Paradoxical reaction

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A paradoxical reaction (or paradoxical effect) is an effect of a chemical substance, such as a medical drug, that is opposite to what would usually be expected. An example of a paradoxical reaction is pain caused by a pain relief medication.

Contents

Paradoxical reactions may be more common in people with ADHD. [1]

Substances

Amphetamines

Amphetamines are a class of psychoactive drugs that are stimulants. Paradoxical drowsiness can sometimes occur in adults. [2] 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. [3] New research however disputes this claim, suggesting that ADHD stimulants have similar effects in adults with and without ADHD. [4] [5]

Antibiotics

The paradoxical effect or Eagle effect (named after Harry Eagle, who first described it) refers to an observation of an increase in survivors, seen when testing the activity of an antimicrobial agent. [6] 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 a minority of cases, antidepressants can lead to violent thoughts of suicide or self-harm, as observed in some patients during and after treatment, which is in marked contrast to their intended effect. [7] A 1991 study found that children and adolescents were more sensitive to paradoxical reactions of self-harm and suicidal ideation while taking fluoxetine (commonly known as Prozac). [8] 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 their inclinations, the patient may find themself in the situation of being both still dysphoric enough to want to commit suicide but newly free of endogenous barriers against doing so.[ citation needed ]

Antipsychotics

Chlorpromazine, an antipsychotic and antiemetic 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. [9]

These may be more common in elderly dementia patients. Apparent worsening of dementia may be due to the anticholinergic side effects of many antipsychotics. [10]

Barbiturates

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. [11] Prerequisity 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.

Barbiturates such as pentobarbital have been shown to cause paradoxical hyperactivity in an estimated 1% of children, who display symptoms similar to the hyperactive-impulsive subtype of attention deficit hyperactivity disorder. Intravenous caffeine administration can return these patients' behaviour to baseline levels. [12]

Benzodiazepines

Benzodiazepines, a class of psychoactive drugs called the "minor" tranquilizers, have varying hypnotic, sedative, anxiolytic, anticonvulsant, and muscle relaxing properties, but they may create the exact opposite effects. Susceptible individuals may respond to benzodiazepine treatment with an increase in anxiety, aggressiveness, agitation, confusion, disinhibition, loss of impulse control, talkativeness, violent behavior, and even convulsions. Paradoxical adverse effects may even lead to criminal behavior. [13] Severe behavioral changes resulting from benzodiazepines have been reported including mania, schizophrenia, anger, impulsivity, and hypomania. [14]

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. [15]

Paradoxical effects of benzodiazepines appear to be dose related, that is, likelier to occur with higher doses. [16]

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 medication 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. [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 of EEG readings in patients with seizure disorders. [19]

Caffeine

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 different effect of caffeine on individuals with ADHD compared to the general population.

Naltrexone

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

Diphenhydramine (often referred to by the trade name Benadryl) is an anticholinergic antihistamine medicine commonly used to treat allergic reactions and symptoms of a common cold, such as coughing. Its anticholinergic properties also cause it to act as a sedative, and for this reason it is also used to treat insomnia. [24] Diphenhydramine is also used off-label for its sedative properties, particularly by parents seeking to make their children sedated or sleep during long-haul flights. This use of diphenhydramine has been criticised 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 and irritability. [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 the CYP2D6 enzyme, and that a metabolite of diphenhydramine may be to blame. [27]

Causes

GABAA receptor with its five subunits and where various ligands bind. GABAa receptor.gif
GABAA receptor with its five subunits and where various ligands bind.

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 single neurons in subcortical areas of the human brain is usually not accessible.

There are, however, multiple indications that paradoxical reactions upon – for example – benzodiazepines, barbiturates, inhalational anesthetics, propofol, neurosteroids, and alcohol are associated with structural deviations of GABAA 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.

See also

Related Research Articles

<span class="mw-page-title-main">Amphetamine</span> Central nervous system stimulant

Amphetamine is a central nervous system (CNS) stimulant that is used in the treatment of attention deficit hyperactivity disorder (ADHD), narcolepsy, and obesity. Amphetamine was discovered as a chemical in 1887 by Lazăr Edeleanu, and then as a drug in the late 1920s. It exists as two enantiomers: levoamphetamine and dextroamphetamine. Amphetamine properly refers to a specific chemical, the racemic free base, which is equal parts of the two enantiomers in their pure amine forms. The term is frequently used informally to refer to any combination of the enantiomers, or to either of them alone. Historically, it has been used to treat nasal congestion and depression. Amphetamine is also used as an athletic performance enhancer and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant. It is a prescription drug in many countries, and unauthorized possession and distribution of amphetamine are often tightly controlled due to the significant health risks associated with recreational use.

<span class="mw-page-title-main">Attention deficit hyperactivity disorder</span> Neurodevelopmental disorder

Attention deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder characterised by executive dysfunction occasioning symptoms of inattention, hyperactivity, impulsivity and emotional dysregulation that are excessive and pervasive, impairing in multiple contexts, and otherwise age-inappropriate.

<span class="mw-page-title-main">Stimulant</span> Drug that increases activity of central nervous system

Stimulants are a class of drugs that increase the activity of the brain and the spinal cord. They are used for various purposes, such as enhancing alertness, attention, motivation, cognition, mood, and physical performance. Some of the most common stimulants are caffeine, nicotine, amphetamine, methamphetamine, cocaine, and modafinil.

<span class="mw-page-title-main">Methylphenidate</span> Central nervous system stimulant

Methylphenidate, sold under the brand names Ritalin and Concerta among others, is a central nervous system (CNS) stimulant used medically to treat attention deficit hyperactivity disorder (ADHD) and, to a lesser extent, narcolepsy. It is a primary medication for ADHD ; it may be taken by mouth or applied to the skin, and different formulations have varying durations of effect, commonly ranging from 2–4 hours.

<span class="mw-page-title-main">Sedative</span> Drug that reduces excitement without inducing sleep

A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but the majority of them affect the neurotransmitter gamma-aminobutyric acid (GABA). In spite of the fact that each sedative acts in its own way, most produce relaxing effects by increasing GABA activity.

<span class="mw-page-title-main">Dextroamphetamine</span> CNS stimulant and isomer of amphetamine

Dextroamphetamine is a potent central nervous system (CNS) stimulant and enantiomer of amphetamine that is prescribed for the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used as an athletic performance and cognitive enhancer, and recreationally as an aphrodisiac and euphoriant.

Stimulant psychosis is a mental disorder characterized by psychotic symptoms. It involves and typically occurs following an overdose or several day 'binge' on psychostimulants; however, one study reported occurrences at regularly prescribed doses in approximately 0.1% of individuals within the first several weeks after starting amphetamine or methylphenidate therapy. Methamphetamine psychosis, or long-term effects of stimulant use in the brain, depend upon genetics and may persist for some time.

<span class="mw-page-title-main">Adderall</span> Drug mixture used mainly to treat ADHD and narcolepsy

Adderall and Mydayis are trade names for a combination drug called mixed amphetamine salts containing four salts of amphetamine. The mixture is composed of equal parts racemic amphetamine and dextroamphetamine, which produces a (3:1) ratio between dextroamphetamine and levoamphetamine, the two enantiomers of amphetamine. Both enantiomers are stimulants, but differ enough to give Adderall an effects profile distinct from those of racemic amphetamine or dextroamphetamine, which are marketed as Evekeo and Dexedrine/Zenzedi, respectively. Adderall is used in the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy. It is also used illicitly as an athletic performance enhancer, cognitive enhancer, appetite suppressant, and recreationally as a euphoriant. It is a central nervous system (CNS) stimulant of the phenethylamine class.

<span class="mw-page-title-main">Dexmethylphenidate</span> CNS Stimulant

Dexmethylphenidate, sold under the brand name Focalin among others, is a potent central nervous system (CNS) stimulant used to treat attention deficit hyperactivity disorder (ADHD) in those over the age of five years. It is taken by mouth. The immediate release formulation lasts up to five hours while the extended release formulation lasts up to twelve hours. It is the more active enantiomer of methylphenidate.

<span class="mw-page-title-main">Fasciculation</span> Spontaneous, involuntary muscle twitch

A fasciculation, or muscle twitch, is a spontaneous, involuntary muscle contraction and relaxation, involving fine muscle fibers. They are common, with as many as 70% of people experiencing them. They can be benign, or associated with more serious conditions. When no cause or pathology is identified, they are diagnosed as benign fasciculation syndrome.

Cross-tolerance is a phenomenon that occurs when tolerance to the effects of a certain drug produces tolerance to another drug. It often happens between two drugs with similar functions or effects—for example, acting on the same cell receptor or affecting the transmission of certain neurotransmitters. Cross-tolerance has been observed with pharmaceutical drugs such as anti-anxiety agents and illicit substances, and sometimes the two of them together. Often, a person who uses one drug can be tolerant to a drug that has a completely different function. This phenomenon allows one to become tolerant to a drug that they have never used before.

<span class="mw-page-title-main">Polysubstance use</span> Use of multiple psychoactive substances

Polysubstance use or poly drug use refers to the use of combined psychoactive substances. Polysubstance use may be used for entheogenic, recreational, or off-label indications, with both legal and illegal substances. In many cases one drug is used as a base or primary drug, with additional drugs to leaven or compensate for the side effects, or tolerance, of the primary drug and make the experience more enjoyable with drug synergy effects, or to supplement for primary drug when supply is low.

<span class="mw-page-title-main">Attention deficit hyperactivity disorder controversies</span>

Despite the scientifically well-established nature of attention deficit hyperactivity disorder (ADHD), its diagnosis, and its treatment, each of these has been controversial since the 1970s. The controversies involve clinicians, teachers, policymakers, parents, and the media. Positions range from the view that ADHD is within the normal range of behavior to the hypothesis that ADHD is a genetic condition. Other areas of controversy include the use of stimulant medications in children, the method of diagnosis, and the possibility of overdiagnosis. In 2009, the National Institute for Health and Care Excellence, while acknowledging the controversy, stated that the current treatments and methods of diagnosis are based on the dominant view of the academic literature.

A combination drug or a fixed-dose combination (FDC) is a medicine that includes two or more active ingredients combined in a single dosage form. Terms like "combination drug" or "combination drug product" can be common shorthand for an FDC product, although the latter is more precise if in fact referring to a mass-produced product having a predetermined combination of drugs and respective dosages. And it should also be distinguished from the term "combination product" in medical contexts, which without further specification can refer to products that combine different types of medical products—such as device/drug combinations as opposed to drug/drug combinations. When a combination drug product is a "pill", then it may also be a kind of "polypill" or combopill.

<span class="mw-page-title-main">Lisdexamfetamine</span> Central nervous system stimulant prodrug

Lisdexamfetamine, most commonly sold under the brand name Vyvanse and Elvanse among others, is a stimulant medication that is used to treat attention deficit hyperactivity disorder (ADHD) in children and adults, and for moderate-to-severe binge eating disorder in adults. Lisdexamfetamine is taken by mouth. Its effects generally begin within two hours and last for up to 14 hours. In the United Kingdom, it is usually less preferred to methylphenidate for the treatment of children.

Attention deficit hyperactivity disorder management options are evidence-based practices with established treatment efficacy for ADHD.

Substance-induced psychosis is a form of psychosis that is attributed to substance intoxication. It is a psychosis that results from the effects of chemicals or drugs. Various psychoactive substances have been implicated in causing or worsening psychosis in users.

Amphetamine type stimulants (ATS) are a group of synthetic drugs that are chemical derivatives of the parent compound alpha-methylphenethylamine, also known as amphetamine. Common ATS includes amphetamine, methamphetamine, ephedrine, pseudoephedrine, 3,4-methylenedioxymethamphetamine (MDMA), 3,4-methylenedioxyamphetamine (MDA) and 3,4-methylenedioxyethylamphetamine (MDEA). ATS when used illicitly has street names including ice, meth, crystal, crank, bennies, and speed. Within the group of amphetamine-type stimulants, there are also prescription drugs including mixed amphetamine salts, dextroamphetamine, and lisdexamfetamine.

<span class="mw-page-title-main">Prescription drug addiction</span> Medical condition

Prescription drug addiction is the chronic, repeated use of a prescription drug in ways other than prescribed for, including using someone else’s prescription. A prescription drug is a pharmaceutical drug that may not be dispensed without a legal medical prescription. Drugs in this category are supervised due to their potential for misuse and substance use disorder. The classes of medications most commonly abused are opioids, central nervous system (CNS) depressants and central nervous stimulants. In particular, prescription opioid is most commonly abused in the form of prescription analgesics.

References

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  2. ↑ Tecce JJ, Cole JO (August 1974). "Amphetamine effects in man: paradoxical drowsiness and lowered electrical brain acitivity (CNV)". Science. 185 (4149): 451–3. Bibcode:1974Sci...185..451T. doi:10.1126/science.185.4149.451. PMID   4841149. S2CID   26068007.
  3. ↑ Segal, D. S.; Kuczenski, R. (1987-09-01). "Individual differences in responsiveness to single and repeated amphetamine administration: behavioral characteristics and neurochemical correlates". Journal of Pharmacology and Experimental Therapeutics. 242 (3): 917–926. ISSN   0022-3565. PMID   3656119.
  4. ↑ Arnsten, Amy F. T. (November 2006). "Stimulants: Therapeutic Actions in ADHD". Neuropsychopharmacology. 31 (11): 2376–2383. doi: 10.1038/sj.npp.1301164 . ISSN   1740-634X. PMID   16855530. S2CID   36283770.
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  9. ↑ Chlorpromazine - Adverse Effects- Behavioral Reactions [ permanent dead link ]
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  13. ↑ Bramness JG, Skurtveit S, Mørland J (June 2006). "Flunitrazepam: psychomotor impairment, agitation and paradoxical reactions". Forensic Science International. 159 (2–3): 83–91. doi:10.1016/j.forsciint.2005.06.009. PMID   16087304.
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  15. ↑ Senninger JL, Laxenaire M (April 1995). "[Violent paradoxal reactions secondary to the use of benzodiazepines]" [Violent paradoxical reactions secondary to the use of benzodiazepines]. Annales médico-psychologiques (in French). 153 (4): 278–81, discussion 281–2. PMID   7618826.
  16. ↑ Mancuso CE, Tanzi MG, Gabay M (September 2004). "Paradoxical reactions to benzodiazepines: literature review and treatment options". Pharmacotherapy. 24 (9): 1177–85. doi:10.1592/phco.24.13.1177.38089. PMID   15460178. S2CID   38614605. Archived from the original on 2012-12-13. Retrieved 2007-04-18.
  17. ↑ "Letter: Tranquilizers causing aggression". British Medical Journal. 1 (5952): 266. February 1975. doi:10.1136/bmj.1.5952.266. PMC   1672080 . PMID   234269.
  18. ↑ 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. PMID   15316710. S2CID   20629702.
  19. ↑ Perlwitz R, Grimmberger E, Schmidtsdorf R (June 1980). "[Immediate effect of intravenous clonazepam on the EEG]". Psychiatrie, Neurologie, und Medizinische Psychologie. 32 (6): 338–44. PMID   7403357.
  20. ↑ Rainer, Langguth, Berthold Bär, Rüdiger Wodarz, Norbert Wittmann, Markus Laufkötter. Correspondence (letter to the editor): Paradoxical Reaction in ADHD. Deutscher Arzte Verlag. OCLC   809702040.{{cite book}}: CS1 maint: multiple names: authors list (link)
  21. ↑ Yan, Wudan (2021-09-07). "Why Does Coffee Sometimes Make Me Tired?". The New York Times. ISSN   0362-4331 . Retrieved 2023-01-15.
  22. ↑ Wright, Tricia E. (September 2020), "Pharmacotherapy for Opioid Use Disorders in Special Populations", Substance Use Disorders, Oxford University Press, pp. 185–202, doi:10.1093/med/9780190920197.003.0011, ISBN   978-0-19-092019-7 , retrieved 2023-01-15
  23. ↑ Younger, Jarred; Parkitny, Luke; McLain, David (2014-02-15). "The use of low-dose naltrexone (LDN) as a novel anti-inflammatory treatment for chronic pain". Clinical Rheumatology. 33 (4): 451–459. doi:10.1007/s10067-014-2517-2. ISSN   0770-3198. PMC   3962576 . PMID   24526250. S2CID   16191753.
  24. ↑ "Diphenhydramine: drowsy (sedating) antihistamine". nhs.uk. 2018-09-21. Retrieved 2024-01-11.
  25. ↑ "Why It's Time to Rethink Our Use of Benadryl". www.nationwidechildrens.org. Retrieved 2024-01-11.
  26. ↑ Shubailat, Nadine. "Benadryl Baby: Should You Give Allergy Drugs to Calm Kids Before Flying?". ABC News. Retrieved 2024-01-11.
  27. ↑ de Leon, Jose; Nikoloff, D. Michele (February 2008). "Paradoxical excitation on diphenhydramine may be associated with being a CYP2D6 ultrarapid metabolizer: three case reports". CNS Spectrums. 13 (2): 133–135. doi:10.1017/s109285290001628x. ISSN   1092-8529. PMID   18227744. S2CID   10856872.
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