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

placebo

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Manual therapy is a commonly recommended treatment of low back pain (LBP), yet few studies have directly compared the effectiveness of thrust (spinal manipulation) vs non-thrust (spinal mobilization) techniques. This study evaluated the comparative effectiveness of spinal manipulation and spinal mobilization at reducing pain and disability compared with a placebo control group (sham cold laser) in a cohort of young adults with chronic LBP.

This single-blinded (investigator-blinded), placebo-controlled randomized clinical trial with 3 treatment groups was conducted at the Ohio Musculoskeletal and Neurological Institute at Ohio University from June 1, 2013, to August 31, 2017. Of 4903 adult patients assessed for eligibility, 4741 did not meet inclusion criteria, and 162 patients with chronic LBP qualified for randomization to 1 of 3 treatment groups. Participants received 6 treatment sessions of (1) spinal manipulation, (2) spinal mobilization, or (3) sham cold laser therapy (placebo) during a 3-week period. Licensed clinicians (either a doctor of osteopathic medicine or physical therapist), with at least 3 years of clinical experience using manipulative therapies provided all treatments.

Primary outcome measures were the change from baseline in Numerical Pain Rating Scale (NPRS) score over the last 7 days and the change in disability assessed with the Roland-Morris Disability Questionnaire (scores range from 0 to 24, with higher scores indicating greater disability) 48 to 72 hours after completion of the 6 treatments.

A total of 162 participants (mean [SD] age, 25.0 [6.2] years; 92 women [57%]) with chronic LBP (mean [SD] NPRS score, 4.3 [2.6] on a 1-10 scale, with higher scores indicating greater pain) were randomized.

  • 54 participants were randomized to the spinal manipulation group,
  • 54 to the spinal mobilization group,
  • 54 to the placebo group.

There were no significant group differences for sex, age, body mass index, duration of LBP symptoms, depression, fear avoidance, current pain, average pain over the last 7 days, and self-reported disability. At the primary end point, there was no significant difference in change in pain scores between spinal manipulation and spinal mobilization (0.24 [95% CI, -0.38 to 0.86]; P = .45), spinal manipulation and placebo (-0.03 [95% CI, -0.65 to 0.59]; P = .92), or spinal mobilization and placebo (-0.26 [95% CI, -0.38 to 0.85]; P = .39). There was no significant difference in change in self-reported disability scores between spinal manipulation and spinal mobilization (-1.00 [95% CI, -2.27 to 0.36]; P = .14), spinal manipulation and placebo (-0.07 [95% CI, -1.43 to 1.29]; P = .92) or spinal mobilization and placebo (0.93 [95% CI, -0.41 to 2.29]; P = .17). A comparison of treatment credibility and expectancy ratings across groups was not statistically significant (F2,151 = 1.70, P = .19), indicating that, on average, participants in each group had similar expectations regarding the likely benefit of their assigned treatment.

The authors concluded that in this randomized clinical trial, neither spinal manipulation nor spinal mobilization appeared to be effective treatments for mild to moderate chronic LBP.

This is an exceptionally well-reported study. Yet, one might raise a few points of criticism:

  1. The comparison of two active treatments makes this an equivalence study, and much larger sample sizes are required or such trials (this does not mean that the comparisons are not valid, however).
  2. The patients had rather mild symptoms; one could argue that patients with severe pain might respond differently.
  3. Chiropractors could argue that the therapists were not as expert at spinal manipulation as they are; had they employed chiropractic therapists, the results might have been different.
  4. A placebo control group makes more sense, if it allows patients to be blinded; this was not possible in this instance, and a better placebo might have produced different findings.

Despite these limitations, this study certainly is a valuable addition to the evidence. It casts more doubt on spinal manipulation and mobilisation as an effective therapy for LBP and confirms my often-voiced view that these treatments are not the best we can offer to LBP-patients.

 

Excessive eccentric exercise of inadequately conditioned skeletal muscle results in focal sites of injury within the muscle fibres. These injuries cause pain which usually is greatest about 72 hours after the exercise. This type of pain is called delayed-onset muscle soreness (DOMS) and provides an accessible model for studying the effects of various treatments that are said to have anaesthetic activities; it can easily be reproducibly generated without lasting harm or ethical concerns.

In so-called alternative medicine (SCAM) DOMS is employed regularly to test treatments which are promoted for pain management. Thus several acupuncture trials using this method have become available. Yet, the evidence for the effects of acupuncture on DOMS is inconsistent which begs the question whether across all trials an effects emerges.

The aim of this systematic review therefore was to explore the effects of acupuncture on DOMS. Studies investigating the effect of acupuncture on DOMS in humans that were published before March 2020 were obtained from 8 electronic databases. The affected muscles, groups, acupuncture points, treatment sessions, assessments, assessment times, and outcomes of the included articles were reviewed. The data were extracted and analysed via a meta-analysis.

A total of 15 articles were included, and relief of DOMS-related pain was the primary outcome. The meta-analysis showed that there were no significant differences between acupuncture and sham/control groups, except for acupuncture for DOMS on day 1 (total SMD = -0.62; 95% CI = -1.12∼0.11, P < 0.05) by comparing with control groups.

The authors concluded that acupuncture for DOMS exhibited very-small-to-small and small-to-moderate effects on pain relief for the sham and no acupuncture conditions, respectively. Evidence indicating the effects of acupuncture on DOMS was little because the outcome data during the follow-up were insufficient to perform an effective meta-analysis.

A mere glance at the Forrest plot reveals that acupuncture is unlikely to have any effect on DOMS at all. The very small average effect that does emerge originates mainly from one outlier, the 2008 study by Itoh et al. This trial was published by three acupuncturists from the Department of Clinical Acupuncture and Moxibustion, Meiji University of Integrative Medicine, Kyoto, Japan. It has numerous weaknesses, for instance there are just 10 volunteers in each group, and can therefore be safely discarded.

In essence, this means that there is no good evidence that acupuncture is effective at reducing pain caused by DOMS.

The purpose of this feasibility study was to:

(1) educate participants about the concept of Reiki,

(2) give participants the opportunity to experience six Reiki therapy sessions and subsequently assess outcomes on chronic pain,

(3) assess participants’ impression of and willingness to continue using and recommending Reiki therapy as adjunct for the treatment of chronic pain.

Using a prospective repeated measures pre- and postintervention design, a convenience sample of 30 military health care beneficiaries with chronic pain were educated about Reiki and received six 30-minute Reiki sessions over 2 to 3 weeks. Pain was assessed using a battery of pain assessment tools as well as assessment of impression of and willingness to share the concept of Reiki.

Repeated measures ANOVA analyses showed that there was significant decrease (P < 0.001) in present, average, and worst pain over the course of the six sessions with the most significant effect occurring up to the fourth session. When a variety of descriptor of pain was assessed, Reiki had a significant effect on 12 out of the 22 assessed, with the most significant effect on pain that was described as tingling/pins and needles (P = 0.001), sharp (P = 0.001), and aching (P = 0.001). Pain’s interference with general activity, walking, relationships, sleep, enjoyment of life, and stress significantly decreased (P < 0.001 to P = 0.002). Impression of improvement scores increased 27 % by session 6, and one’s knowledge about Reiki improved 43%. Eighty-one percent of the participants stated that they would consider scheduling Reiki sessions if they were offered with 70% desiring at least four sessions per month.

The authors concluded that 30-minute Reiki session, performed by a trained Reiki practitioner, is feasible in an outpatient setting with possible positive outcomes for participants who are willing to try at least four consecutive sessions. Reiki has the ability to impact a variety of types of pain as well as positively impacting those activities of life that pain often interferes with. However, education and the opportunity to experience this energy healing modality are key for its acceptance in military health care facilities as well as more robust clinical studies within the military health care system to further assess its validity and efficacy.

Where to begin?

  • As a feasibility study, this trial should not evaluate outcome data; yet the paper focusses on them.
  • To educate people one does certainly not require to conduct a study.
  • That Reiki ‘is feasible in an outpatient setting‘ is obvious and does not need a study either.
  • The finding that ‘Reiki had a significant effect’ is an unjustified and impermissible extrapolation; without a control group, it is not possible to determine whether the treatment or placebo-effects, or the regression towards the mean, or the natural history of the condition, or a mixture of these phenomena caused the observed outcome.
  • The conclusion that ‘Reiki has the ability to impact a variety of types of pain as well as positively impacting those activities of life that pain often interferes with’ is quite simply wrong.
  • The authors mention that ‘This study was approved by the U.S. Army Medical Research and Materiel Command Institutional Review Board’; I would argue that the review board must have been fast asleep.

Someone alerted me to a short article (2008) of mine that I had forgotten about. In it, I mention the 32 Cochrane reviews of acupuncture available at the time and the fact that they showed very little in favour of acupuncture. This made me wonder to what extent the situation might have changed in the last 12 years. So, I made a renewed attempt at evaluating this evidence. The entire exercise comes in three parts:

  1. My original paper from 2008
  2. The current evidence from Cochrane reviews
  3. Comments on the new evidence

PART 1

Acupuncture has a long history of ups and downs. Its latest renaissance started in 1971, when a journalist in President Nixon’s press corps experienced symptomatic relief after being treated for postoperative abdominal distension. He reported this experience in The New York Times, which triggered a flurry of interest and research. In turn, it was discovered that needling might release endorphins in the brain or act via the gate control mechanism. Thus, plausible modes of action seemed to have been found, and the credibility of acupuncture increased significantly. Numerous clinical trials were initiated, and their results often suggested that acupuncture is clinically effective for a surprisingly wide range of conditions. Both a World Health Organization report and a National Institutes of Health consensus conference provided long lists of indications for which acupuncture allegedly was of proven benefit.

Many of the clinical studies, however, lacked scientific rigor. Most experts therefore remained unconvinced about the true value of acupuncture, particularly as a treatment for all ills. Some investigators began to suspect that the results were largely due to patient expectation. Others showed that the Chinese literature, a rich source of acupuncture trials, does not contain a single negative study of acupuncture, thus questioning the reliability of this body of evidence.

A major methodological challenge was the adequate control for placebo effects in clinical trials of acupuncture. Shallow needling or needling at non-acupuncture points had been used extensively for this purpose. Whenever the results of such trials did not show what acupuncture enthusiasts had hoped, they tended to claim that these types of placebos also generated significant therapeutic effects. Therefore, a negative result still would be consistent with acupuncture being effective. The development of non-penetrating needles was aimed at avoiding such problems. These “stage dagger”-like devices are physiologically inert and patients cannot tell them from real acupuncture. Thus, they fulfil the criteria for a reasonably good placebo.

The seemingly difficult question of whether acupuncture works had become complex—what type of acupuncture, for what condition, compared with no treatment, standard therapy, or to placebo, and what type of placebo? Meanwhile, hundreds of controlled clinical trials had become available, and their results were far from uniform. In this situation, systematic reviews might be helpful in establishing the truth, particularly Cochrane reviews, which tend to be more rigorous, transparent, independent, and up-to-date than other reviews. The traditional Chinese concept of acupuncture as a panacea is reflected in the fact that 32 Cochrane reviews are currently (January 2008) available, and a further 35 protocols have been registered. The notion of acupuncture as a “heal all” is not supported by the conclusions of these articles. After discarding reviews that are based on only 3 or fewer primary studies, only 2 evidence-based indications emerge: nausea/vomiting and headache. Even this evidence has to be interpreted with caution; recent trials using the above-mentioned “stage-dagger” devices as placebos suggest that acupuncture has no specific effects in either of these conditions.

Further support for the hypothesis that acupuncture is largely devoid of specific therapeutic effects comes from a series of 8 large randomized controlled trials (RCTs) initiated by German health insurers (Figure). These studies had a similar, 3-parallel-group design: pain patients were randomized to receive either real acupuncture, shallow needling as a placebo control, or no acupuncture. Even though not entirely uniform, the results of these studies tend to demonstrate no or only small differences in terms of analgesic effects between real and placebo acupuncture. Yet, considerable differences were observed between the groups receiving either type of acupuncture and the group that had no acupuncture at all.

The most recent, as-yet-unpublished trial also seems to confirm the “placebo hypothesis.” This National Institutes of Health-sponsored RCT included 640 patients with chronic back pain. They received either individualized acupuncture according to the principles of traditional Chinese medicine, or a standardized form of acupuncture, or sham acupuncture. The results demonstrate that acupuncture added to usual care was superior to usual care alone, individualized acupuncture was not more effective than standardized acupuncture, and neither type of real acupuncture was more effective than sham acupuncture.

Figure

Schematic representation of the recent acupuncture trials all following a similar 3-group design. These 8 randomized controlled trials related to chronic back pain, migraine, tension headache, and knee osteoarthritis (2 trials for each indication). Their total sample size was in excess of 5000. Patients in the “no acupuncture” group received either standard care or were put on a waiting list. Sham acupuncture consisted of shallow needling at non-acupuncture points. Real acupuncture was semi-standardized. The differences between the effects of both types of acupuncture and no acupuncture were highly significant in each study. The differences between sham and real acupuncture were, with the exception of osteoarthritis, not statistically significant.

Enthusiasts employ such findings to argue that, in a pragmatic sense, acupuncture is demonstrably useful: it is clearly better than no acupuncture at all. Even if it were merely a placebo, what really matters is to alleviate pain of suffering patients, never mind the mechanism of action. Others are not so sure and point out that all well-administrated treatments, even those that generate effects beyond placebo, will induce a placebo response. A treatment that generates only non-specific effects (for conditions that are amenable to specific treatments) cannot be categorized as truly effective or useful, they insist.

So, after 3 decades of intensive research, is the end of acupuncture nigh? Given its many supporters, acupuncture is bound to survive the current wave of negative evidence, as it has survived previous threats. What has changed, however, is that, for the first time in its long history, acupuncture has been submitted to rigorous science—and conclusively failed the test.

[references in the original paper]

Part 2 will be posted tomorrow.

I have been sceptical about Craniosacral Therapy (CST) several times (see for instance here, here and here). Now, a new paper might change all this:

The systematic review assessed the evidence of Craniosacral Therapy (CST) for the treatment of chronic pain. Randomized clinical trials (RCTs) assessing the effects of CST in chronic pain patients were eligible. Pain intensity and functional disability were the primary outcomes. Risk of bias was assessed using the Cochrane tool.

Ten RCTs with a total of 681 patients suffering from neck and back pain, migraine, headache, fibromyalgia, epicondylitis, and pelvic girdle pain were included.

Compared to treatment as usual, CST showed greater post intervention effects on:

  • pain intensity (SMD=-0.32, 95%CI=[−0.61,-0.02])
  • disability (SMD=-0.58, 95%CI=[−0.92,-0.24]).

Compared to manual/non-manual sham, CST showed greater post intervention effects on:

  • pain intensity (SMD=-0.63, 95%CI=[−0.90,-0.37])
  • disability (SMD=-0.54, 95%CI=[−0.81,-0.28]) ;

Compared to active manual treatments, CST showed greater post intervention effects on:

  • pain intensity (SMD=-0.53, 95%CI=[−0.89,-0.16])
  • disability (SMD=-0.58, 95%CI=[−0.95,-0.21]) .

At six months, CST showed greater effects on pain intensity (SMD=-0.59, 95%CI=[−0.99,-0.19]) and disability (SMD=-0.53, 95%CI=[−0.87,-0.19]) versus sham. Secondary outcomes were all significantly more improved in CST patients than in other groups, except for six-month mental quality of life versus sham. Sensitivity analyses revealed robust effects of CST against most risk of bias domains. Five of the 10 RCTs reported safety data. No serious adverse events occurred. Minor adverse events were equally distributed between the groups.

The authors concluded that, in patients with chronic pain, this meta-analysis suggests significant and robust effects of CST on pain and function lasting up to six months. More RCTs strictly following CONSORT are needed to further corroborate the effects and safety of CST on chronic pain.

Robust effects! This looks almost convincing, particularly to an uncritical proponent of so-called alternative medicine (SCAM). However, a bit of critical thinking quickly discloses numerous problems, not with this (technically well-made) review, but with the interpretation of its results and the conclusions. Let me mention a few that spring into my mind:

  1. The literature searches were concluded in August 2018; why publish the paper only in 2020? Meanwhile, there might have been further studies which would render the review outdated even on the day it was published. (I know that there are many reasons for such a delay, but a responsible journal editor must insist on an update of the searches before publication.)
  2. Comparisons to ‘treatment as usual’ do not control for the potentially important placebo effects of CST and thus tell us nothing about the effectiveness of CST per se.
  3. The same applies to comparisons to ‘active’ manual treatments and ‘non-manual’ sham (the purpose of a sham is to blind patients; a non-manual sham defies this purpose).
  4. This leaves us with exactly two trials employing a sham that might have been sufficiently credible to be able to fool patients into believing that they were receiving the verum.
  5. One of these trials (ref 44) is far too flimsy to be taken seriously: it was tiny (n=23), did not adequately blind patients, and failed to mention adverse effects (thus violating research ethics [I cannot take such trials seriously]).
  6. The other trial (ref 41) is by the same research group as the review, and the authors award themselves a higher quality score than any other of the primary studies (perhaps even correctly, because the other trials are even worse). Yet, their study has considerable weaknesses which they fail to discuss: it was small (n=54), there was no check to see whether patient-blinding was successful, and – as with all the CST studies – the therapist was, of course, no blind. The latter point is crucial, I think, because patients can easily be influenced by the therapists via verbal or non-verbal communication to report the findings favoured by the therapist. This means that the small effects seen in such studies are likely to be due to this residual bias and thus have nothing to do with the intervention per se.
  7. Despite the fact that the review findings depend critically on their own primary study, the authors of the review declared that they have no conflict of interest.

Considering all this plus the rather important fact that CST completely lacks biological plausibility, I do not think that the conclusions of the review are warranted. I much prefer the ones from my own systematic review of 2012. It included 6 RCTs (all of which were burdened with a high risk of bias) and concluded that the notion that CST is associated with more than non‐specific effects is not based on evidence from rigorous RCTs.

So, why do the review authors first go to the trouble of conducting a technically sound systematic review and meta-analysis and then fail utterly to interpret its findings critically? I might have an answer to this question. Back in 2016, I included the head of this research group, Gustav Dobos, into my ‘hall of fame’ because he is one of the many SCAM researchers who never seem to publish a negative result. This is what I then wrote about him:

Dobos seems to be an ‘all-rounder’ whose research tackles a wide range of alternative treatments. That is perhaps unremarkable – but what I do find remarkable is the impression that, whatever he researches, the results turn out to be pretty positive. This might imply one of two things, in my view:

I let my readers chose which possibility they deem to be more likely.

Radiation-induced xerostomia (RIX) is a common, often debilitating, adverse effect of radiation therapy among patients with head and neck cancer. Quality of life can be severely affected, and current treatments have limited benefit. Acupuncture is often recommended, but does it work? This study was aimed at finding out whether acupuncture can prevent RIX in patients with head and neck cancer undergoing radiation therapy.

The 2-center, phase 3, randomized clinical trial compared a standard care control (SCC) with true acupuncture (TA) and sham acupuncture (SA) among patients with oropharyngeal or nasopharyngeal carcinoma who were undergoing radiation therapy in comprehensive cancer centres in the United States and China. Patients were enrolled between December 16, 2011, and July 7, 2015. Final follow-up was August 15, 2016. Analyses were conducted February 1 through 28, 2019. Either TA or SA using a validated acupuncture placebo device were performed 3 times per week during a 6- to 7-week course of radiation therapy. The primary end point was RIX, as determined by the Xerostomia Questionnaire in which a higher score indicates worse RIX, for combined institutions 1 year after radiation therapy ended. Secondary outcomes included incidence of clinically significant xerostomia (score >30), salivary flow, quality of life, salivary constituents, and role of baseline expectancy related to acupuncture on outcomes.

Of 399 patients randomized, 339 were included in the final analysis, including 112 patients in the TA group, 115 patients in the SA group, and 112 patients in the SCC group. For the primary aim, the adjusted least square mean (SD) xerostomia score in the TA group (26.6 [17.7]) was significantly lower than in the SCC group (34.8 [18.7]) (P = .001; effect size = -0.44) and marginally lower but not statistically significant different from the SA group (31.3 [18.6]) (P = .06; effect size = -0.26). Incidence of clinically significant xerostomia 1 year after radiation therapy ended followed a similar pattern, with 38 patients in the TA group (34.6%), 54 patients in the SA group (47.8%), and 60 patients in the SCC group (55.1%) experiencing clinically significant xerostomia (P = .009). Post hoc comparisons revealed a significant difference between the TA and SCC groups at both institutions, but TA was significantly different from SA only at Fudan University Cancer Center, Shanghai, China (estimated difference [SE]: TA vs SCC, -9.9 [2.5]; P < .001; SA vs SCC, -1.7 [2.5]; P = .50; TA vs SA, -8.2 [2.5]; P = .001), and SA was significantly different from SCC only at the University of Texas MD Anderson Cancer Center, Houston, Texas (estimated difference [SE]: TA vs SCC, -8.1 [3.4]; P = .016; SA vs SCC, -10.5 [3.3]; P = .002; TA vs SA, 2.4 [3.2]; P = .45).

The authors concluded that this randomized clinical trial found that TA resulted in significantly fewer and less severe RIX symptoms 1 year after treatment vs SCC. However, further studies are needed to confirm clinical relevance and generalizability of this finding and to evaluate inconsistencies in response to sham acupuncture between patients in the United States and China.

In essence this two-centre study shows that:

  • real acupuncture is better than usual care, but the effect size is small and of doubtful clinical relevance;
  • real acupuncture is not significantly better than sham acupuncture;
  • the findings differ remarkably between the US and the Chinese centre.

I find the last point the most interesting one. We know from previous research that acupuncture studies from China are notoriously unreliable; they never report a negative result and there is evidence that data fabrication is rife in China. The new findings seems to throw more light on this notion. In the US centre, real and sham acupuncture generated practically identical results. By contrast, in the Chinese centre, real acupuncture generated significantly better results than sham. The authors offer several hypotheses to explain this remarkable phenomenon. Yet, in my view, the most likely one is that Chinese researchers are determined to show that acupuncture is effective. Thus all sorts of unconscious or even conscious biases might get introduced into such studies.

In essence, trial therefore confirms that acupuncture is little more than a theatrical placebo, particularly if we consider the US data which, in my opinion, are more trustworthy.

Lorenzo Cohen, Professor of Palliative, Rehabilitation, and Integrative Medicine and director of the Integrative Medicine Program as well as senior author of the paper unsurprisingly disagrees. He was quoted saying: “The evidence is to a point where patients should incorporate acupuncture alongside radiation treatment as a way to prevent the severity of dry mouth symptoms. I think with this study we can add acupuncture to the list for the prevention and treatment of xerostomia, and the guidelines for the use of acupuncture in the oncology setting should be revised to include this important chronic condition.”

Who do you think is closer to the truth?

The U.S. Food and Drug Administration (FDA) issued another warning about homeopathy. Here are some of the most relevant excerpts:

… Homeopathic products … are marketed without FDA review and may not meet modern standards for safety, effectiveness, quality and labeling. FDA uses a risk-based approach to monitor these products and to evaluate reports of adverse effects.

… Homeopathic drug products are made from a wide range of substances, including ingredients derived from plants, healthy or diseased animal or human sources, minerals and chemicals, including known poisons. These products have the potential to cause significant and even permanent harm if they are poorly manufactured, since that could lead to contaminated products or products that have potentially toxic ingredients at higher levels than are labeled and/or safe, or if they are marketed as substitute treatments for serious or life-threatening diseases and conditions, or to vulnerable populations. In addition, some products may be labeled as homeopathic that do not conform to traditional homeopathic principles.

As the homeopathy industry continues to grow at a rapid pace, we want to clarify for both consumers and industry how we assess the potential safety risks of these products. That’s why in 2017, the FDA issued a draft guidance discussing our, risk-based enforcement approach to drug products labeled as homeopathic. Today, we are taking two new steps toward clarifying this approach.

First, we have revised the 2017 draft guidanceExternal Link Disclaimer to provide further information around our approach and are asking for public input on the revised draft. The draft guidance details a risk-based enforcement policy prioritizing certain categories of homeopathic products that could pose a higher risk to public health, including products with particular ingredients and routes of administration, products for vulnerable populations, and products with significant quality issues. We encourage the public to review this revised draft guidance and comment before it is finalized. We will consider feedback gathered through this new public comment period, the more than 4,500 comments interested stakeholders submitted on the original 2017 draft guidance, and information gleaned from a 2015 public hearing on the current use of homeopathic drug products. When finalized, this guidance will help provide transparency regarding the categories of homeopathic drug products that we intend to prioritize under our risk-based enforcement approach.

Second, the agency is withdrawingExternal Link Disclaimer the Compliance Policy Guide (CPG) 400.400, entitled “Conditions Under Which Homeopathic Drugs May be Marketed.” Risk is an important driver of the FDA’s regulatory and enforcement actions for all drug products, including homeopathic drug products. Since the issuance of CPG 400.400 in 1988, the FDA has encountered multiple situations in which homeopathic drug products posed a significant risk to patients, even though the products, as labeled, appeared to meet the conditions described in CPG 400.400. However, CPG 400.400 is inconsistent with our risk-based approach to regulatory and enforcement action generally and therefore does not reflect our current thinking. Therefore, it is appropriate to withdraw CPG 400.400 at this time.

… the FDA has issued warning letters to companies who produce homeopathic drug products for significant violations of current good manufacturing practice (CGMP) regulations and various other violations. So far in 2019, we’ve issued more than 10 warning letters to companies for violations concerning homeopathic products. Recently, we issued warning letters to Kadesh Inc., U.S. Continental Marketing, Inc., Fill It Pack It Inc. and Bershtel Enterprises LLC dba WePackItAll, which had jointly manufactured and packaged eye drops produced in non-sterile conditions which could result in serious eye infections. These warning letters should alert all companies that homeopathic drug products must be manufactured and labeled in accordance with the requirements of the Federal Food, Drug, and Cosmetic Act and agency regulations…

_________________________________________________

If you ask me, ‘homeopathic drug products’ is a misleading name. A drug is defined as a medicine or other substance which has a physiological effect when ingested or otherwise introduced into the body. But highly diluted homeopathics do not contain a substance that has physiological effects.

They should be called

  • homeopathics,
  • homeopathic pseudo-drugs,
  • homeopathic placebos,
  • or fake drugs.

And their labels should make it clear that:

  • these products contain no active ingredients,
  • and have not been shown to work beyond placebo.

That would be the type of honest and transparent information which consumers deserve and have a right to.

 

Spinal manipulation is a treatment employed by several professions, including physiotherapists and osteopaths; for chiropractors, it is the hallmark therapy.

  • They use it for (almost) every patient.
  • They use it for (almost) every condition.
  • They have developed most of the techniques.
  • Spinal manipulation is the focus of their education and training.
  • All textbooks of chiropractic focus on spinal manipulation.
  • Chiropractors are responsible for most of the research on spinal manipulation.
  • Chiropractors are responsible for most of the adverse effects of spinal manipulation.

Spinal manipulation has traditionally involved an element of targeting the technique to a level of the spine where the proposed movement dysfunction is sited. This study evaluated the effects of a targeted manipulative thrust versus a thrust applied generally to the lumbar region.

Sixty patients with low back pain were randomly allocated to two groups: one group received a targeted manipulative thrust (n=29) and the other a general manipulation thrust (GT) (n=31) to the lumbar spine. Thrust was either localised to a clinician-defined symptomatic spinal level or an equal force was applied through the whole lumbosacral region. The investigators measured pressure-pain thresholds (PPTs) using algometry and muscle activity (magnitude of stretch reflex) via surface electromyography. Numerical ratings of pain and Oswestry Disability Index scores were collected.

Repeated measures of analysis of covariance revealed no between-group differences in self-reported pain or PPT for any of the muscles studied. The authors concluded that a GT procedure—applied without any specific targeting—was as effective in reducing participants’ pain scores as targeted approaches.

The authors point out that their data are similar to findings from a study undertaken with a younger, military sample, showing no significant difference in pain response to a general versus specific rotation, manipulation technique. They furthermore discuss that, if ‘targeted’ manipulation proves to be no better than ‘general’ manipulation (when there has been further research, more studies), it would challenge the need for some current training courses that involve comprehensive manual skill training and teaching of specific techniques. If simple SM interventions could be delivered with less training, than the targeted approach currently requires, it would mean a greater proportion of the population who have back pain could access those general manipulation techniques. 

Assuming that the GT used in this trial was equivalent to a placebo control, another interpretation of these results is that the effects of spinal manipulation are largely or even entirely due to a placebo response. If this were confirmed in further studies, it would be yet one more point to argue that spinal manipulation is not a treatment of choice for back pain or any other condition.

I have often discussed the fact that many proponents of so-called alternative medicine (SCAM) have in recent years adopted the following argument: even if our SCAM were just a placebo, it would still be useful. After all, placebo effects are real and increasingly backed by sound science. The argument is deeply flawed, yet it convinces many lay people.

A recent article by Fabrizio Benedetti, the leading researcher in the area of placebo, is addressing exactly this issue. I feel that it is sufficiently important to quote it extensively here:

… a number of biochemical pathways, such as endogenous opioids and cannabinoids,5,6 and brain regions, like the prefrontal cortex, have been found to be involved in placebo analgesia. Likewise, dopamine and the basal ganglia circuitry have been found to mediate placebo responses in Parkinson’s disease. Although this is wonderful news for science, this may not be the case for society. The number of nonmedical organizations and healers that rely on this hard science, and actually justify their odd and bizarre procedures, has increased over the past few years. The main claim is that any procedure boosting patients’ expectations, which represent the main mediator of placebo effects, is acceptable because it can activate the same biochemical pathways and neural networks that have been made credible by hard science…

The crucial point here is that when hard science started investigating placebo effects, it unconsciously produced a shift in quackery thinking. In fact, charlatans are becoming more and more aware that their bizarre interventions could work through a placebo effect. Indeed, whereas hard science has so far denied any scientific basis for nonconventional therapies, now the very same hard science certifies that the placebo effect has scientific grounds. Therefore, quacks are no longer interested in showing that their pseudo-interventions work; rather, they justify their use on the basis of the possibility that these bizarre interventions may induce strong placebo effects…

… A first point that should be emphasized is that placebos do not cure, but rather, they may sometimes improve quality of life. There is plenty of confusion on this point, and unfortunately, many claim that they can cure virtually all illnesses with placebos. Hard science tells us that placebos can reduce symptoms such as pain and muscle rigidity in Parkinson’s disease, yet the progression of the disease is not affected; for example, in Parkinson’s disease, neurons keep degenerating even though some symptoms can be reduced for a short time.4 The second point is related to the first. The type of disease is crucial, and we need to make people understand that pain is different from cancer and that anxiety differs from infectious diseases. The psychological component of some illnesses can indeed be modulated by placebos, but placebos cannot stop cancer growth, nor can they kill the bacteria of pneumonia. The third point is related to the difference between real placebo effects and spontaneous remissions. So far, hard science has studied the placebo effect within a time span of hours/days, thereby limiting our knowledge to short-lasting effects. Consequently, long-lasting effects can be often attributed to spontaneous remissions.

In addition to these three important points, we should also make patients understand that a diagnosis is required before any sort of therapy. An apparently trivial pain may conceal a danger; thus, it must never be treated unless a diagnosis has been made before, and this can be made only by physicians. Moreover, not only should we discuss and consider the positive effects of placebos and the impact they may have in clinical trials and medical practice, but we should also pay much of our attention to the negative counterpart, that is, the misuse and abuse by quacks, charlatans, shamans, and nonmedical organizations. Thus, we need to inform the whole society that the benefits following a nonconventional healing procedure are attributable to a placebo effect in most of the cases. Last but not least, we need to be more honest on the real efficacy of many pharmacological and nonpharmacological treatments, acknowledging that some of them are useful whereas some others are not: This will boost patients’ trust and confidence in medicine further, which I believe are the best foes of quackery…

…Unfortunately, quackery has today one more weapon on its side, which is paradoxically represented by the hard science–supported placebo mechanisms. This new “scientific quackery” can do a lot of damage; thus, we must be very cautious and vigilant as to how the findings of hard science are exploited. The study of the biology of these vulnerable aspects of mankind may unravel new mechanisms of how our brain works, but it may have a profound negative impact on our society as well. We cannot accept a world where expectations can be enhanced with any means and by anybody. This is a perspective that would surely be worrisome and dangerous. I believe that some reflections are necessary in order to avoid a regression of medicine to past times, in which quackery and shamanism were dominant. Unfortunately, the new knowledge about placebos by hard science is now backfiring on it. What we need to do is to stop for a while and reflect on what we are doing and how we want to move forward. A crucial question to answer is, Does placebo research boost pseudoscience?

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I am immensely thankful to Prof Benedetti to make such clear and long-overdue statements. They will be most helpful in refuting the myth that homeopathy, para-normal healing, reflexology, acupuncture, chiropractic, etc., etc. are legitimate and uselful therapies, even if they are not better than a placebo. Using placebo therapies in routine care is not in the best interest of either the patient or progress.

An abstract from the recent ‘2nd OFFICIAL SIPS CONFERENCE ON PLACEBO STUDIES’ caught my attention. It is not available on-line; therefore let me reproduce it here in full:

The role of placebo effects in mindfulness-based analgesia 1. Jonathan Davies. University of Sydney, Sydney, NSW, Australia. 2. Louise Sharpe. University of Sydney, Sydney, NSW, Australia. 3. Melissa Day. University of Queensland, Brisbane, QLD, Australia. 4. Ben Colagiuri. University of Sydney, Sydney, NSW, Australia.

Background: Mindfulness meditation can reduce pain both in experimental and clinical settings, though it is not known to what extent mindfulness-specific vs placebo-like expectancy effects account for these changes. This study aimed to: 1. establish whether placebo effects contribute to mindfulness-mediated analgesia; and 2. identify putative cognitive mechanisms responsible for placebo- vs mindfulness-mediated analgesia. Methods: We compared the effects of focussed-attention mindfulness training (6 x 20 min), sham mindfulness, and a no-treatment in a double-blind RCT for experimental heat pain. Sham mindfulness instructions lacked the ‘active ingredients’ of the real training but were matched on all other contextual factors. Results: Both real and sham mindfulness training led to greater pain tolerance relative to no treatment, but there was no difference between the real and sham training. This was accompanied by increased expectancy, beliefs, and pain-related cognitive processes in the two mindfulness groups relative to no treatment, but again there were no differences between real and sham training on these outcomes. There were no effects on pain intensity, pleasantness or threshold. Conclusion: These findings suggest that mindfulness training – at least those involving focused-attention – may lead to improved pain tolerance via the placebo effect rather than any specific mindfulness-related mechanisms. Potential mediators of these effects will be discussed.

I find this study remarkable in two ways:

  1. It shows that, with a bit of fantasy, ingenuity and will, one can design and use sham procedures even in clinical trials of mind/body therapies.
  2. Its results suggest that, if one does control for placebo effects, these treatments may not prove to be more than a placebo therapy.

What implications might this have for clinical practice?

Mindfulness is currently hugely popular. It would not be surprising, if the news that it might rely purely on placebo effects would calm down the enthusiasm about this treatment. Many might ask, does it matter? As long as patients benefit, the mechanism of action seems irrelevant. This, of course, is an interesting debate which we have had on this blog many times before.

What do you think?

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