with nephrotic syndrome ³⁰. After ingesting oral midazolam 17.5 mg, the child experienced an abrupt change in behavior. During this episode, the boy became uncontrollable and confused and started screaming and kicking. The behaviors ceased after he received flumazenil 0.15 mg intravenously; the boy had no recollection of his adverse reaction. This case suggests that flumazenil may be an effective option for treating paradoxical reactions to benzodiazepines in children.

The frequency of paradoxical reactions to benzodiazepines in children requiring emergent endoscopy was prospectively evaluated in a 48-month study ³³. Of the 2617 children aged 1-17 years who received midazolam and meperidine before undergoing endoscopy, 36 children (1.4%) experienced paradoxical reactions, including tachycardia, inconsolable crying, restlessness with agitation, dysphoria, and disorientation. The total doses of meperidine and midazolam were 1-2 mg/kg and 0.1-0.5 mg/kg, respectively, and the mean time to onset of adverse effect was 17 minutes after administration of the sedatives. Reversal of the behaviors was successful with intravenous physostigmine (dose not reported, six patients) and intravenous flumazenil 0.01 mg/kg (30 patients). The onset and duration of these reactions and time to recovery did not correlate with patients’ age. Of note, three of the 36 patients received meperidine alone for additional endoscopy procedures; there were no behavioral changes or adverse effects reported. Limitations of this study include its nonrandomized design as well as the use of both agents for sedation. However, based on previous reports, the authors concluded that midazolam is the more likely cause of the paradoxical reactions.

A research group described their experiences with midazolam for conscious sedation in 222 children aged 2.5-18 years undergoing endoscopic procedures ³⁴. Twenty-five of the children experienced a paradoxical reaction after receiving meperidine 1-2 mg/kg and midazolam 0.1-0.3 mg/kg. The reactions were classified as agitation, refusing intubation, head shaking, restlessness, and tachycardia. In 23 instances the procedures were continued despite these behaviors. In two cases, the procedures were stopped but resumed after administration of flumazenil 0.01 mg/kg intravenously.

Paradoxical reaction to benzodiazepines treatment options

Treatment of paradoxical reactions secondary to benzodiazepines is supportive, with airway and blood pressure management. In addition, a limited number of case studies report the use of physostigmine, flumazenil, and haloperidol ⁷.

Physostigmine was the first agent used to manage paradoxical reactions to benzodiazepines ³⁵. Physostigmine is an acetylcholinesterase inhibitor that readily crosses the blood-brain barrier and is associated with various adverse effects, including nausea, vomiting, epigastric pain, miosis, bradycardia, salivation, and dyspnea. Once in the central nervous system, the drug increases cholinergic stimulation and may reverse drug-induced central nervous system depression. It is thought that its role in benzodiazepine reversal is due to a nonspecific analeptic effect. Reversal of paradoxical reactions has not been consistent; therefore, physostigmine is generally not recommended in the management of paradoxical reactions to benzodiazepines ²⁶.

Flumazenil is an imidazobenzodiazepine compound used clinically as a benzodiazepine antagonist ³⁶. It is an intravenous agent that competitively antagonizes GABA-benzodiazepine receptors in the central nervous system. The drug displays dose-independent pharmacokinetics. It distributes rapidly into the body with a quick onset of action of 1-2 minutes and has an elimination half-life of 0.7-1.3 hours. Flumazenil has a large volume of distribution (0.95 L/kg) and is only 50% bound to plasma proteins. The drug is completely metabolized through hepatic pathways.

Flumazenil is indicated for reversal of benzodiazepine sedation. Clinically, it has been given before administration of benzodiazepines to modify their effects. Administration of flumazenil in adults is accomplished by intravenous titration with a bolus of 0.5 mg followed by 0.1 mg until a desired response is achieved. Doses of 0.3-0.5 mg have been used successfully in the reversal of paradoxical reactions while maintaining sedation and retaining amnesia. Sedative reversal in pediatric patients at least 1 year old may be achieved with a starting dose of flumazenil 0.01 mg/kg (up to 0.2 mg) intravenously over 15 seconds ³⁷. Additional doses of 0.01 mg/kg (up to 0.2 mg) may be repeated to achieve the desired level of consciousness. The maximum recommended dose of flumazenil in children is 0.05 mg/kg or 1.0 mg, whichever is lower. For most pediatric cases, successful management of paradoxical reactions with flumazenil has been attained with doses of 0.01 mg/kg ³⁴.

Haloperidol may be a safe alternative to flumazenil for treating paradoxical reactions to benzodiazepines ²⁴. The drug is a butyrophenone-derivative antipsychotic agent clinically used in the treatment of psychiatric disorders, Tourette’s syndrome, delirium, and in children with attention-deficit-hyperactivity disorder ³⁸. Haloperidol is metabolized in the liver, is 92% bound to plasma proteins, and has a half-life of 20 hours. Although the exact mechanism is unknown, it is thought that haloperidol’s action on dopaminergic receptors in the central nervous system results in a calming effect ²⁴. Haloperidol may be beneficial in patients with severe coronary artery disease because it avoids the adverse effects of increased left ventricular end diastolic pressure, hypertension, and tachycardia, all of which are sometimes seen with flumazenil and may lead to myocardial infarction in patients with coronary artery disease. The most trouble-some adverse effects associated with haloperidol are extrapyramidal reactions. A total dose of haloperidol 10 mg intravenously, delivered in two divided doses, has been used to treat benzo-diazepine-induced paradoxical reactions in adults.

References

1. Paradoxical excitation on diphenhydramine may be associated with being a CYP2D6 ultrarapid metabolizer: three case reports. CNS Spectr. 2008 Feb;13(2):133-5. https://doi.org/10.1017/S109285290001628X
2. Tecce JJ, Cole JO (1974). “Amphetamine Effects in Man: Paradoxical Drowsiness and Lowered Electrical Brain Activity (CNV)”. Science Magazine. 185 (4149): 451–453. doi:10.1126/science.185.4149.451
3. EAGLE H, MUSSELMAN AD. The rate of bactericidal action of penicillin in vitro as a function of its concentration, and its paradoxically reduced activity at high concentrations against certain organisms. J Exp Med. 1948;88(1):99–131. doi:10.1084/jem.88.1.99 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2135799/pdf/99.pdf
4. Teicher MH, Glod C, Cole JO (February 1990). “Emergence of intense suicidal preoccupation during fluoxetine treatment”. Am J Psychiatry. 147 (2): 207–10. doi:10.1176/ajp.147.2.207
5. King RA, Riddle MA, Chappell PB, et al. (March 1991). “Emergence of self-destructive phenomena in children and adolescents during fluoxetine treatment”. J Am Acad Child Adolesc Psychiatry. 30 (2): 179–86. doi:10.1097/00004583-199103000-00003
6. Phenobarbital. https://www.epilepsy.com/medications/phenobarbital
7. Mancuso, Carissa E.; Tanzi, Maria G.; Gabay, Michael (September 2004). “Paradoxical Reactions to Benzodiazepines: Literature Review and Treatment Options”. Pharmacotherapy. 24 (9): 1177–1185. doi:10.1592/phco.24.13.1177.38089 https://doi.org/10.1592/phco.24.13.1177.38089
8. Flunitrazepam: Psychomotor impairment, agitation and paradoxical reactions. Forensic Sci. Int. 159 (2–3): 83–91. doi:10.1016/j.forsciint.2005.06.009 https://doi.org/10.1016/j.forsciint.2005.06.009
9. Cole JO; Kando JC. (1993). “Adverse behavioral events reported in patients taking alprazolam and other benzodiazepines”. The Journal of Clinical Psychiatry. 54 (Suppl:49–61): 62–3.
10. Weinbroum AA, Szold O, Ogorek D, Flasishon R. The midazolam-induced paradox phenomenon is reversible by flumazenil: epidemiology, patient characteristics and review of the literature. Eur J Anaesthesiol 2001;18:789-97.
11. Short TG, Forrest P, Galletly DC. Paradoxical reactions to benzodiazepines: a genetically determined phenomenon? Anaesth Intens Care 1987;15:330-45.
12. Fiset L, Milgrom P, Beirne R, Roy-Byrne P. Disinhibition of behaviors with midazolam: report of a case. J Oral Maxillofac Surg 1992;50:645-9.
13. Goldney RD. Paradoxical reaction to a new minor tranquilizer. Med J Aust 1977;1:139-40.
14. Senninger JL; Laxenaire M. (1995). “[Violent paradoxal reactions secondary to the use of benzodiazepines]”. Annales médico-psychologiques. 153 (4): 278–81. https://www.ncbi.nlm.nih.gov/pubmed/7618826
15. Letter: Tranquilizers causing aggression. Br Med J. 1975;1(5952):266. doi:10.1136/bmj.1.5952.266 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1672080/pdf/brmedj01431-0052a.pdf
16. Berman ME, Jones GD, McCloskey MS (February 2005). “The effects of diazepam on human self-aggressive behavior”. Psychopharmacology. 178 (1): 100–6. doi:10.1007/s00213-004-1966-8
17. Perlwitz R; Grimmberger E; Schmidtsdorf R (June 1980). “[Immediate effect of intravenous clonazepam on the EEG]”. Psychiatr Neurol Med Psychol (Leipz). 32 (6): 338–44. https://www.ncbi.nlm.nih.gov/pubmed/7403357
18. Gardos G. Disinhibition of behavior by antianxiety drugs. Psychosomatics 1980;21:1025-6.
19. Strahan A, Rosenthal J, Kaswan M, Winston A. Three case reports of acute paroxysmal excitement associated with alprazolam treatment. Am J Psychiatry 1985;142:859-61.
20. Regestein QR, Reich P. Agitation observed during treatment with newer hypnotic drugs. J Clin Psychiatry 1985;46:280-3.
21. Binder RL. Three case reports of behavioral disinhibition with clonazepam. Gen Hosp Psychiatry 1987;9:151-3.
22. Marchevsky S, Isaacs G, Nitzan I. Behavioral disinhibition with clonazepam [letter]. Gen Hosp Psychiatry 1988;10:447.
23. Miwa LJ, Lobo BL. Midazolam disinhibition reaction [letter]. Drug Intell Clin Pharm 1988;22:725.
24. Khan LC, Lustik SJ. Treatment of a paradoxical reaction to midazolam with haloperidol. Anesth Analg 1997;85:213-15.
25. Rodrigo CR. Flumazenil reverses paradoxical reaction with midazolam. Anesth Prog 1991;38:65-8.
26. Honan VJ. Paradoxical reaction to midazolam and control with flumazenil. Gastrointest Endosc 1994;40:86-8.
27. Thurston TA, Williams CGA, Foshee S. Reversal of a paradoxical reaction to midazolam with flumazenil. Anesth Analg 1996;83:192.
28. Fulton SA, Mullen KD. Completion of upper endoscopic procedures despite paradoxical reaction to midazolam: a role for flumazenil? Am J Gastroenterol 2000;95:809-11.
29. Robin C, Trieger N. Paradoxical reactions to benzodiazepines in intravenous sedation: a report of 2 cases and review of the literature. Anesth Prog 2002;49:128-32.
30. Thakker P, Gallagher TM. Flumazenil reverses paradoxical reaction to midazolam in a child. Anaesth Intens Care 1996;24:505-7.
31. Roelofse JA, Stegmann DH, Hartshorne J, Joubert JJ. Paradoxical reactions to rectal midazolam as premedication in children. Int J Oral Maxillofac Surg 1990;19:2-6.
32. Doyle WL, Perrin L. Emergence delirium in a child given oral midazolam for conscious sedation. Ann Emerg Med 1994;24:1173-5.
33. Massanari M, Novitsky J, Reinstein LJ. Paradoxical reactions in children associated with midazolam use during endoscopy. Clin Pediatr 1997;36:681-4.
34. Saltik IN, Ozen H. Role of flumazenil for paradoxical reaction to midazolam during endoscopic procedures in children. Am J Gastroenterol 2000;95:3011-12.
35. Caldwell CB, Gross JB. Physostigmine reversal of midazolam-induced sedation. Anesthesiology 1982;57:125-7.
36. Whitwam JG, Amrein R. Pharmacology of flumazenil. Acta Anaesthesiol Scand 1995;39(suppl 108):3-14.
37. Roche Pharmaceuticals. Romazicon (flumazenil) injection package insert. Nutley, NJ; 2000.
38. McEvoy GK, ed. AHFS drug information 2003. Bethesda, MD: American Society of Health-System Pharmacists, 2003.