Paradoxical reaction

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

Substances

Amphetamines

Amphetamines are a class of psychoactive drugs that are stimulants. Paradoxical drowsiness can sometimes occur in adults.[1]

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.[2] 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.[3] Children and adolescents are more sensitive to paradoxical reactions of self-harm and suicidal ideation while taking antidepressants but cases are still very rare.[4]

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.[5]

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.[6] 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.

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.[7] Severe behavioral changes resulting from benzodiazepines have been reported including mania, schizophrenia, anger, impulsivity, and hypomania.[8]

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.[9]

Paradoxical effects of benzodiazepines appear to be dose related, that is, likelier to occur with higher doses.[10]

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.[11]

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.[12]

Benzodiazepines can sometimes cause a paradoxical worsening of EEG readings in patients with seizure disorders.[13]

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

The mechanism of a paradoxical reaction could as yet (2019) not be fully clarified in any of the cases. This is due to the condition 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.

There are estimates that about 2-3% of the general population may suffer from serious emotional disorders due to such receptor deviations, with up to 20% suffering from moderate disorders of this kind. It is generally assumed that the receptor alterations are, at least partly, due to genetic and also epigenetic deviations. There are indication that the latter may be triggered by, among other factors, social stress or occupational burnout.[14][15][16][17]

References
  1. 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. PMID 4841149.
  2. Eagle H, Musselman AD (July 1948). "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. 88 (1): 99–131. doi:10.1084/jem.88.1.99. PMC 2135799. PMID 18871882.
  3. 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. PMID 2301661.
  4. 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. PMID 2016219.
  5. Chlorpromazine - Adverse Effects- Behavioral Reactions
  6. http://professionals.epilepsy.com/medications/p_phenobarbital_commonside.html
  7. Bramness JG, Skurtveit S, Mørland J (June 2006). "Flunitrazepam: psychomotor impairment, agitation and paradoxical reactions". Forensic Sci. Int. 159 (2–3): 83–91. doi:10.1016/j.forsciint.2005.06.009. PMID 16087304.
  8. 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. PMID 8262890.
  9. Senninger JL; Laxenaire M. (1995). "[Violent paradoxal reactions secondary to the use of benzodiazepines]". Annales médico-psychologiques. 153 (4): 278–81. PMID 7618826.
  10. 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. PMID 15460178. Archived from the original on 2012-12-13. Retrieved 2007-04-18.
  11. "Letter: Tranquilizers causing aggression". British Medical Journal. 1 (5952): 266. February 1, 1975. doi:10.1136/bmj.1.5952.266. PMC 1672080. PMID 234269.
  12. 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.
  13. 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. PMID 7403357.
  14. Robin C, Trieger N (2002). "Paradoxical reactions to benzodiazepines in intravenous sedation: a report of 2 cases and review of the literature". Anesth Prog. 49 (4): 128–32. PMC 2007411. PMID 12779114.
  15. Paton, Carol (2002). "Benzodiazepines and disinhibition: a review". Psychiatric Bulletin. Royal College of Psychiatrists. 26 (12): 460–462. doi:10.1192/pb.26.12.460. ISSN 0955-6036. PDF.
  16. Bäckström T, Bixo M, Johansson M, Nyberg S, Ossewaarde L, Ragagnin G (2014). "Allopregnanolone and mood disorders". Prog Neurobiol. 113: 88–94. doi:10.1016/j.pneurobio.2013.07.005. PMID 23978486.CS1 maint: multiple names: authors list (link) PDF.
  17. Brown EN, Lydic R, Schiff ND (2010). "General anesthesia, sleep, and coma". N Engl J Med. 363 (27): 2638–50. doi:10.1056/NEJMra0808281. hdl:1721.1/69878. PMC 3162622. PMID 21190458.CS1 maint: multiple names: authors list (link)
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