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

risk/benefit

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Guest post by Emeritus Professor Alastair MacLennan AO, MB ChB, MD, FRCOG, FRANZCOG

The sale and promotion of a therapeutic drug in most countries require rigorous assessment and licencing by that country’s therapeutic regulatory body. However, a new surgical technique can escape such checks and overview unless the technique is subject to local medical ethics review in the context of a research trial. New medical devices in Australia such as carbon dioxide or Er-YAG lasers can be listed on its therapeutic register without critical review of their efficacy and safety. Thermal injury to the postmenopausal vaginal wall in the hope of rejuvenating it has become a lucrative fad for some surgeons outside formal well-conducted clinical trials.

There are many published studies of this technique but the large majority are small, uncontrolled and observational. The few randomised controlled trials using sham controls show a placebo effect and debatable clinical efficacy with limited follow-up of adverse effects. A review of these therapies in July 2020 published by The National Institute for Health and Care Excellence summarised apparent claims for some efficacy in terms of vaginal dryness, dyspareunia, sexual function, and incontinence but noted confounding in the study’s designs such as concurrent breast cancer treatments, local oestrogen therapy and lubricants (!). Most studies had very limited follow up for adverse events but elsewhere the literature has reported burns, infection, increased dyspareunia and scarring. There is no physiological mechanism by which burning atrophic vaginal epithelium will magically rejuvenate it.

A recent well-conducted randomised sham-controlled trial with a 12-month follow-up of Fractional Carbon Dioxide Laser for the treatment of vaginal symptoms associated with menopause has been published in JAMA by Li et al has shown no efficacy for this treatment(2).

At 12 months, there was no difference in overall symptom severity based on a 0-100 scale (zero equals no symptoms), with a reduction in symptom severity of 17.2 in the treatment group compared with 26.6 in the sham group.

The treatment had no impact on quality of life. “Sexual activity rates and quality of sex were not significantly different between the groups at baseline or 12 months”. The study compared 46 paired vaginal wall biopsies, taken at baseline and six months into treatment, and no significant histological improvement with laser was evident.

“The annual cost of laser treatment to the individual for management of vaginal menopausal symptoms was reported to be AUD$2,733, and because there is no demonstrable difference versus sham treatment, it cannot be considered to be cost-effective.”

Although one could still call for more quality sham-controlled randomised trials in different circumstances there is no justification for touting this therapy commercially. Complications following this therapy outside of ethical trials could become the next medico-legal mine-field.

Vaginal atrophy in the years after menopause is almost universal and is primarily due to oestrogen deficiency. The efficient solution is local vaginal oestrogen or systemic hormone replacement therapy. However, the misreporting of the Women’s Health Initiative and Million Women’s Study has created exaggerated fear of oestrogen therapies and thus a market for alternative and often unproven therapies (3). The way forward is education and tailoring of hormonal therapies to minimise risk and maximise efficacy and quality of life and not to resort to quackery.

References

1. https://www.nice.org.uk/guidance/ipg697/documents/overview

2. Li FG, Maheux-Lacroix S, Deans R et al. Effect of Fractional Carbon Dioxide Laser vs Sham Treatment on Symptom Severity in Women With Postmenopausal Vaginal Symptoms A Randomized Clinical Trial. JAMA. 2021;326:1381-1389.

3. MacLennan AH. Evidence-based review of therapies at the menopause. Int J Evid Based Healthc 2009; 7: 112-123.

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.

“Edzard and his ilk are not really serious about honoring the Hippocratic tradiiton of “First, do no harm,” and even then, they will spin what seemingly good responses to homeopathic treatment as a placebo.”

This comment came recently from our good friend Dana Ullman, and it made me think again about homeopathy and the ‘first do no harm’ principle.

  • The first thing to note is that the Hippocratic oath does not contain this sentence.
  • And the second thing to stress is that clinicians are doing harm regularly. The ‘first do no harm’ principle has long been understood to mean that clinicians should always take care that their actions generate more benefit than harm.

As we discussed all this in more detail before, I do not intend to dwell on it. Today, I rather consider three exemplary scenarios in order to investigate how the principle of doing more good than harm applies to homeopathy (or indeed any other form of so-called alternative medicine (SCAM)).

SCENARIO 1:

PATIENT WITH A SELF-LIMITING CONDITION

Let’s assume our patient has a cold and consults her physician who prescribes a homeopathic remedy. One could argue that no harm is done in such a situation. The treatment will not help beyond a placebo effect, but the cold will disappear in just a few days, and the patient will not suffer any side effects. This attitude is common but it disregards the following potential harms:

  1. The cost for the treatment.
  2. The possibility that our patient suffered for several days needlessly from cold symptoms that might be treatable.
  3. The possibility of our patient getting the erroneous impression that homeopathy is an effective therapy (because the cold did go away quickly) and therefore opts to use it for future, more serious illnesses.

What if the physician only prescribed homeopathy because the patient asked him to do so? Strictly speaking, the above-named issues still apply in this situation. The ethical thing would have been to inform the patient what the best evidence tells us (namely that homeopathy is a placebo therapy), provide assurance about the nature of the condition, and prescribe effective treatments as needed.

And what if the physician does all of these things and, in addition, prescribes homeopathy because the patient wants it? In this case, the possibility of harms 1 and 3 does still apply.

SCENARIO 2

PATIENT WITH A CHRONIC CONDITION

Consider a patient suffering from arthritis who consults her physician who prescribes homeopathic remedies as the sole therapy. In such a situation, the following harms apply:

  1. The cost for the treatment.
  2. The possibility that our patient suffers needlessly from symptoms that are treatable. As the symptoms can be serious, this would often amount to medical negligence.

What if the physician only prescribed homeopathy because the patient asked him to do so and the patient refuses conventional therapies? In such cases, it is the physician’s ethical duty to inform the patient about the best evidence as it pertains to homeopathy and conventional treatments for her condition. Failure to do so would amount to negligence. The patient is then free to decide, of course. But so is the physician; nobody can force him/her to prescribe ineffective treatments. If no consensus can be reached, the patient might have to change physician.

And what if the physician does inform the patient adequately but also prescribes homeopathy because the patient wants it? In this case, the possibility of harms 1 and 3 does still apply.

SCENARIO 3

PATIENT WITH A LIFE-THREATENING CONDITION

Consider a young man with testicular cancer who consults his doctor who prescribes homeopathic remedies as the sole therapy. In such a situation, the physician is grossly negligent and could be struck off because of negligence.

What if the physician prescribed homeopathy because the patient asked him to do so and refuses conventional therapies? In such a case, it is the ethical duty of the physician to inform the patient about the best evidence as it pertains to homeopathy and to the conventional treatment for his cancer. Failure to do so would amount to negligence. The patient is then free to decide, of course. But so is the physician; nobody can force him to prescribe ineffective treatments. If no consensus can be reached between the physician and the patient, the patient might have to change physician.

And what if the physician does inform the patient adequately makes sure he receives effective oncological treatments, but also prescribes homeopathy because the patient insists on it? In this case, the possibility of harms 1 and 3 does still apply.

These scenarios are, of course, rather schematic and, in everyday practice, many other factors might need considering. They nevertheless show that the ‘do more good than harm’ principle does not support homeopathy (or any other ineffective SCAM). In other words, the practice of homeopathy is not ethical.

But what if someone (like Dana Ullman) strongly believes in the effectiveness of homeopathy? In this case, he or she is not acting according to the best available evidence – and that, of course, is also unethical.

 

Past life regression therapy (PLRT) is, according to one practitioner, a therapeutic technique for accessing and re-experiencing your past lives directly.  A branch of hypnotherapy, past life regression therapy has grown over the last 50 years to be an important addition to the healing arts. This website also informs us that:

Past life regression is an amazing, full-sensory experience.  You might experience the memory as a vivid movie, or see only vague flashes of images that prompt the narrative.  You might hear gunshots or explosions on a battlefield, or music at a dance.  It is possible to recall smells too:  smoke from a fire, leather from a saddle, or the sweat of a dirty body.

As the story unfolds, you feel real emotions appropriate to the story.  You may cry when you re-experience deep sadness at the death of a beloved child, feel despair in the pit of your stomach as you witness a massacre, or elation at a long-awaited homecoming from war.  And just as you can recall strong emotions, you feel the pain of an arrow piercing your body as you are dying, or the heaviness of a load you’re carrying on your back.  These physical sensations and emotions are very real in the moment, but pass quickly as you move through the past life story and death.

PLRT is used by some clinicians for anxiety disorders, mood disorders, gender dysphoria, and other conditions. One survey suggested that 22% of European cancer patients use PLRT as a so-called alternative medicine (SCAM) to treat their illness. Some proponents argue that, since the exploration of the event/memory is actually helping the client resolve the challenge, the overall process can have immense therapeutic benefit, provided it is done responsibly and effectively.

So, it is effective because it is effective??? Such assurances make my alarm bells ring loud and clear. And I am not alone. It has been argued that PLRT is unethical:

  • First, it is not evidence-based. Past life regression is based on the reincarnation hypothesis, but this hypothesis is not supported by evidence, and in fact, it faces some insurmountable conceptual problems. If patients are not fully informed about these problems, they cannot provide informed consent, and hence, the principle of autonomy is violated.
  • Second, past life regression therapy has the great risk of implanting false memories in patients, and thus, causing significant harm. This is a violation of the principle of non-malfeasance, which is surely the most important principle in medical ethics.

I was unable to find convincing evidence that PLRT is effective. Furthermore, PLRT is by no means cheap; a typical session lasts two hours and costs $350. This suggests that PLRT is

  • unproven,
  • expensive,
  • and unsafe.

In other words, it is not a therapeutic option that I would recommend to anyone for any condition.

Mesotherapy is a treatment where fine needles or a high-pressure ‘gun’ are used to inject vitamins, enzymes, hormones, plant extracts, etc. into the skin of a patient. Michel Pistor, a French doctor, developed the therapy in 1952. It was originally used to relieve pain. Today, mesotherapy is also employed for a range of further indications:

  • remove fat in areas like the stomach, thighs, buttocks, hips, legs, arms, and face
  • reduce cellulite
  • fade wrinkles and lines
  • tighten loose skin
  • recontour the body
  • lighten pigmented skin
  • treat alopecia, a condition that causes hair loss

Mesotherapy is said to deliver drugs into the middle layer (mesoderm) of the skin. It is claimed to correct underlying issues like poor circulation and inflammation that cause skin damage.

Many different drugs can be used for mesotherapy, including:

  • prescription medicines like vasodilators and antibiotics
  • hormones such as calcitonin and thyroxin
  • enzymes like collagenase and hyaluronidase
  • herbal extracts
  • homeopathic remedies
  • vitamins and minerals
  • vaccines

According to the Italian Mesotherapy Society, the mechanisms of action of mesotherapy can be summarised as follows:

But is there at all any sound evidence that mesotherapy works?

It turns out that there are few rigorous studies. The most recent review concluded that mesotherapy proved to be more effective than systemic therapy in the treatment of local pain and functional limitations caused by a variety of musculoskeletal conditions. However, because of the heterogeneity of the analysed studies in terms of injected drugs, administration technique, associated treatments, frequency and total number of sessions, more randomized controlled trials are needed, comparing a standardized mesotherapy protocol with a systemic treatments.

Mesotherapy is not free of serious adverse effects. They include bacterial infections, hair loss, scarring, panniculitis, tissue necrosis, allergic reactions, and other complications.

So, is mesotherapy a treatment that might be recommended?

  • Its effectiveness remains unproven.
  • It can cause serious adverse effects.
  • It is by no means cheap.

I think these facts answer the question fairly well.

They say, one has to try everything at least once – except line-dancing and incest. So, when I was invited to co-organize a petition, I considered it and thought: WHY NOT?

Here is the text (as translated by myself) of our petition to the German Medical Association:

 

 

Dear President Dr Reinhardt,

Dear Ms Lundershausen,

Mrs Held,

Dear Ms Johna,

We, the undersigned doctors, would like to draw your attention to the insistence of individual state medical associations on preserving “homeopathy” as a component of continuing medical education. We hope that you, by virtue of your office, will ensure a nationwide regulation so that this form of sham treatment [1], as has already happened in other European countries, can no longer call itself part of medicine.

We justify our request by the following facts:

  1. After the landmark vote in Bremen in September 2019 to remove “homeopathy” from the medical training regulations, 10 other state medical associations have so far followed Bremen’s example. For reasons of credibility and transparency, it would be desirable if the main features of the training content taught were not coordinated locally in the future, but centrally and uniformly across the country so that there is no “training tourism”. Because changes to a state’s own regulations of postgraduate training are only binding for the examination committee of the respective state, this does not affect national regulations but is reduced to only a symbolic character without sufficient effects on the portfolio of medical education nationwide.
  2. Medicine always works through the combination of a specifically effective part and non-specific placebo effects. By insisting on a pseudo-medical methodology – as is “homeopathy” represents in our opinion – patients are deprived of the specific effective part and often unnecessarily deprived of therapy appropriate to the indication. Tragically, it happens again and again that the “therapeutic window of opportunity” for an appropriate therapy is missed, tumors can grow to inoperable size, etc.
  3. Due to the insistence of individual state medical associations on the “homeopathic doctrine of healing” as part of the medical profession, we are increasingly exposed to the blanket accusation that, by tolerating this doctrine, we are supporting and promoting ways of thinking and world views that are detached from science. This is a dangerous situation, which in times of a pandemic manifests itself in misguided aggression reflected not just in vaccination skepticism and vaccination refusal, but also in unacceptable personal attacks and assaults on vaccinating colleagues in private practice.
[1] Homöopathie – die Fakten [unverdünnt] eBook : Ernst, Edzard, Bretthauer, Jutta: Amazon.de: Kindle-Shop

Responsible:

Dr. med. Dent. Hans-Werner Bertelsen

Prof. Dr. med. Edzard Ernst

George A. Rausche

You can sign the petition here:

Petition an die Bundesärztekammer › Sachverständiger kriminalistische Forensik, Foto- Videoforensik, digitale Forensik und der Identifikation lebender Personen nach Bildern (rauscher.xyz)

 

Static or motion manual palpation tests of the spine are commonly used by chiropractors and osteopaths to assess pain location and reproduction in low back pain (LBP) patients. But how reliable are they?

The purpose of this review was to evaluate the reliability and validity of manual palpation used for the assessment of LBP in adults. The authors systematically searched five databases from 2000 to 2019 and critically appraised the internal validity of studies using QAREL and QUADAS-2 instruments.

A total of 2023 eligible articles were identified, of which 14 were at low risk of bias. Evidence suggests that reliability of soft tissue structures palpation is inconsistent, and reliability of bony structures and joint mobility palpation is poor. Preliminary evidence was found to suggest that gluteal muscle palpation for tenderness may be valid in differentiating LBP patients with and without radiculopathy.

The authors concluded that the reliability of manual palpation tests in the assessment of LBP patients varies greatly. This is problematic because these tests are commonly used by manual therapists and clinicians. Little is known about the validity of these tests; therefore, their clinical utility is uncertain. High quality validity studies are needed to inform the clinical use of manual palpation tests.

I have repeatedly drawn attention to the fact that the diagnostic methods used by chiropractors and osteopaths are of uncertain or disproven validity (see for instance here, or here). Why is that important?

Imagine you consult a chiropractor or osteopath. Simply put, this is what is likely to happen:

  • They listen to your complaint.
  • They do a few tests which are of dubious validity.
  • They give you a diagnosis that is meaningless.
  • They treat you with manual therapies that are neither effective nor safe.
  • You pay.
  • They persuade you that you need many more sessions.
  • You pay regularly.
  • When eventually your pain has gone away, they persuade you to have useless maintenance treatment.
  • You pay regularly.

In a nutshell, they have very little to offer … which explains why they attack everyone who dares to disclose this.

Cannabis seems often to be an emotional subject where more heat than light is generated. Does it work for chronic pain? This cannot be such a difficult question to answer definitively. Yet, systematic reviews have provided conflicting results due, in part, to limitations of analytical approaches and interpretation of findings.

A new systematic review is therefore both necessary and welcome. It aimed at determining the benefits and harms of medical cannabis and cannabinoids for chronic pain. Included were all randomised clinical trials of medical cannabis or cannabinoids versus any non-cannabis control for chronic pain at ≥1-month follow-up.

A total of 32 trials with 5174 adult patients were included, 29 of which compared medical cannabis or cannabinoids with placebo. Medical cannabis was administered orally (n=30) or topically (n=2). Clinical populations included chronic non-cancer pain (n=28) and cancer-related pain (n=4). Length of follow-up ranged from 1 to 5.5 months.

Compared with placebo, non-inhaled medical cannabis probably results in a small increase in the proportion of patients experiencing at least the minimally important difference (MID) of 1 cm (on a 10 cm visual analogue scale (VAS)) in pain relief (modelled risk difference (RD) of 10% (95% confidence interval 5% to 15%), based on a weighted mean difference (WMD) of −0.50 cm (95% CI −0.75 to −0.25 cm, moderate certainty)). Medical cannabis taken orally results in a very small improvement in physical functioning (4% modelled RD (0.1% to 8%) for achieving at least the MID of 10 points on the 100-point SF-36 physical functioning scale, WMD of 1.67 points (0.03 to 3.31, high certainty)), and a small improvement in sleep quality (6% modelled RD (2% to 9%) for achieving at least the MID of 1 cm on a 10 cm VAS, WMD of −0.35 cm (−0.55 to −0.14 cm, high certainty)). Medical cannabis taken orally does not improve emotional, role, or social functioning (high certainty). Moderate certainty evidence shows that medical cannabis taken orally probably results in a small increased risk of transient cognitive impairment (RD 2% (0.1% to 6%)), vomiting (RD 3% (0.4% to 6%)), drowsiness (RD 5% (2% to 8%)), impaired attention (RD 3% (1% to 8%)), and nausea (RD 5% (2% to 8%)), but not diarrhoea; while high certainty evidence shows greater increased risk of dizziness (RD 9% (5% to 14%)) for trials with <3 months follow-up versus RD 28% (18% to 43%) for trials with ≥3 months follow-up; interaction test P=0.003; moderate credibility of subgroup effect).

The authors concluded that moderate to high certainty evidence shows that non-inhaled medical cannabis or cannabinoids results in a small to very small improvement in pain relief, physical functioning, and sleep quality among patients with chronic pain, along with several transient adverse side effects, compared with placebo.

This is a high-quality review. Its findings will disappoint the many advocates of cannabis as a therapy for chronic pain management. The bottom line, I think, seems to be that cannabis works but the effect is not very powerful, while we have treatments for managing chronic pain that are both more effective and arguably less risky. So, its place in clinical routine is debatable.

PS

Cannabis is, of course, a herbal remedy and therefore belongs to so-called alternative medicine (SCAM). Yet, I am aware that the medical cannabis preparations used in most studies are based on single cannabinoids which makes them conventional medicines.

In their 2019 systematic review of spinal manipulative therapy (SMT) for chronic back pain, Rubinstein et al included 7 studies comparing the effect of SMT with sham SMT.

They defined SMT as any hands-on treatment of the spine, including both mobilization and manipulation. Mobilizations use low-grade velocity, small or large amplitude passive movement techniques within the patient’s range of motion and control. Manipulation uses a high-velocity impulse or thrust applied to a synovial joint over a short amplitude near or at the end of the passive or physiological range of motion. Even though there is overlap, it seems fair to say that mobilization is the domain of osteopaths, while manipulation is that of chiropractors.

The researchers found:

  • low-quality evidence suggesting that SMT does not result in a statistically better effect than sham SMT at one month,
  • very low-quality evidence suggesting that SMT does not result in a statistically better effect than sham SMT at six and 12 months.
  • low-quality evidence suggesting that, in terms of function, SMT results in a moderate to strong statistically significant and clinically better effect than sham SMT at one month. Exclusion of an extreme outlier accounted for a large percentage of the statistical heterogeneity for this outcome at this time interval (SMD −0.27, 95% confidence interval −0.52 to −0.02; participants=698; studies=7; I2=39%), resulting in a small, clinically better effect in favor of SMT.
  • very low-quality evidence suggesting that, in terms of function, SMT does not result in a statistically significant better effect than sham SMT at six and 12 months.

This means that SMT has effects that are very similar to placebo (the uncertain effects on function could be interpreted as the result of residual de-blinding due to a lack of an optimal placebo or sham intervention). In turn, this means that the effects patients experience are largely or completely due to a placebo response and that SMT has no or only a negligibly small specific effect on back pain. Considering the facts that SMT is by no means risk-free and that less risky treatments exist, the inescapable conclusion is that SMT cannot be recommended as a treatment of chronic back pain.

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