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Medication: development of tolerance


Medication: development of tolerance

In a few cases, tolerance to stimulants may develop.1
Although this is rather unusual2, it is possible.34
At high doses, tolerance development occurs more frequently at56 and could therefore possibly also be a consequence of an overdose. However, there are known cases in which there was certainly no overdose.

A meta-analysis of 87 randomized placebo-controlled double-blind studies found no evidence of habituation effects with prolonged use of:7

  • Methylphenidate
  • Amphetamine drugs
  • Atomoxetine
  • α2 antagonists (guanfacine, clonidine)
  • Caution: Studies on the development of tolerance to MPH in rats that investigated administration in drug doses (10 mg/kg are not uncommon) or drug administration forms (intravenous, rapid and high dopamine increase)8 are not transferable to the effect of drug administration (oral/patch, slow and low dopamine increase), as this defines the central difference between drugs and medication. In addition, particularly high doses were often given.

After 2 years of taking MPH, people with ADHD showed a significant recurrence of hyperactivity and inattention when discontinuing910

1. Types of tolerance development

Types of tolerance development are:3

  • early development of tolerance
    • rare
  • gradual or “late tolerance” over the years
    • slightly more frequent than early tolerance
  • “complete tolerance” (complete loss of the benefit of the drug)
    • very rare
  • partial tolerance (partial loss of benefit)
    • more often than complete tolerance
    • and possibly a larger percentage who exhibit “partial tolerance” (partial loss of benefit). Strategies to combat stimulant tolerance include: switching stimulant class (e.g., from MPH to AMP and vice versa); taking medication breaks to reset tolerance; using other treatments such as psychotherapy, non-stimulant medications; and clinical reassessment (in light of factors such as medication adherence, comorbid conditions, or the natural history of ADHD over time).
  • Tachyphylaxis
    • rapid development of tolerance to certain drugs
    • In contrast to classical tolerance, the system is initially exhausted in the case of tachyphylaxis and an increase in dose is unsuccessful.11

2. Action strategies for developing tolerance

REVIEW on treatment options for treatment-resistant ADHD: Cortese et al.1

  • Increasing the dose of stimulants
    • short-term interim solution at best
    • what is meant here is not the usual dose adjustment required once or twice within the first year of treatment, but an ongoing loss of efficacy
  • higher dosage increases the risk of habituation56 and therefore possibly the result of an overdose
    • stimulants can always be discontinued without any problems when taken orally / patches are used
  • constantly increasing the dose of stimulants at short intervals is not a solution
    • to be distinguished from one or two dose adjustments in the first year
  • short drug vacations can help sensitive people with ADHD to reduce the development of tolerance
    • Lower dosage at weekends
    • Skip weekends
    • a break of several weeks can then restore the long-term effect
  • Change of active ingredient
    • from MPH to AMP
    • from AMP to MPH
    • If the substitute is less effective, it may help to switch back after about a month. It has been reported that in a number of cases the tolerance disappeared after one month.6
      • 3 interesting individual cases with a treatment pattern of regular changes of the drug class are reported by Handelman et al.3
  • Combination medication
    • reduced stimulant content through combination with non-stimulants can contribute to reduced tolerance build-up
  • Question the reliability of the patient’s medication intake
  • clinical reassessment
    • natural course of ADHD over time?
    • added / removed massive chronic stress?
    • Cessation of intensive sporting activity?
      • can cause significant improvement in ADHD symptoms
    • repeat ADHD diagnosis if necessary
    • comorbid diseases
      • joined?
      • Changes in treatment?
      • Pregnancy?
  • Change of other medication
    • especially in the case of initial and sudden tolerance development
    • Addition of drugs that promote the degradation enzyme?
    • Elimination of drugs that are broken down or inhibited by the same degradation enzyme?
  • Changes in the stomach or urine pH value?
    • Change due to medication
    • Change due to a change in diet

3. Pharmacokinetic tolerance development

A variant of pharmacokinetic tolerance development is an increased synthesis of transporters that remove the substance from the site of action. Examples:12

  • P-glycoprotein (permeability glycoprotein)13
    • Transporter protein in the cell membrane that transports exogenous substances out of the brain cells
    • Member of the ABC transporter family (ATP-binding cassette transporter)
    • is particularly expressed in blood-brain barrier cells
    • affects the permeability of the blood-brain barrier for some drugs
    • causes active re-transport of many relatively large (>400 Da) hydrophobic drugs into the blood
    • P-glycoprotein reduces the effect of these drugs
    • P-glycoprotein is encoded by the MDR1 gene14
      • Gene variants of the MDR-1 gene influence the efficacy of P-glycoprotein
      • If the function or expression of P-glycoprotein is reduced, the blood-brain barrier is weakened and drugs can increasingly enter the brain, which can increase their effect even though the blood plasma level is unchanged.14

More on the effect of medication at Duration of effect of medication for ADHD.

  1. Cortese S, Newcorn JH, Coghill D (2021): A Practical, Evidence-informed Approach to Managing Stimulant-Refractory Attention Deficit Hyperactivity Disorder (ADHD). CNS Drugs. 2021 Oct;35(10):1035-1051. doi: 10.1007/s40263-021-00848-3. PMID: 34403134.

  2. Bespalov A, Müller R, Relo AL, Hudzik T (2016): Drug Tolerance: A Known Unknown in Translational Neuroscience. Trends Pharmacol Sci. 2016 May;37(5):364-378. doi: 10.1016/ PMID: 26935643.

  3. Handelman K, Sumiya F (2022): Tolerance to Stimulant Medication for Attention Deficit Hyperactivity Disorder: Literature Review and Case Report. Brain Sci. 2022 Jul 22;12(8):959. doi: 10.3390/brainsci12080959. PMID: 35892400; PMCID: PMC9332474. REVIEW

  4. Safer DJ, Allen RP (1989): Absence of tolerance to the behavioral effects of methylphenidate in hyperactive and inattentive children. J Pediatr. 1989 Dec;115(6):1003-8. doi: 10.1016/s0022-3476(89)80759-0. PMID: 2585214.

  5. Kupietz SS, Winsberg BG, Richardson E, Maitinsky S, Mendell N (1988): Effects of methylphenidate dosage in hyperactive reading-disabled children: I. Behavior and cognitive performance effects. J Am Acad Child Adolesc Psychiatry. 1988 Jan;27(1):70-7. doi: 10.1097/00004583-198801000-00011. PMID: 3343209.

  6. Ross DC, Fischhoff J, Davenport B (2002): Treatment of ADHD when tolerance to methylphenidate develops. Psychiatr Serv. 2002 Jan;53(1):102. doi: 10.1176/ PMID: 11773663.

  7. Castells, Ramon, Cunill, Olivé, Serrano (2020): Relationship Between Treatment Duration and Efficacy of Pharmacological Treatment for ADHD: A Meta-Analysis and Meta-Regression of 87 Randomized Controlled Clinical Trials. J Atten Disord. 2020 Feb 20:1087054720903372. doi: 10.1177/1087054720903372. PMID: 32075485.

  8. Frolov A, Reyes-Vasquez C, Dafny N (2015): Behavioral and neuronal recording of the nucleus accumbens in adolescent rats following acute and repetitive exposure to methylphenidate. J Neurophysiol. 2015 Jan 1;113(1):369-79. doi: 10.1152/jn.00633.2013. PMID: 25318764; PMCID: PMC4294568.

  9. Matthijssen, Dietrich, Bierens, Kleine Deters, van de Loo-Neus, van den Hoofdakker, Buitelaar, Hoekstra (2019): Effects of Discontinuing Methylphenidate on Strengths and Difficulties, Quality of Life and Parenting Stress. J Child Adolesc Psychopharmacol. 2019 Dec 24. doi: 10.1089/cap.2019.0147.

  10. Matthijssen, Dietrich, Bierens, Kleine Deters, van de Loo-Neus, van den Hoofdakker, Buitelaar, Hoekstra (2019): Continued Benefits of Methylphenidate in ADHD After 2 Years in Clinical Practice: A Randomized Placebo-Controlled Discontinuation Study. Am J Psychiatry. 2019 Sep 1;176(9):754-762. doi: 10.1176/appi.ajp.2019.18111296.

  11. DocCheck Flexikon: Tachyphylaxie abgerufen 25.02.23

  12. Rillich (2019): Das dopaminerge System im Gehirn des Menschen: molekulare Grundlagen, Anatomie, Physiologie und Pathologie

  13. Schinkel AH (1999): P-Glycoprotein, a gatekeeper in the blood-brain barrier. Adv Drug Deliv Rev. 1999 Apr 5;36(2-3):179-194. doi: 10.1016/s0169-409x(98)00085-4. PMID: 10837715.

  14. Schwab, Matthias; Marx, Claudia; Zanger, Ulrich M.; Eichelbaum, Michel; Fischer-Bosch, Margarete (2002): Pharmakogenetik der Zytochrom-P-450-Enzyme: Bedeutung für Wirkungen und Nebenwirkungen von Medikamenten. Dtsch Arztebl 2002; 99(8): A-497 / B-400 / C-377

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