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

systematic review

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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.

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.

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.

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.

Homeopaths believe that their remedies work for every condition imaginable and that naturally includes irritable bowel syndrome (IBS). But what does the evidence show?

The aim of this pilot study was to evaluate the efficacy of individualized homeopathic treatment in patients with IBS. The study was carried out at the National Homeopathic Hospital of the Secretary of Health, Mexico City, Mexico and included 41 patients: 3 men and 38 women, mean age 54 ± 14.89 years, diagnosed with IBS as defined by the Rome IV Diagnostic criteria. Single individualized homeopathics were prescribed for each patient, taking into account all presenting symptoms, clinical history, and personality via repertorization using RADAR Homeopathic Software. The homeopathic remedies were used at the fifty-millesimal (LM) potency per the Mexican Homeopathic Pharmacopoeia starting with 0/1 and increasing every month (0/2, 0/3, 0/6). Severity scales were applied at the beginning of treatment and every month for 4 months of treatment. The evaluation was based on comparing symptom severity scales during treatment.

The results demonstrated that 100% of patients showed some improvement and 63% showed major improvement or were cured. The study showed a significant decrease in the severity of symptom scores 3 months after the treatment, with the pain score showing a decrease already one month after treatment.

The authors state that the results highlight the importance of individualized medicine regimens using LM potency, although the early decrease in pain observed could also be due to the fact that Lycopodium clavatum and Nux vomica were the main homeopathic medicine prescribed, and these medicines contain many types of alkaloids, which have shown significant analgesic effects on pain caused by physical and chemical stimulation.

The authors concluded that this pilot study suggests that individualized homeopathic treatment using LM potencies benefits patients with IBS.

Where to begin?

Let me mention just a few rather obvious points:

  1. A pilot study is not for evaluating the efficacy, but for testing the feasibility of a definitive trial.
  2. The study has no control group, therefore the outcome cannot be attributed to the treatment but is most likely due to a mixture of placebo effects, regression towards the mean, and natural history of IBS.
  3. The conclusions are not warranted.
  4. The paper was published in the infamous Altern Ther Health Med.

Just to make sure that nobody is fooled into believing that homeopathy might nonetheless be effective for IBS. Here is what the Cochrane review on this subject tells us: no firm conclusions regarding the effectiveness and safety of homeopathy for the treatment of IBS can be drawn. Further high quality, adequately powered RCTs are required to assess the efficacy and safety of clinical and individualised homeopathy for IBS compared to placebo or usual care.

In my view, even the conclusion of the Cochrane review is odd and slightly misleading. The correct conclusion would have been something more to the point:

THE CURRENT TRIAL EVIDENCE FAILS TO INDICATE THAT HOMEOPATHY IS AN EFFECTIVE TREATMENT FOR IBS.

The authors of this review start their paper with the following statement:

Acupuncture has demonstrated effectiveness for symptom management among breast cancer survivors.

This, I think, begs the following question: if they already know that, why do they conduct a systematic review of the subject?

The answer becomes clear as we read thier article: they want to add another paper to the literature that shows they are correct in their assumption.

So, they do the searches and found 26 trials (2055 patients), of which 20 (1709 patients) could be included in the meta-analysis. Unsurprisingly, their results show that acupuncture was more effective than control groups in improving pain intensity [standardized mean difference (SMD) = -0.60, 95% confidence intervals (CI) -1.06 to -0.15], fatigue [SMD = -0.62, 95% CI -1.03 to -0.20], and hot flash severity [SMD = -0.52, 95% CI -0.82 to -0.22].  Compared with waitlist control and usual care groups, the acupuncture groups showed significant reductions in pain intensity, fatigue, depression, hot flash severity, and neuropathy. No serious adverse events were reported related to acupuncture intervention. Mild adverse events (i.e., bruising, pain, swelling, skin infection, hematoma, headache, menstrual bleeding) were reported in 11 studies.

The authors concluded that this systematic review and meta-analysis suggest that acupuncture significantly reduces multiple treatment-related symptoms compared with the usual care or waitlist control group among breast cancer survivors. The safety of acupuncture was inadequately reported in the included studies. Based on the available data, acupuncture seems to be generally a safe treatment with some mild adverse events. These findings provide evidence-based recommendations for incorporating acupuncture into clinical breast cancer symptom management. Due to the high risk of bias and blinding issues in some RCTs, more rigorous trials are needed to confirm the efficacy of acupuncture in reducing multiple treatment-related symptoms among breast cancer survivors.

Yes, I agree: this is an uncritical white-wash of the evidence. So, why do I bother to discuss this paper? After all, the acupuncture literature is littered with such nonsense.

Well, to my surprise, the results did contain a little gem after all.

A subgroup analysis of the data indicated that acupuncture showed no significant effects on any of the treatment-related symptoms compared with the sham acupuncture groups.

In other words, this paper confirms what has been discussed repeatedly on this blog (see for instance here, here, and here):

Acupuncture seems to be a placebo therapy!

Bromelain, papain and chymotrypsin are proteolytic enzymes. They can be found in fruits such as pineapple or papaya, but also in the human body, namely in the pancreas. Besides their enzymatic functions, they have long been said to have a wide range of positive health effects. For instance, it is claimed that they reduce side effects and even improve the outcome of cancer therapies. This systematic review examined the existing evidence on the role that these enzymes which are available as food supplements might play in cancer treatment.

A total of 15 studies with 3,008 patients could be included in this systematic review. Patients treated with enzymes were diagnosed with various entities of gastrointestinal, gynecologic, head and neck, and lung cancer as well as hematological malignancies. The therapy concepts included mainly oral intake of enzymes in addition to conventional therapies. Investigated outcomes were:

  • side-effects of anticancer therapy,
  • quality of life,
  • anticancer effects,
  • survival rates.

Due to conflicting results and moderate quality of the included studies, the evidence is insufficient to attribute positive effects to enzymes in terms of better tolerability of the various antineoplastic therapies or even improvement in treatment efficacy. In most cases, enzyme therapy was well tolerated; side-effects were mainly gastrointestinal complaints such as diarrhea or meteorism.

The authors concluded that there is no clear therapeutic benefit of enzymes neither as supportive therapy nor as part of antineoplastic therapy.

I fully agree with this conclusion. In fact, in my new book that is just being published, I summarised the evidence for enzyme therapy (and many more alternative cancer therapies) in very similar terms: the evidence to suggest that enzyme therapy might be an effective treatment for any type of cancer is less than convincing.

I find it highly irresponsible to claim otherwise. Cancer patients are vulnerable and can easily be tempted to opt for one of the many quack treatments that are said to be both effective and free of nasty adverse effects. If they do try such options, they usually pay dearly, and not just in monetary terms.

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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