Aparadoxical reaction (orparadoxical effect) is an effect of achemical substance, such as amedical drug, that is opposite to what would usually be expected. An example of a paradoxical reaction ispain caused by apain relief medication.
Amphetamines are a class ofpsychoactive drugs that arestimulants. Paradoxical drowsiness can sometimes occur in adults.[1] Research from the 1980s popularized the belief that ADHD stimulants such as amphetamine have a calming effect in individuals with ADHD, but opposite effects in the general population.[2] Research in the early 2000s, however, disputes this claim, suggesting that ADHD stimulants have similar effects in adults with and without ADHD.[3][4]
The paradoxical effect orEagle effect (named afterHarry Eagle, who first described it) refers to an observation of an increase in survivors, seen when testing the activity of anantimicrobial agent.[5] Initially when anantibiotic agent is added to a culture media, the number ofbacteria that survive drops, as one would expect. But after increasing the concentration beyond a certain point, the number of bacteria that survive, paradoxically, increases.[citation needed]
In a minority of cases,antidepressants can lead to violentthoughts of suicide or self-harm, as observed in some patients during and after treatment, which is in marked contrast to their intended effect.[6] A 1991 study found that children and adolescents were more sensitive to paradoxical reactions of self-harm and suicidal ideation while takingfluoxetine (commonly known as Prozac).[7]
Chlorpromazine, anantipsychotic andantiemetic drug which is classed as a "major"tranquilizer, may cause paradoxical effects such as agitation, hallucinations, excitement, insomnia, bizarre dreams, aggravation of psychotic symptoms and toxic confusional states.[8]
These may be more common in elderly dementia patients. The apparent worsening ofdementia may be due to theanticholinergic side effects of many antipsychotics.[9]
Phenobarbital can cause hyperactivity in children. This may follow after a small dose of 20 mg, on condition of no phenobarbital administered in previous days.[10] Prerequisite for this reaction is a continued sense of tension. The mechanism of action is not known, but it may be started by the anxiolytic action of the phenobarbital.[citation needed]
Barbiturates such aspentobarbital have been shown to cause paradoxical hyperactivity in an estimated 1% of children, who display symptoms similar to the hyperactive-impulsive subtype ofattention deficit hyperactivity disorder. Intravenouscaffeine administration can return these patients' behavior to baseline levels.[11] Some case reports postulate a high rate (10-20%) of paradoxical response to anesthesia in ADHD patients, though this has not been objectively corroborated in controlled studies.[12]
Benzodiazepines, a class of psychoactive drugs called the "minor"tranquilizers, have varyinghypnotic,sedative,anxiolytic,anticonvulsant, andmuscle relaxing properties, but they may create the exact opposite effects. Susceptible individuals may respond to benzodiazepine treatment with an increase inanxiety,aggressiveness,agitation,confusion,disinhibition, loss ofimpulse control,talkativeness,violent behavior, and evenconvulsions. Paradoxical adverse effects may even lead tocriminal behavior.[13] Severe behavioral changes resulting from benzodiazepines have been reported includingmania,hypomania,psychosis, anger and impulsivity.[14]
Paradoxical rage reactions due to benzodiazepines occur as a result of an altered level of consciousness, which generatesautomatic behaviors,anterograde amnesia and uninhibited aggression. These aggressive reactions may be caused by a disinhibitingserotonergic mechanism.[15]
Paradoxical effects of benzodiazepines appear to be dose-related, that is, likelier to occur with higher doses.[16]
In a letter to theBritish Medical Journal, it was reported that a high proportion of parents referred for actual or threatenedchild abuse were taking medication at the time, often a combination ofbenzodiazepines andtricyclic 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.[17]
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.[18]
Benzodiazepines can sometimes cause a paradoxical worsening ofEEG readings in patients with seizure disorders.[19]
Caffeine is believed by many to cause paradoxical calmness or sedation in individuals with ADHD.[20] There is insufficient evidence to determine if sedation caused by caffeine is due to a true paradoxical reaction, or rather from dehydration and sleep deprivation caused by the caffeine.[21] Furthermore, there are no conclusive studies showing a differential effect of caffeine in individuals with ADHD compared to the general population.[citation needed]
Naltrexone blocks the opioid receptors, acting opposite to most opioid pain medications.[22] It can be used to negate the effects of opioid painkillers. At doses around one-tenth of the typical dose, naltrexone has been used for pain relief.Low-dose naltrexone is believed to have an anti-inflammatory effect. This is an off-label use and not widely accepted by the medical and scientific community.[23]
Diphenhydramine (often referred to by the trade nameBenadryl) is ananticholinergicantihistamine medicine commonly used to treat allergic reactions and symptoms of acommon cold, such ascoughing. Its central antihistaminergic properties also cause it to act as asedative, and for this reason it is also used to treatinsomnia.[24] Diphenhydramine is also used off-label for its sedative properties, particularly by parents seeking to make their children sedated or sleep duringlong-haul flights. This use of diphenhydramine has been criticized for a number of reasons, ranging from ethical to safety concerns,[25] but also due to the risk of diphenhydramine's paradoxical reaction, which induces hyperactivity andirritability.[26] This phenomenon can also be observed in adults who use the medication as a sleep aid. The prevalence of this paradoxical reaction is unknown, but research into the phenomenon suggests that it may be as a result of the medicine's interactions with theCYP2D6 enzyme, and that ametabolite of diphenhydramine may be to blame.[27]
The mechanism of a paradoxical reaction has as yet (2019) not been fully clarified, in no small part due to the fact that signal transfer of singleneurons insubcortical areas of the human brain is usually not accessible.[citation needed]
There are, however, multiple indications that paradoxical reactions upon – for example – benzodiazepines, barbiturates,inhalational anesthetics,propofol,neurosteroids, andalcohol are associated with structural deviations ofGABAA receptors. The combination of the five subunits of the receptor (see image) can be altered in such a way that for example, the receptor's response to GABA remains unchanged but the response to one of the named substances is dramatically different from the normal one.[citation needed]