Nocebo, ADHD and Cochrane

For the past few years now, I’ve been following the debate on the quality of the studies of ADHD medication, and it strikes me that there seems to be an anti-ADHD medications agenda being pushed by The Cochrane Institute and in particular Ole Jakob Storebø, Ph.D.. We ask them, why?

Nocebo

: a harmless substance or treatment that when taken by or administered to a patient is associated with harmful side effects or worsening of symptoms due to negative expectations or the psychological condition of the patient

Merriam-Webster.com, Merriam-Webster

Introduction

The ever-raging battle for dominance over the truth is not only a concern of people who are into topics such as ‘Deep-State’, ‘Big Pharma’ and ‘Anti-Vaccine”. In regard to ADHD medication and the evidence-based guidelines and recommendations, one can only stand back and watch the scientists argue over what is right and what’s not. Since I don’t really appreciate not knowing what is actually the consensus or truth if you will, about the medication that I myself and my entire family takes everyday to cope with our ADHD/Autism symptoms, I’ve decided to look into this mess.

The Battleground

I’ve found numerous references to this ‘Nocebo‘ concept in publications from Cochrane Institute’s Ole Jakob Storebø et al. over the past 3-4 years, and I felt a need to understand what the criticism from Cochrane Institute is all about, since they have aggressively marketed their opinions in both journals, news media and in their press releases.

So I went hunting for quotes from their literature:

[…]We must advance our clinical research base through well-powered, methodologically rigorous, and honestly reported randomized clinical trials, with an equal focus on benefit and harms, secure blinding (e.g., use of a “nocebo” placebo to control for the adverse events in methylphenidate, if such a substance can be produced)[…]

Storebø, O. J., Faltinsen, E., Zwi, M., Simonsen, E., & Gluud, C. (2018). The Jury Is Still Out on the Benefits and Harms of Methylphenidate for Children and Adolescents With Attention-Deficit/Hyperactivity Disorder. Clinical Pharmacology & Therapeutics. doi:10.1002/cpt.1149

[…]Although we appreciate the work by Cortese and colleagues, we hope that future reviews will address the outlined issues and move from group-level data to individual participant data to explore patient-related variables further. We strongly encourage longer-lasting and rigorously designed randomised clinical trials on medications for patients with ADHD (incorporating active placebos with so-called nocebo components), to improve the current evidence base.[…]

Faltinsen, E. G., Gluud, C., Simonsen, E., Zwi, M., & Storebø, O. J. (2018). Unbalanced risk-benefit analysis of ADHD drugs. The Lancet Psychiatry, 5(11), 870. doi:10.1016/s2215-0366(18)30334-1

[…]Padilha and colleagues presented novel data on head-to-head drug comparisons for attention deficit hyperactivity disorder in their network, and we thank them for this. However, with the low quality reported in previous Cochrane reviews, it is difficult to properly interpret the evidence put forward, let alone exert confidence in the head-to-head comparisons. High-quality randomised clinical trials in this field seem to be sorely lacking.[…]

Faltinsen, E. G., Storebø, O. J., & Gluud, C. (2018). Methodological concerns with network meta-analysis on drugs for attention deficit hyperactivity disorder. European Child & Adolescent Psychiatry. doi:10.1007/s00787-018-1164-6

[…] Risk of bias in the included comparative studies ranged from moderate to critical, with most studies showing critical risk of bias. We evaluated all non-comparative studies at critical risk of bias. The GRADE quality rating of the evidence was very low.[…]

Storebø, O. J., Pedersen, N., Ramstad, E., Kielsholm, M. L., Nielsen, S. S., Krogh, H. B., … Gluud, C. (2018). Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents – assessment of adverse events in non-randomised studies. Cochrane Database of Systematic Reviews. doi:10.1002/14651858.cd012069.pub2.

[…]On the issue of nocebo, we acknowledge that there are substantial ethical dilemmas around their use. Several authors have underlined the importance of the use of ‘active placebo’ (nocebo) in clinical trials. This is a methodological issue and we would like to stress that nocebos would need to first be shown to be safe in adults, and methylphenidate versus nocebo trials also shown to favour methylphenidate in adults. Only then would nocebo controlled trials be ethically defensible in children.[…]

Storebø, O. J., Zwi, M., Krogh, H. B., Moreira-Maia, C. R., Holmskov, M., Gillies, D., … Gluud, C. (2016). Evidence on methylphenidate in children and adolescents with ADHD is in fact of “very low quality.” Evidence Based Mental Health, 19(4), 100–102. doi:10.1136/eb-2016-102499

Nocebo

Nocebo … find a healthy child, pop a nocebo pill in them and wait for them to present some ‘ADHD-like’ symptoms. Then you give them some ADHD medication and measure how well it treats their symptoms … Afterwards you compare that result to the result you get from testing children with ADHD and their effect of the same medication. Lastly, you compare this to a control group of normal kids without ADHD and figure out what the differences are …

Hmm … I don’t know about you but I find it pretty Dr. Josef Mengele-like to give healthy children a pill that makes them have symptoms of a severe mental disorder like ADHD, just to be able to hold the bragging right and taunt the opposing side? but hey, that just me …

Oh no, wait a minute … isn’t there something called Universal Declaration of Human Rights? and doesn’t that state that; All human beings are born free and equal in dignity and rights and No one shall be subjected to torture or to cruel, inhuman or degrading treatment or punishment

Or as Prof. Dr. Dr. Tobias Banaschewski (not a type-O, he actually have two separate doctorates) have stated it, in a reply to Storebø et al.

[…] In addition, Storebø and colleagues proposed implementing long-term nocebo-controlled studies. Nocebos are substances with no known benefit but similar adverse events as the active comparator. In our opinion, this is unethical and conflicts with §33 of the Declaration of Helsinki.[…] (Banaschewski et al., 2018)

Storebø, O. J., Simonsen, E., & Gluud, C. (2016). Methylphenidate for Attention-Deficit/Hyperactivity Disorder—Reply. JAMA, 316(9), 995. doi:10.1001/jama.2016.10300

[…]We also disagree on whether nocebos should be used in future trials. On the contrary, continuing to use drugs that are not sufficiently evidence-based may be unethical. We also suggested nocebo trials be performed in adults before considering conducting them in children.[…] (Storebø et al., 2018)

Storebø, O. J., Simonsen, E., & Gluud, C. (2016). Methylphenidate for Attention-Deficit/Hyperactivity Disorder—Reply. JAMA, 316(9), 995. doi:10.1001/jama.2016.10300

Then they target NICE 2018

The National Institute for Care and Excellence (UK) are renowned for their thorough work on creating comprehensive guidelines on ADHD. They have done so for many years now, and in March 2018, the latest edition (NG87) was published.

It updated the recommendations for medicinal treatment of ADHD to adhere to the latest consensus from scientific evidence in ADHD research. It states the following:

Medication choice – children aged 5 years and over and young people

Recommendations 1.7.7 to 1.7.10 update NICE’s technology appraisal guidance on methylphenidate, atomoxetine and dexamfetamine for ADHD in children and adolescents (TA98).

1.7.7 Offer methylphenidate (either short or long acting) as the first line pharmacological treatment for children aged 5 years[4] and over and young people with ADHD. [2018]

1.7.8 Consider switching to lisdexamfetamine for children aged 5 years[5] and over and young people who have had a 6‑week trial of methylphenidate at an adequate dose and not derived enough benefit in terms of reduced ADHD symptoms and associated impairment. [2018]

1.7.9 Consider dexamfetamine[6] for children aged 5 years and over and young people whose ADHD symptoms are responding to lisdexamfetamine but who cannot tolerate the longer effect profile. [2018]

1.7.10 Offer atomoxetine or guanfacine to children aged 5 years[7] and over and young people if:

  • they cannot tolerate methylphenidate or lisdexamfetamine or
  • their symptoms have not responded to separate 6‑week trials of lisdexamfetamine and methylphenidate, having considered alternative preparations and adequate doses. [2018]

Medication choice – adults 

1.7.11 Offer lisdexamfetamine[8] or methylphenidate[9] as first-line pharmacological treatment for adults with ADHD. [2018]

1.7.12 Consider switching to lisdexamfetamine for adults who have had a 6‑week trial of methylphenidate at an adequate dose but have not derived enough benefit in terms of reduced ADHD symptoms and associated impairment. [2018]

1.7.13 Consider switching to methylphenidate for adults who have had a 6‑week trial of lisdexamfetamine at an adequate dose but have not derived enough benefit in terms of reduced ADHD symptoms and associated impairment. [2018]

1.7.14 Consider dexamfetamine[10] for adults whose ADHD symptoms are responding to lisdexamfetamine but who cannot tolerate the longer effect profile. [2018]

1.7.15 Offer atomoxetine[11] to adults if:

  • they cannot tolerate lisdexamfetamine or methylphenidate or
  • their symptoms have not responded to separate 6‑week trials of lisdexamfetamine and methylphenidate, having considered alternative preparations and adequate doses. [2018]

Now that really got Storebø et al. railed up, so much so that they to time off from helping patients like me to better cope with my mental disorder, to write a lengthy comment on this new guideline.

[…]The 2018 NICE guidance on pharmacological treatments for ADHD is nevertheless informed by systematic reviews with serious methodological limitations and low-quality studies. Although the guideline document elaborates on the rationale behind medication decisions, the low quality of evidence is never addressed to readers. It seems unlikely that patients, clinicians and families will have the time or energy to properly evaluate the lengthy NICE reviews, deeming efforts to determine the qualitative rationale behind the strong practice recommendations favouring methylphenidate and lisdexamfetamine, more difficult than necessary. Importantly, NICE reserves the right to recommend treatments based on scarce evidence and the experience of committee members alone. But should not readers at least be made explicitly aware of such justifications?[…]

Faltinsen, E., Zwi, M., Castells, X., Gluud, C., Simonsen, E., & Storebø, O. J. (2018). Updated 2018 NICE guideline on pharmacological treatments for people with ADHD: a critical look. BMJ Evidence-Based Medicine, bmjebm–2018–111110. doi:10.1136/bmjebm-2018-111110

Well, Dr. Storebø, one patient did actually read all those publications, just to let you know … which is why I found all your stuff, as well …


Since nobody even took the time to reply to their criticism (wonder why?), I decided to make sure that the NICE 2018 was taken into account, as the National Health Institute in Denmark was preparing to update their own National Klinisk Retningslinje (NKR) (National Guideline) and low and behold, I actually managed to have this included into the reference material as well as have them adjust some of their recommendations in the guideline, who would’ve thought that possible?

Normally I’m not a spiteful person, but in this case I couldn’t help myself gloating, as I knew that the honourable Ole Jakob Storebø, Ph.D. had just exited from the governing body for that guideline, and therefore didn’t have the ‘cloud’ to block this 🙂 (I may not be a Dr. Dr. or a Ph.D., but I am an A.D.H.D. and A.U.T.I.S.T. so don’t f… with me, I’m terrible tenacious when I go down my rabbit holes …


I ask a trusted advisor …

This made me a bit curious and I asked by ‘mentor’ on ADHD for the past 5+ years, Dr. Russell A. Barkley, Ph.D., on his opinion on this subject matter, and here what he replied:


First, the GRADE system employed to judge the quality of the evidence from the drug trials has itself been called into serious question by other scientists, has no evidence of validity, and is not reliable.
See here: http://journals.plos.org/plosmedicine/article?id=10.1371/journal.pmed.1000094.

Thus, judging the quality of evidence against a set of criteria that have no evidence for their validity no matter how many organizations have adopted them is itself very puzzling. 

Second, it is not so much what is said here but what goes unsaid. Yes, the critique says that the studies were all short term, which is true. But that is because it is impossible, at least in this country where most of the research is done, to even do a trial of MPH or any other approved ADHD drug that lasts more than a few weeks in comparison to a placebo.

No IRB, institutional review board, here would ever approve such a study as it is deemed unethical and harmful to withhold a proven effective treatment from research participants for any longer than this due to the risks or harms incurred from the disorder if left untreated.

Consequently, longer term safety and efficacy must be judged from naturalistic follow up studies, which find no harms, and from adverse event reports to regulators.

MPH has been used with millions of people in this country and worldwide and the results from reviews of large government and insurance datasets concerning adverse events are consistent with the results of the short term trials reviewed here. Some annoying side effects but none serious.

Why weren’t the published results from these large prescription databases discussed in the review to provide a larger context for understanding the results of the shorter term trials?

We have 58 years of such data in the US even if not from randomized trials. To ignore it while reaching conclusions about a drug is at best puzzling. 

Third, the requirement that studies must use a “nocebo” shows that the authors are not aware that such studies would also not be permitted by IRBs not only for the reasons given above but also because you cannot inflict suffering and harm on people, via inducing side effects, when there is no offsetting benefit to doing so.

I am not aware that any such nocebo exists that can specifically create MPH side effects in the equivalent proportion of people and to the equivalent degree as MPH.

And even if such a currently fantasy drug existed no IRB here would permit its use. So the authors are asking for the impossible while judging the existing database against a fantasy.

That is not a very fair assessment of the prevailing evidence even if they are technically correct about the short term duration of most trials, done mostly of necessity. 

(Dr. Russell A. Barkley, Ph.D.)


Conclusion

I have, on several occasions, asked Storebø et al. for comments, but he do not seem to find it necessary for a ‘respectable’ scientist (and psychologist) like himself (who is public servant employed by the federal government in Denmark to do research, as well as an Adjunct at the University of Southern Denmark) to answer questions from a simpleton like myself. So sadly, I cannot report on his argument for his agenda of anti-ADHD medication.

One thing is certain though; he has got an agenda and he is sticking to it … but he is not very public about what that might be, so I have to bite my time and wait for this mystery to get ‘clear’ to us all.

/Peter ‘ADDspeaker‘ Vang


References

The Jury Is Still Out on the Benefits and Harms of Methylphenidate for Children and Adolescents With Attention-Deficit/Hyperactivity Disorder

Storebø, O. J., Faltinsen, E., Zwi, M., Simonsen, E., & Gluud, C. (2018). The Jury Is Still Out on the Benefits and Harms of Methylphenidate for Children and Adolescents With Attention-Deficit/Hyperactivity Disorder. Clinical Pharmacology & Therapeutics. doi:10.1002/cpt.1149

Updated 2018 NICE guideline on pharmacological treatments for people with ADHD: a critical look

Faltinsen, E., Zwi, M., Castells, X., Gluud, C., Simonsen, E., & Storebø, O. J. (2018). Updated 2018 NICE guideline on pharmacological treatments for people with ADHD: a critical look. BMJ Evidence-Based Medicine, bmjebm–2018–111110. doi:10.1136/bmjebm-2018-111110 

Unbalanced risk-benefit analysis of ADHD drugs

Faltinsen, E. G., Gluud, C., Simonsen, E., Zwi, M., & Storebø, O. J. (2018). Unbalanced risk-benefit analysis of ADHD drugs. The Lancet Psychiatry, 5(11), 870. doi:10.1016/s2215-0366(18)30334-1

Methodological concerns with network meta-analysis on drugs for attention deficit hyperactivity disorder

Faltinsen, E. G., Storebø, O. J., & Gluud, C. (2018). Methodological concerns with network meta-analysis on drugs for attention deficit hyperactivity disorder. European Child & Adolescent Psychiatry. doi:10.1007/s00787-018-1164-6

Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents – assessment of adverse events in non-randomised studies

Storebø, O. J., Pedersen, N., Ramstad, E., Kielsholm, M. L., Nielsen, S. S., Krogh, H. B., … Gluud, C. (2018). Methylphenidate for attention deficit hyperactivity disorder (ADHD) in children and adolescents – assessment of adverse events in non-randomised studies. Cochrane Database of Systematic Reviews. doi:10.1002/14651858.cd012069.pub2

Evidence on methylphenidate in children and adolescents with ADHD is in fact of “very low quality”

Storebø, O. J., Zwi, M., Krogh, H. B., Moreira-Maia, C. R., Holmskov, M., Gillies, D., … Gluud, C. (2016). Evidence on methylphenidate in children and adolescents with ADHD is in fact of “very low quality.” Evidence Based Mental Health, 19(4), 100–102. doi:10.1136/eb-2016-102499

Methylphenidate for Attention-Deficit/Hyperactivity Disorder—Reply

Storebø, O. J., Simonsen, E., & Gluud, C. (2016). Methylphenidate for Attention-Deficit/Hyperactivity Disorder—Reply. JAMA, 316(9), 995. doi:10.1001/jama.2016.10300

Personal correspondence with Dr. Russell A. Barkley, Ph.D. as quoted in the article, with permission from Dr. Barkley.