Critical Thinking in Medicine

1. Critical Thinking in Medicine Eric S. Farbman, MD

2. Scams Hoaxes Parkinson’s Disease:Bogus Treatments Eric S. Farbman, MD Quackery

3. Hoaxes, Scams, Quackery • Non-medical treatments without proven benefit • Medical fraud • Designed to enrich the promoter of the treatment more so than the patient • In some cases, these can be dangerous to the health of the patient as well

4. Why Are People Vulnerable? • Lack of suspicion—if it is on television, the internet, etc., then it must be true • Overconfidence—some people believe that they are better equipped than scientists in determining whether something works • Desperation—the sincere hope that something works when nothing else has • Conspiracy—distrustful of the medical profession but attracted to “natural” methods

5. Why Do the Methods Seem to Work? • There is a poor grasp of innate probability • In a group of 23 people, what are the odds that two share the same birthday? • There is a belief that all effects must have deliberate causes • There is a tendency towards selective memory • There is the placebo effect • There is a desire to please the individual • There is the natural course of the disease

6. What is Quackery? • It is the promotion of methods that have no evidence and lack a scientific rationale • Malpractice usually involves negligence rather than fraud • Some promoters are scam artists, some are blind “true believers”

7. Types of Hoax Treatments • Vitamins/Supplements • Procedures • “Alternative medicine” practitioners

8. Supplements

9. Getting a Medication Approved • Since 1938, every medication has to go through a New Drug Application (NDA) process before getting approval in the U.S. • The goals of the NDA are: • Is the drug safe and effective for its proposed use, and do the benefits outweigh the risks? • Is the labelling (package insert) appropriate, and what should it contain? • Are the manufacturing methods adequate to maintain the drug’s identity, strength, and purity?

10. Studies Required by the FDA • First the sponsor must submit data showing that the drug is reasonably safe for use in small-scale clinical studies • At this pre-clinical stage, the FDA will ask for: • A pharmacological profile of the drug • Determine acute toxicity in at least two species of animals • Conduct short-term toxicity studies ranging from two weeks to three months

11. Studies Required by the FDA:On the Road to Drug Approval • Phase I: Develop drug’s safety profile • Normally subjects are healthy volunteers • Determines how drug is absorbed, distributed in the body, metabolized, and excreted • Phase II: Determine the drug’s safety and assess side effects • Given to volunteers who have the disease • Determine optimal dosage of the drug

12. Studies Required by the FDA:On the Road to Drug Approval • Phase III: Verify the effectiveness of the drug against the condition that it targets • This also continues to investigate the safety of the drug and record possible side effects and adverse reactions from long-term use. • These studies are randomized, double-blind, placebo-controlled studies. • Often have at least 1000 patients enrolled • If the medication is effective, the trial is deemed successful—“pivotal”. Normally two pivotal trials are needed to ensure validity of the trials

13. Studies Required by the FDA:After Drug Approval • Phase IV: Once the drug is on the market, the company must continue to perform observational studies to evaluate the drug’s safety during routine use. • The company may also monitor any usage of the drug for un-approved indications. • Trials may be done based on those usages, but the company CANNOT advertise “off-label” use

15. Studies Required forSupplement Approval None!

16. Health and Education Act of 1994 • Defined a dietary supplement as: • A product (other than tobacco) that is intended to supplement the diet • Is intended for ingestion in pill, capsule, tablet, or liquid form • Is not represented for use as a conventional food • Is labelled as a “dietary supplement” • Nutritional support statements do not have to be approved by the FDA • This law has made it very difficult for the FDA to ban dangerous dietary supplements.

17. “Legitimate” Supplements • Vitamin E • Gluathione • Coenzyme Q10 • Vitamin B6 • Folic Acid Which of these agents has a double-blind trial that supports its benefit in PD?

18. CoEnzyme Q10

19. CoEnzyme Q10 • Eighty people in study • Randomized to placebo, 300mg/day, 300mg twice/day, 300mg 4x/day • Followed for 16 months or until the patient needed treatment with levodopa • Primary variable was a change in UPDRS • Statistically signifcant benefits seen at highest dose, trending towards benefit at lower doses

20. Why Is CoQ10 Thought to Work? • Causes of Parkinson’s Disease are not known • Thought to be at least partially due to oxidation (“rusting”) of the brain • CoQ10 is a potent anti-oxidant • So, what about other anti-oxidants?

21. Vitamin E • One of the few supplements to have a well-designed negative trial • Original selegiline trials had four arms • Selegiline/Placebo • Selegiline/Vitamin E • Placebo/Vitamin E • Placebo/Placebo • No effect on progression of PD by itself • No enhancement of selegiline in combination

22. Glutathione • 9 patients with early, untreated PD were given IV gluathione 600mg twice/day for 30 days • All improved significantly after therapy as measured by CURS • Evaluates rigidity, tremor, speech, facial expression, bradykinesia, gait, postural stability • After 30 days of therapy were completed, the therapeutic effect lasted an additional 2 months

23. 100 Ropinirole (n=464) * 80 Placebo (n=464) ‡ 73% † 60 60% 57% Percentage of Patients 53% 40 41% 40% 20 n=187 n=193 n=146 n=137 n=131 n=134 0 n=187 n=193 n=146 n=137 n=131 n=134 TREAT RLS US1 TREAT RLS 12 TREAT RLS 23 Problems with Gluathione Study • Very small sample size • No control group—no placebo arm • Original study done in 1996; where are the follow-up studies?

25. Less Reputable Supplements

29. Other Treatments • Prakotin • I’m not sure what it is • It shows up on some websites • The word “prakotin” does not show up in the medline database

32. Low Dose Naltrexone • Naltrexone was approved by the FDA in 1984 • Dose was 50mg for the purpose of helping heroin or opium addicts • Works by blocking opioid receptors • Supposedly a smaller dose (4.5mg) enhances the body’s immune system and its response to many diseases including Parkinson’s disease

33. Low Dose Naltrexone (cont’d) • There is nothing in the literature to support its use in neurological disease • There is virtually nothing in the literature to support its use in anything • Any benefits reported for Parkinson disease are purely anecdotal

34. LDN in the Medical Literature

36. “Medical” Procedures

37. Chelation • A chelator is an organic compound that forms stable bonds with metal atoms. • They often are used for acute metal toxicity • Often times they have serious side effects

38. Chelating Agents • Dimercaprol • Given intramuscularly • Used for arsenic, lead, mercury, cadmium poisoning • Side effects: Headache, nausea, vomiting • Penicillamine • Treatment for copper poisoning and Wilson’s disease • Side effects: Aplastic anemia, lupus, hemolytic anemia

39. Chelating Agents (cont’d) • Edetate (EDTA) • Possible chelator of many things • Usually used for lead poisoning • Side effect: nephrotoxicity • Deferoxamine • Used for acute iron intoxication • Does not cross blood brain barrier • Side effects: skin reactions, neurotoxicity (i.e. retinal degeneration), hepatic and renal dysfunction, severe coagulopathies, hypotensive shock

40. Chelation Therapy • There are no trials that show any benefit in PD • Even if we assume that excess iron is part of the pathology, there is no chelator that can effectively cross into the brain to remove this iron without side effects • There are well-designed trials for other conditions which have yielded negative results • Using chelation instead of proven treatments (i.e. CABG) can have fatal consequences

42. Hyperbaric Medicine • The delivery of pressurized oxygen to the body • Useful (and approved) for treating • Decompression sickness (“The Bends”) • Carbon Monoxide Poisoning • Cyanide poisoning • Burns • Necrotizing soft tissue infections

43. Hyperbaric Medicine in PD • 2 abstracts/articles from various International Congresses on Hyperbaric Medicine • One article (originally in Russian literature) • All supposedly show benefit

44. Hyperbaric in PD: Abstract 1 • 72 y.o. male diagnosed with idiopathic PD • Started on sinemet 10/100 three times/day • Eighteen months after diagnosis, he started on hyperbaric oxygenation and had great results. He was also able to come off of his sinemet • Problems: • Dose of sinemet is insufficient • Disease is probably mild at time of treatment • Scale used to rate improvement is not validated

45. Hyperbaric in PD: Abstract 2 • Fifteen patients (8 men, 7 women) • Etiology of PD: • 7 idiopathic • 4 vasculopathic • 3 post-encephalic • 1 other kind • No controls • Nothing said about medication changes • Difficult to know what to make of results

46. Hyperbaric in PD: Russian article • 64 patients (29 men, 35 women) • Duration of illness ranged from 1 – 15 years • Etiology • Atherosclerosis of cerebral vessels in 49 patients • This combined with arterial hypertension in 6 • History of encephalitis in 8 • Closed head trauma in 1 • Results: • “Good treatment results were noted in 18…” • “Therapeutic effect was considered satisfactory in 26…” • No measurement scales of any kind were used!

47. Other Devices with No FDA Approved Indications

50. “Alternative Medicine” Practitioners