MD, PhD, FMedSci, FRSB, FRCP, FRCPEd.

clinical trial

In so-called alternative medicine (SCAM), vitamin D is often recommended for a range of indications, including cancer prevention. Observational studies did indeed suggest that low vitamin D status may be a risk factor for cancer. On the basis of such evidence, a team of researchers sought to determine if vitamin D supplementation lowers the risk of cancer and precancers.

The Vitamin D and type 2 diabetes (D2d) cancer outcomes study (D2dCA) is an ancillary study to the D2d study, which was conducted at 22 academic medical centers in the United States. Participants had prediabetes and overweight/obesity and were free of cancer for the previous 5 years. Participants were randomized to receive vitamin D3 4000 IU daily or placebo. At scheduled study visits (4 times/year), cancer and precancer events were identified by questionnaires. Clinical data were collected and adjudicated for all reported events. Cox proportional hazard models compared the hazard ratio (HR) of incident cancers and precancers between groups.

Over a median follow-up period of 2.9 years, among 2385 participants (mean age 60 years and 25-hydroxyvitamin D 28 ng/mL), there were 89 cases of cancer. The hazard ratio (HR) of incident cancer for vitamin D vs placebo was 1.07 (95% CI 0.70, 1.62). Of 241 participants with incident precancers, 239 had colorectal adenomatous polyps. The HR for colorectal polyps for vitamin D vs placebo was 0.83 (95% CI 0.64, 1.07).

The authors concluded that, in the D2d population of participants with prediabetes and overweight/obesity, not selected for vitamin D insufficiency, vitamin D supplementation did not have a significant effect on risk of incident cancer or colorectal polyps.

For some reason, the discussions about the value of vitamin D for any condition tend to be dominated by emotion rather than evidence. This is particularly true in the realm of SCAM. The trial is a significant step forward. It is rigorous and generates clear findings. Let’s hope it will contribute to a more rational debate about the value of vitamin D in cancer prevention.

Gua sha, sometimes referred to as “scraping”, “spooning” or “coining”, is a traditional Chinese treatment that has also been adopted in several other Asian countries. It has long been popular in Vietnam and is now also becoming
well-known in the West. The treatment consists of scraping the skin with a smooth edge placed against the pre-oiled skin surface, pressed down firmly, and then moved downwards along muscles or meridians, the assumed ‘energy’ channels of traditional Chinese medicine. According to its proponents, gua sha stimulates the flow of the vital energy ‘chi’ and releases unhealthy bodily matter from blood stasis within sored, tired, stiff or injured areas.

An international team of authors has revisited gua sha, a therapy that we have discussed repeatedly on this blog (see here and here). The authors offer the following summary:

Gua sha is a traditional healing technique that aims to create petechiae on the skin for a believed therapeutic benefit. Natural healings are mostly based on repeated observations and anecdotal information. Hypothetical model for healing does not always fit the modern understanding. Yet, the mechanisms underlying Gua Sha have not been empirically established. Contemporary scientific research can now explain some events of traditional therapies that were once a mystery. It is assumed that Gua Sha therapy can serve as a mechanical signal to enhance the immune surveillance function of the skin during the natural resolving of the petechiae, through which scraping may result in therapeutic benefits. The current review, without judging the past hypothetical model, attempts to interpret the experience of the ancient healings in terms of contemporary views and concepts.

The authors conclude that this narrative review draws up a survey of scientific sources on an ancient healing, scraping therapy. It is hypothesized that the skin, the nervous system and immune system interact with one another to generate a cascade of physiological responses to the scraping, through which scraping may result in therapeutic benefits. Within the scope and limitations of this review, only a brief overview could be given of the potential relationship between the observed outcomes and scraping therapy. Implementing effective traditional healings within health systems will require appropriate knowledge translations and future prospective studies.

And they add the following ket points:

  1. The observed therapeutic effects following scraping therapy may be a physiological response to the minor bruising.
  2. Scraping is assumed to be a mechanical signal to elicit the immune function of the skin.
  3. Through natural resolving of the scraping marks (petechiae) a cascade of physiological responses are generated.
  4. Counterirritation and placebo effect can also contribute to positive effects for symptom relief.

I think that this paper is a good example for highlighting a common misunderstanding in so-called alternative medicine (SCAM): the confusion about how and whether any given therapy might work.

It is in my view utterly irrelevant, to consider or investigate the mechanisms of action of a SCAM that has not been proven to be an effective treatment of a disease or symptom. Such an approach can only lead to confusion about the value of the SCAM in question. In the present case, it makes gua sha look almost like a reasonable therapy, and consumers who read the paper might conclude that gua sha is worth trying.

A deliberately exaggerated example might make this clearer: If I fall down the staircase, a multitude of physiological effects of the fall could easily be verified on my body. Yet, nobody would claim that throwing patients down the stairs is of therapeutic value. Likewise, the forceful scratching of the skin is bound to have all sorts of physiological effects. These are, however, totally irrelevant until someone has shown that the procedure also has therapeutic value.

To put it bluntly: who cares how a SCAM works when it is unproven that it works?

Muscular dystrophies are a rare, severe, and genetically inherited disorders characterized by progressive loss of muscle fibers, leading to muscle weakness. The current treatment includes the use of steroids to slow muscle deterioration by dampening the inflammatory response. Chinese herbal medicine (CHM) has been offered as adjunctive therapy in Taiwan’s medical healthcare plan, making it possible to track CHM usage in patients with muscular dystrophies. This investigation explored the long-term effects of CHM use on the overall mortality of patients with muscular dystrophies.

A total of 581 patients with muscular dystrophies were identified from the database of Registry for Catastrophic Illness Patients in Taiwan. Among them, 80 and 201 patients were CHM users and non-CHM users, respectively. Compared to non-CHM users, there were more female patients, more comorbidities, including chronic pulmonary disease and peptic ulcer disease in the CHM user group. After adjusting for age, sex, use of CHM, and comorbidities, patients with prednisolone usage exhibited a lower risk of overall mortality than those who did not use prednisolone. CHM users showed a lower risk of overall mortality after adjusting for age, sex, prednisolone use, and comorbidities. The cumulative incidence of the overall survival was significantly higher in CHM users. One main CHM cluster was commonly used to treat patients with muscular dystrophies; it included Yin-Qiao-San, Ban-Xia-Bai-Zhu-Tian-Ma-Tang, Zhi-Ke (Citrus aurantium L.), Yu-Xing-Cao (Houttuynia cordata Thunb.), Che-Qian-Zi (Plantago asiatica L.), and Da-Huang (Rheum palmatum L.).

The authors concluded that the data suggest that adjunctive therapy with CHM may help to reduce the overall mortality among patients with muscular dystrophies. The identification of the CHM cluster allows us to narrow down the key active compounds and may enable future therapeutic developments and clinical trial designs to improve overall survival in these patients.

I disagree!

What the authors have shown is a CORRELATION, and from that, they draw conclusions implying CAUSATION. This is such a fundamental error that one has to wonder why a respected journal let it go past.

A likely causative explanation of the findings is that the CHM group of patients differed in respect to features that the statistical evaluations could not control for. Statisticians can never control for factors that have not been measured and are thus unknown. A possibility in the present case is that these patients had adopted a different lifestyle together with employing CHM which, in turn, resulted in a longer survival.

As we have discussed ad nauseam on this blog, spinal manipulation therapy (SMT) can cause serious adverse events, including spinal epidural hematoma (SEH), an emergency that can cause severe neurological dysfunction. Chinese surgeons have reported three cases of SEH after SMT.

  • The first case was a 30-year-old woman who experienced neck pain and numbness in both upper limbs immediately after SMT. Her symptoms persisted after 3 d of conservative treatment, and she was admitted to our hospital. Magnetic resonance imaging (MRI) demonstrated an SEH, extending from C6 to C7.
  • The second case was a 55-year-old man with sudden back pain 1 d after SMT, numbness in both lower limbs, an inability to stand or walk, and difficulty urinating. MRI revealed an SEH, extending from T1 to T3.
  • The third case was a 28-year-old man who suddenly developed symptoms of numbness in both lower limbs 4 h after SMT. He was unable to stand or walk and experienced mild back pain. MRI revealed an SEH, extending from T1 to T2.

All three patients underwent surgery after failed conservative treatment. Blood clots were found during the operation in case 1 and case 2, and the postoperative pathology confirmed a hematoma. In case three, a vein ruptured during the operation, causing massive bleeding. The three patients recovered to ASIA grade E on day 5, 1 wk, and day 10 after surgery, respectively. All patients returned to normal after 3 mo of follow-up.

Imaging examinations of case 1. A: T1-weighted preoperative magnetic resonance imaging (MRI) image shows high signal intensity (orange arrow); B and C: Preoperative T2-weighted image shows low signal intensity, and an axial T2-weighted image demonstrates that the hematoma occurred in the posterior region (white arrow); D: Preoperative enhanced MRI suggests an enhanced hematoma signal (orange arrow); E: Intraoperative photograph shows that spinal cord compression has recovered; F: Postoperative pathology suggested a hematoma; G and H: X-ray at the 3-mo follow-up indicated intact internal fixation.

The authors concluded that before proceeding with SMT, each patient should be evaluated in detail and checked for risk factors. In cases where the physical condition changes rapidly, physicians should be alert to the danger and send the patient to the emergency department for a complete MRI examination. We recommend surgery if neurological symptoms appear.

In their paper, the authors also review 15 further cases of SEH that have been previously published. They stress several times in their article that this complication is rare. In my view, this begs the question: how do they know? As there is no post-marketing surveillance of chiropractors or other clinicians doing SMT, I would insist that nobody can be sure about the true incidence of SEH or any other complication after SMT.

Therapeutic touch (TT) is a form of paranormal or energy healing developed by Dora Kunz (1904-1999), a psychic and alternative practitioner, in collaboration with Dolores Krieger, a professor of nursing. TT is popular and practised predominantly by US nurses; it is currently being taught in more than 80 colleges and universities in the U.S., and in more than seventy countries. According to one TT-organisation, TT is a holistic, evidence-based therapy that incorporates the intentional and compassionate use of universal energy to promote balance and well-being. It is a consciously directed process of energy exchange during which the practitioner uses the hands as a focus to facilitate the process.

The question is: does TT work beyond a placebo effect?

This review synthesized recent (January 2009–June 2020) investigations on the effectiveness and safety of therapeutic touch  (TT) as a therapy in clinical health applications. A rapid evidence assessment (REA) approach was used to review recent TT research adopting PRISMA 2009 guidelines. CINAHL, PubMed, MEDLINE, Cochrane databases, Web of Science, PsychINFO, and Google Scholar were screened between January 2009-March 2020 for studies exploring TT therapies as an intervention. The main outcome measures were for pain, anxiety, sleep, nausea, and functional improvement.

Twenty-one studies covering a range of clinical issues were identified, including 15 randomized controlled trials, four quasi-experimental studies, one chart review study, and one mixed-methods study including 1,302 patients. Eighteen of the studies reported positive outcomes. Only four exhibited a low risk of bias. All others had serious methodological flaws, bias issues, were statistically underpowered, and scored as low-quality studies. Over 70% of the included studies scored the lowest score possible on the GSRS weight of evidence scale. No high-quality evidence was found for any of the benefits claimed.

The authors drew the following conclusions:

After 45 years of study, scientific evidence of the value of TT as a complementary intervention in the management of any condition still remains immature and inconclusive:

  • Given the mixed result, lack of replication, overall research quality and significant issues of bias identified, there currently exists no good quality evidence that supports the implementation of TT as an evidence‐based clinical intervention in any context.
  • Research over the past decade exhibits the same issues as earlier work, with highly diverse poor quality unreplicated studies mainly published in alternative health media.
  • As the nature of human biofield energy remains undemonstrated, and that no quality scientific work has established any clinically significant effect, more plausible explanations of the reported benefits are from wishful thinking and use of an elaborate theatrical placebo.

TT turns out to be a prime example of a so-called alternative medicine (SCAM) that enthusiastic amateurs, who wanted to prove TT’s effectiveness, have submitted to multiple trials. Thus the literature is littered with positive but unreliable studies. This phenomenon can create the impression – particularly to TT fans – that the treatment works.

This course of events shows in an exemplary fashion that research is not always something that creates progress. In fact, poor research often has the opposite effect. Eventually, a proper scientific analysis is required to put the record straight (the findings of which enthusiasts are unlikely to accept).

In view of all this, and considering the utter implausibility of TT, it seems an unethical waste of resources to continue researching the subject. Similarly, continuing to use TT in clinical settings is unethical and potentially dangerous.

A second look at old research suggested that the recommended dose for vitamin C is far too low. Here is the abstract of the recently published  paper:

A double-blind controlled trial initiated in 1944 has led to the common narrative that a 10-mg daily vitamin C intake is adequate to prevent and treat impaired wound healing, and by inference, other collagen-related diseases such as heart disease or stroke. The WHO relies on this narrative to set the recommended nutrient intake for vitamin C. This narrative, however, is based on what is known as the eyeball method of data assessment. The 1944 trial published individual participant data on scar strength providing an opportunity to statistically probe the validity of the 10-mg narrative, something which has not yet been done. The findings show that a vitamin C intake that averages to 10 mg/d over a mean follow-up of 11.5 mo was associated with a 42% weakened scar strength when compared with 80 mg vitamin C intake/d (P < 0.001). The observed dose-response curve between scar strength and vitamin C intake suggests that the daily vitamin C intake needed to prevent collagen-related pathologies is in the range recommended by the National Academy of Medicine and the European Food Safety Authority (75 to 110 mg/d), not the WHO recommendation (45 mg/d). The findings also show that a vitamin C intake that averages to 65 mg/d over a mean follow-up of 6.5 mo failed to restore the normal wound-healing capacity of vitamin C-depleted tissues; such tissues had a 49% weaker scar strength when compared with nondepleted tissues (P < 0.05). Thus, average daily vitamin C intakes ∼50% higher than the WHO recommends may fail to treat existing collagen-related pathologies. It is concluded that the prior lack of statistical analyses of a landmark trial may have led to a misleading narrative on the vitamin C needs for the prevention and treatment of collagen-related pathologies.

The lead author of the recent re-analysis, Professor Philippe Hujoel from the Department of Epidemiology, School of Public Health, University of Washington, Seattle, said: “The vitamin C experiment is a shocking study. They depleted people’s vitamin C levels long-term and created life-threatening emergencies. It would never fly now. The findings of the re-analyses of the Sorby data suggest that the WHO’s recommendation is too low to prevent weak scar strength. Robust parametric analyses of the trial data reveal that an average daily vitamin C intake of 95mg is required to prevent weak scar strength for 97.5 percent of the population. Such a vitamin C intake is more than double the daily 45mg vitamin C intake recommended by the WHO but is consistent with the writing panels for the National Academy of Medicine and (other) countries.”

The original research of 1944 was headed by the British-German biologist and Nobel-prize winner Sir Hans Adolf Krebs. At the time, researchers conducted an experiment that controlled and monitored vitamin C consumption of just 20 volunteers. They were each given varying amounts of vitamin C,  which helps the body to produce collagen – and given wounds to observe how quickly their scar tissue healed. The research aimed to ascertain how much vitamin C navy members living off rations is required in order to prevent them from developing scurvy, rather than how much is needed to boost health overall.

Prof Hujoel concluded that: “The failure to reevaluate the data of a landmark trial with novel statistical methods as they became available may have led to a misleading narrative on the vitamin C needs for the prevention and treatment of collagen-related pathologies.”

Kratom (Mitragyna speciosa, Korth.) is an evergreen tree that is indigenous to Southeast Asia. It is increasingly being used as a recreational drug, to help with opium withdrawal, and as a so-called alternative medicine (SCAM) for pain, erectile dysfunction, as a mood stabilizer, and for boosting energy or concentration.  When ingested, Kratom leaves produce stimulant and opioid-like effects (see also my previous post).

Kratom contains 7‑hydroxymitragynine, which is active on opioid receptors. The use of kratom carries significant risks, e.g. because there is no standardized form of administration as well as the possibility of direct damage to health and of addiction.

There are only very few clinical trials of Kratom. One small placebo-controlled study concluded that the short-term administration of the herb led to a substantial and statistically significant increase in pain tolerance. And a recent review stated that Kratom may have drug interactions as both a cytochrome P-450 system substrate and inhibitor. Kratom does not appear in normal drug screens and, especially when ingested with other substances of abuse, may not be recognized as an agent of harm. There are numerous cases of death in kratom users, but many involved polypharmaceutical ingestions. There are assessments where people have been unable to stop using kratom therapy and withdrawal signs/symptoms occurred in patients or their newborn babies after kratom cessation. Both banning and failure to ban kratom places people at risk; a middle-ground alternative, placing it behind the pharmacy counter, might be useful.

In Thailand, Kratom had been outlawed since 1943 but now it has become (semi-)legal. Earlier this year, the Thai government removed the herb from the list of Category V narcotics. Following this move, some 12,000 inmates who had been convicted when Kratom was still an illegal drug received amnesty. However, Kratom producers, traders, and even researchers will still require licenses to handle the plant. Similarly, patients looking for kratom-based supplements will need a valid prescription from licensed medical practitioners. Thai law still prohibits bulk possession of Kratom. Users are encouraged to handle only minimum amounts of the herb to avoid getting prosecuted for illegal possession.

In 2018, the US Food and Drug Administration stated that Kratom possesses the properties of an opioid, thus escalating the government’s effort to slow usage of this alternative pain reliever. The FDA also wrote that the number of deaths associated with Kratom use has increased to a total of 44, up from a total of 36 since the FDA’s November 2017 report. In the majority of deaths that the FDA attributes to Kratom, subjects ingested multiple substances with known risks, including alcohol.

In most European countries, Kratom continues to be a controlled drug. In the UK the sale, import, and export of Kratom are prohibited. Yet, judging from a quick look, it does not seem to be all that difficult to obtain Kratom via the Internet.

The global market for dietary supplements has grown continuously during the past years. In 2019, it amounted to around US$ 353 billion. The pandemic led to a further significant boost in sales. Evidently, many consumers listened to the sly promotion by the supplement industry. Thus they began to be convinced that supplements might stimulate their immune system and thus protect them against COVID-19 infections.

During the pre-pandemic years, the US sales figures had typically increased by about 5% year on year. In 2020, the increase amounted to a staggering 44 % (US$435 million) during the six weeks preceding April 5th, 2020 relative to the same period in 2019. The demand for multivitamins in the US reached a peak in March 2020 when sales figures had risen by 51.2 %. Total sales of vitamins and other supplements amounted to almost 120 million units for that period alone. In the UK, vitamin sales increased by 63 % and, in France, sales grew by around 40–60 % in March 2020 compared to the same period of the previous year.

Vis a vis such impressive sales figures, one should ask whether dietary supplements really do produce the benefit that consumers hope for. More precisely, is there any sound evidence that these supplements protect us from getting infected by COVID-19? In an attempt to answer this question, I conducted several Medline searches. Here are the conclusions of the relevant clinical trials and systematic reviews that I thus found:

Confused?

Me too!

Does the evidence justify the boom in sales of dietary supplements?

More specifically, is there good evidence that the products the US supplement industry is selling protect us against COVID-19 infections?

No, I don’t think so.

So, what precisely is behind the recent sales boom?

It surely is the claim that supplements protect us from Covid-19 which is being promoted in many different ways by the industry. In other words, we are being taken for a (very expensive) ride.

Exploring preventive therapeutic measures has been among the biggest challenges during the coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A team of Indian and US researchers explored the feasibility and methods of recruitment, retention, and potential signal of efficacy, of selected homeopathic medicines as a preventive measure for developing COVID-19 in a multi-group study.

A six-group, randomized, double-blind, placebo-controlled prophylaxis study was conducted in a COVID-19 exposed population in a quarantine facility in Mumbai, India. Each group received one of the following:

  1. Arsenicum album 30c,
  2. Bryonia alba 30c,
  3. Arsenicum album 30c, Bryonia alba 30c, Gelsemium sempervirens 30c, and Influenzinum 30c
  4. coronavirus nosode CVN01 30c,
  5. Camphora 1M,
  6. placebo.

Six pills twice a day were administered for 3 days. The primary outcome measure used was testing recruitment and retention in this quarantined setting. Secondary outcomes were numbers testing positive for COVID-19 after developing symptoms of illness, the number of subjects hospitalized, and days to recovery.

Good rates of recruitment and retention were achieved. Of 4,497 quarantined individuals, 2,343 sought enrollment, with 2,294 enrolled and 2,233 completing the trial (49.7% recruitment, 97.3% retention). Subjects who were randomized to either Bryonia alba (group 2) or to the CVN01 nosode (group 4) signaled a numerically lower incidence of laboratory-confirmed COVID-19 and a shorter period of illness, with evidence of fewer hospitalizations than those taking placebo. The three other groups did not show signals of efficacy.

The authors concluded that this pilot study supports the feasibility of a larger randomized, double-blind, placebo-controlled trial. Bryonia alba 30c and CVN01 30c should both be explored in disease prevention or shortening the course of disease symptomatology in a COVID-19-exposed population.

Signals of efficacy?

Are they kidding us?

The results failed to be statistically significant!

Hence the conclusions should be rewritten as follows:

This pilot study supports the feasibility of a larger trial in India where people have been told by an irresponsible government to believe in homeopathy. None of the 5 homeopathic treatments generated encouraging findings and none should be explored further. Studies of this nature must be discouraged firstly because homeopaths would not accept the findings of a trial of non-individualized homeopathy, and secondly because such trials will further confuse the public who might think that homeopathy is worth trying.

 

 

 

Kneipp therapy goes back to Sebastian Kneipp (1821-1897), a catholic priest who was convinced to have cured himself of tuberculosis by using various hydrotherapies. Kneipp is often considered by many to be ‘the father of naturopathy’. Kneipp therapy consists of hydrotherapy, exercise therapy, nutritional therapy, phototherapy, and ‘order’ therapy (or balance). Kneipp therapy remains popular in Germany where whole spa towns live off this concept.

The obvious question is: does Kneipp therapy work? A team of German investigators has tried to answer it. For this purpose, they conducted a systematic review to evaluate the available evidence on the effect of Kneipp therapy.

A total of 25 sources, including 14 controlled studies (13 of which were randomized), were included. The authors considered almost any type of study, regardless of whether it was a published or unpublished, a controlled or uncontrolled trial. According to EPHPP-QAT, 3 studies were rated as “strong,” 13 as “moderate” and 9 as “weak.” Nine (64%) of the controlled studies reported significant improvements after Kneipp therapy in a between-group comparison in the following conditions:

  • chronic venous insufficiency,
  • hypertension,
  • mild heart failure,
  • menopausal complaints,
  • sleep disorders in different patient collectives,
  • as well as improved immune parameters in healthy subjects.

No significant effects were found in:

  • depression and anxiety in breast cancer patients with climacteric complaints,
  • quality of life in post-polio syndrome,
  • disease-related polyneuropathic complaints,
  • the incidence of cold episodes in children.

Eleven uncontrolled studies reported improvements in allergic symptoms, dyspepsia, quality of life, heart rate variability, infections, hypertension, well-being, pain, and polyneuropathic complaints.

The authors concluded that Kneipp therapy seems to be beneficial for numerous symptoms in different patient groups. Future studies should pay even more attention to methodologically careful study planning (control groups, randomisation, adequate case numbers, blinding) to counteract bias.

On the one hand, I applaud the authors. Considering the popularity of Kneipp therapy in Germany, such a review was long overdue. On the other hand, I am somewhat concerned about their conclusions. In my view, they are far too positive:

  • almost all studies had significant flaws which means their findings are less than reliable;
  • for most indications, there are only one or two studies, and it seems unwarranted to claim that Kneipp therapy is beneficial for numerous symptoms on the basis of such scarce evidence.

My conclusion would therefore be quite different:

Despite its long history and considerable popularity, Kneipp therapy is not supported by enough sound evidence for issuing positive recommendations for its use in any health condition.

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