pain
Recently, several papers reported about PP353 as a new ‘wonder drug’ for chronic low back pain (cLBP). The reason is that Persica Pharmaceuticals Limited (Persica) announced positive results of a randomised, double-blind, placebo-controlled clinical trial assessing the safety and efficacy of PP353 as a treatment for patients with chronic low back pain (cLBP). PP353 is a specifically formulated combination of linezolid, iohexol and a thermosensitive gel that is injected into the degenerate lumbar disc, delivering prolonged exposure of a high concentration at the site of infection. A 2-dose regime (dosed 4 days apart) is said to eliminate the infection, thus addressing the underlying cause of cLBP which is claimed to be an infection.
Intradiscal administration of 3 mL of PP353 has been reported to be well-tolerated and based on the pharmacokinetics following a single injection, a two-dose regimen of PP353 (150 mg linezolid) on Day 1 and Day 5 ± 1 was selected to explore safety, tolerability, pharmacokinetics, and efficacy in Part B of the Persica 002 study.
The abovementioned efficacy trial enrolled 44 patients who had suffered from cLBP for more than 6 months (mean duration of 5.5 years) and had not been helped by existing non-surgical treatments. They were randomized to receive either PP353 or placebo injected into intervertebral discs. The results of the study demonstrated statistically significant and clinically meaningful results in patients with cLBP. Compared to placebo, the verum led to a 30% reduction of pain after 12 months. The placebo group did not achieve clinically meaningful change from baseline. The PP353 group also reported statistically significant and clinically meaningful reductions in disability with a within-group reduction of 9.4-points (63%) and a between-group reduction of 3.9-points (39%) from placebo in the Full Analysis Set of subjects at 12 months.
The manufacturer claims to provide an alternative, non-opioid, treatment for cLBP patients by replacing the 100-day high-dose oral antibiotics course to treat cLBP with an injectable antibiotic formulation that will achieve high local concentration and adequate duration of exposure in the spine to effect the sterilisation of the infected disc.
Local administration of antibiotic has the potential to elicit a faster response because an effective drug concentration in the infected tissue is immediately achieved. It also significantly reduces the amount of drug required, reducing the likelihood of systemic side effects, especially those associated with perturbation of the gut microbiome.
Intradiscal administration of therapeutics to treat cLBP is an established but mostly ineffective route. Persica believes that an effective treatment must address the underlying cause of disease – the infection. An effective antibacterial therapeutic should reduce the inflammatory stimuli in the intervertebral space and adjacent bone and allow repair over time, leading to a reduction in pain.
During the development of PP353, Persica tested several generic antibiotics in vitro and in vivo to find an antibiotic with the required properties: active against the bacteria identified in disc and herniated tissue samples, little to no resistance in clinical isolates, and the ability to be formulated to provide a depot to extend the duration of exposure.
To enable administration of the antibiotic, Persica developed a unique formulation which delivers the antibiotics to the site of infection and ensures that it remains within the infected area.
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Sounds good?
Yes, perhaps even a little too good to be true!
Here are some of my concerns:
- The manufacturer has, as far as I can see, not published the findings in a peer-reviewed journal and thus wants us to believe the findings without scrutinizing the methodology.
- Even if they eventually do publish the study in full, and even if it turns out to be rigorous, one would still want independent preplications.
- There is an undenialble and very substantial financial interest in the matter (anyone who comes out with an effective and safe pill against cLBP, will quickly make billions!), and one might therefore wonder how objective the manufacturer can be about the merits of PP353.
- The assumption that many cases of cLBP are caused by a disc infection is a well-known theory, but it remains largely unproven.
- As we dicuseed only recently, antibiotics have not been shown to be effective for cLBP.
Clearly, we have to wait and see – but my advice is to take PP353 with a healthy pinch of salt.
A long article on chiropractic casts doubt that chiropractic is useful. Here is an abbreviated version of it:
The chemistry and biology graduate from the University of Georgia, 28-year-old Caitlin Jensen, visited a chiropractor to sort out her lower back pain. During the session, the therapist performed an adjustment. It severed four arteries in her neck. She collapsed shortly after, unable to speak or move. The injury had caused her to suffer a series of strokes. Today, she has regained some movement in her head, legs and arms but she is still unable to speak, is partially blind and relies on a wheelchair.
- One 66-year-old grandmother said a visit to a chiropractor to treat her sore shoulder left her covered in bruises, hearing ringing in her ears and with a splitting pain in her jaw. She was later diagnosed by doctors with trigeminal neuralgia – a chronic pain disorder caused by a trapped or irritated nerve in the neck that causes sudden, electric shock-like pain in the face. She believes the condition – which, three years later, still sometimes leaves her unable to open her mouth wide enough to speak to her grandchildren – was triggered by a chiropractic adjustment of her neck.
- A 55-year-old woman was left with chronic neck and shoulder pain after visiting a chiropractor for a sore back. The pain was so bad she once spent 72 hours immobile and unable to sleep despite taking a concoction of painkillers.
- And a 66-year-old man says his back went into spasm as he was leaving his first chiropractor appointment – which left him hospitalised and bedbound for weeks. The intense treatment, he later learned, had pushed one of the discs of his spine out of place, causing him to lose feeling in his right leg for ever.
The aim of this recent review was to investigate the efficacy of non-surgical and non-interventional treatments for adults with low back pain compared with placebo. It included all randomised controlled trials evaluating non-surgical and non-interventional treatments compared with placebo or sham in adults (≥18 years) suffering from non-specific low back pain.
Random effects meta-analysis was used to estimate pooled effects and corresponding 95% confidence intervals on outcome pain intensity (0 to 100 scale) at first assessment post-treatment for each treatment type and by duration of low back pain—(sub)acute (<12 weeks) and chronic (≥12 weeks). Certainty of the evidence was assessed using the Grading of Recommendations Assessment (GRADE) approach.
A total of 301 trials (377 comparisons) provided data on 56 different treatments or treatment combinations. One treatment for acute low back pain: (non-steroidal anti-inflammatory drugs (NSAIDs)), and five treatments for chronic low back pain:
- exercise,
- spinal manipulative therapy,
- taping,
- antidepressants,
- transient receptor potential vanilloid 1 (TRPV1) agonists)
were found to be efficacious. However, effect sizes were small and of moderate certainty. Three treatments for acute low back pain (exercise, glucocorticoid injections, paracetamol), and two treatments for chronic low back pain (antibiotics, anaesthetics) were not efficacious and are unlikely to be suitable treatment options; moderate certainty evidence. Evidence is inconclusive for remaining treatments due to small samples, imprecision, or low and very low certainty evidence.
The authors concluded that the current evidence shows that one in 10 non-surgical and non-interventional treatments for low back pain are efficacious, providing only small analgesic effects beyond placebo. The efficacy for the majority of treatments is uncertain due to the limited number of randomised participants and poor study quality. Further high-quality, placebo-controlled trials are warranted to address the remaining uncertainty in treatment efficacy along with greater consideration for placebo-control design of non-surgical and non-interventional treatments.
This is an important analysis, not least because of the fact that the research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. The methodology is sound and the results thus seem reliable.
The findings are in keeping with what we have been discussing at nauseam here: no treatment works really well for back pain. For acute symptoms no so-called alternative medicine (SCAM) at all is efficacious. For chronic pain, spinal manipulation therapy (SMT) have small effects. As SMT is neither cheap nor free of risks, excercise is much preferable.
Considering that most SCAMs are heavily promoted for low back pain (e.g. acupuncture, Alexander technique, cupping, Gua Sha, herbal medicine, homeopathy, massage, mind-body therapies, reflexology, Reiki, yoga), this verdict is sobering indeed!
Qi-gong is a branch of Traditional Chinese Medicine that employs meditation, exercise, deep breathing and other techniques with a view of strengthening the assumed life force ‘qi’ and thus improving health and prolong life. Qi-gong has ancient roots in China and has recently also become popular in other countries. There are several distinct forms of qi-gong which can be categorized into two main groups, internal qi-gong and external qi-gong. Internal qi-gong refers to a physical and mental training method for the cultivation of oneself to achieve optimal health in both mind and body. Internal qi-gong is not dissimilar to tai chi but it also employs the coordination of different breathing patterns and meditation. External qi-gong refers to a treatment where qi-gong practitioners direct their qi-energy to the patient with the intention to clear qi-blockages or balance the flow of qi within that patient. According to Taoist and Buddhist beliefs, qi-gong allows access to higher realms of awareness.
The assumptions of qi-gong are not scientifically plausible. But this does not stop enthusiasts to submit it to clinical trials.
A quasi-experimental pretest-posttest study was conducted with 231 adolescent girls aged 13-17 years suffering from premenstrual syndrome (PMS). Participants underwent a 4-week Qi Gong therapy program, with five 45-minute sessions weekly. Data were collected using a demographic questionnaire and Modified PMS Scale, analysing pre- and post-intervention symptoms through descriptive statistics, paired t-tests and chi-square tests.
The intervention significantly reduced PMS severity, with mild PMS cases increasing from 48 (20.78%) to 166 (71.86%) post-intervention. Paired t-tests revealed a highly significant mean difference in PMS scores (T = 12.251, p < 0.001).
The authors concluded that Qi Gong therapy offers a holistic, non-invasive approach for managing PMS by addressing both physiological and emotional dimensions to the condition. Its ability to balance hormones, alleviate stress and improve overall quality of life makes it a valuable addition to PMS care.
This study originated from the Department of Obstetrics and Gynecological Nursing, Nootan college of Nursing, Sankalchand Patel university, Visnagar, Gujarat, India; the Department of Pediatric Nursing of the same institution and the Department of Psychiatric Nursing of the same institution. One would have hoped that its authors know better than to draw such conclusions from such a study. Here are some points of concern:
- There is no reason why the treatment should be holistic.
- The study did not have a control group; causal inferences are thus not waarranted.
- The study did not produce any evidence to show that the treatment addressed either physiological or emotional dimensions.
- The study did not produce any evidence to show that the treatment did anything to hormones.
- The study did not produce any evidence to show that the treatment alleviated stress.
- The study did not produce any evidence to show that the treatment improved quality of life.
- I see no resason why the treatment should be promoted as a valuable addition to PMS care.
- The PMS severity changed after the treatment and not necessarily because of it.
- The true reasons it changed might be multifold, e.g.: placebo, regression towards the mean, social desirability.
- Misleading the public by drawing far-reaching conclusions has the potential to do untold harm.
I have said it often, and it saddens me to have to say it again:
If the quality of research into so-called alternative medicine (SCAM) does not improve dramatically, nobody can blame the public to not take SCAM seriously any more.
On this blog, we have discussed all sorts of so-called alternative medicine (SCAM) but only rarely we scrutinize any of the many gadets and devices that are being promoted under the SCAM umbrella. Therefore, I will in future try to fill this gap.
This study investigated the effects of a magnetic pain relief patch (MPRP) on gait variability in adults. In 10 young men and women, MPRP was attached to 18 bilateral lower limb muscle areas (biceps femoris, gastrocnemius medialis, gastrocnemius lateralis, rectus femoris, soleus, semitendinosus, tibialis anterior, vastus medialis, and vastus lateralis) for 24 hours. Gait parameters collected from the accelerometer sensor were ground contact time, cadence, stance phase, swing phase, double support, stride length, and swing width, and were analyzed as gait variability. Data analysis was performed using the Wilcoxon signed-rank test.
Significant differences were found in the left and right gait cycle time coefficient of variation (CV) (p=0.047 in left, p=0.028 in right), cadence CV (p=0.047 in left and right), and double support CV (p=0.028 in left and right) before and after attachment of the MPRP.
The author concluded that MPRP enhances gait variability and can be utilized as a potential tool to complement noninvasive pain management and rehabilitation strategies. However, further studies are required to prove the long-term benefits and optimal application protocol of MPRP use.
My interpretation is very different!
Background: Static magnets are marketed with claims of effectiveness for reducing pain, although evidence of scientific principles or biological mechanisms to support such claims is limited. We performed a systematic review and meta-analysis to assess the clinical evidence from randomized trials of static magnets for treating pain.
Methods: Systematic literature searches were conducted from inception to March 2007 for the following data sources: MEDLINE, EMBASE, AMED (Allied and Complementary Medicine Database), CINAHL, Scopus, the Cochrane Library and the UK National Research Register. All randomized clinical trials of static magnets for treating pain from any cause were considered. Trials were included only if they involved a placebo control or a weak magnet as the control, with pain as an outcome measure. The mean change in pain, as measured on a 100-mm visual analogue scale, was defined as the primary outcome and was used to assess the difference between static magnets and placebo.
Results: Twenty-nine potentially relevant trials were identified. Nine randomized placebo-controlled trials assessing pain with a visual analogue scale were included in the main meta-analysis; analysis of these trials suggested no significant difference in pain reduction (weighted mean difference [on a 100-mm visual analogue scale] 2.1 mm, 95% confidence interval -1.8 to 5.9 mm, p = 0.29). This result was corroborated by sensitivity analyses excluding trials of acute effects and conditions other than musculoskeletal conditions. Analysis of trials that assessed pain with different scales suggested significant heterogeneity among the trials, which means that pooling these data is unreliable.
Interpretation: The evidence does not support the use of static magnets for pain relief, and therefore magnets cannot be recommended as an effective treatment. For osteoarthritis, the evidence is insufficient to exclude a clinically important benefit, which creates an opportunity for further investigation.
Our systematic review did evidently not stop the author to do his own study – good for him!
But what a study it is!!!
Alert readers will have noticed that the study has no control group. Others might have remarked that the notion of static magnets of this kind doing anything meaningful to our bodies lacks plausibility. Thus the observed effects cannot possibly attributed to the magnet therapy. Most likely they are due to the considerable attention the volunteers received.
Some might argue that such gadgets do no harm – so, why not use them? I would disagree with this notion. Firstly, they cost money and thus harm the finances of gullible consumers. Secondly, they distract people from effective treatments and thus have the potential to prolong the suffering of patients.
In view of all this, I feel I should rewrite the conclusions as follows:
Attention can improve pain and enhance gait variability. MPRP is neither biologically plausibe nor has it been shown to be clinically effective. Responsible clinicians should stop using MPRP and employ effective treatments instead. Future research on MPRP must be categorized as a waste of resources.
This systematic review was aimed at assessing whether spinal manipulative therapy (SMT) procedures (i.e., target, thrust, and region) impacted on pain and disability for adults with spine pain.
The investigators searched PubMed and Epistemonikos for systematic reviews indexed up to February 2022 and conducted a systematic search of 5 databases (MEDLINE, EMBASE, CENTRAL [Cochrane Central Register of Controlled Trials], PEDro [Physiotherapy Evidence Database], and Index to Chiropractic Literature) from January 1, 2018, to September 12, 2023. They included randomized clinical trials (RCTs) from recent systematic reviews and newly identified RCTs published during the review process and employed artificial intelligence to identify potentially relevant articles not retrieved through our electronic database searches. The authors included RCTs of the effects of high-velocity, low-amplitude SMT, compared to other SMT approaches, interventions, or controls, in adults with spine pain. The outcomes were spinal pain intensity and disability measured at short-term (end of treatment) and long-term (closest to 12 months) follow-ups. Risk of bias (RoB) was assessed using version 2 of the Cochrane RoB tool. Results were presented as network plots, evidence rankings, and league tables.
The researchers included 161 RCTs (11 849 participants). Most SMT procedures were equal to clinical guideline interventions and were slightly more effective than other treatments. When comparing inter-SMT procedures, effects were small and not clinically relevant. A general and nonspecific rather than a specific and targeted SMT approach had the highest probability of achieving the largest effects. Results were based on very low- to low-certainty evidence, mainly downgraded owing to large within-study heterogeneity, high RoB, and an absence of direct comparisons.
The authors concluded that there was low-certainty evidence that clinicians could apply SMT according to their preferences and the patients’ preferences and comfort. Differences between SMT approaches appear small and likely not clinically relevant.
What does that mean?
It means that it is largely irrelevant which form of SMT is being used; the outcomes are more or less independet of the technique that is applied. You don’t need to be particularly skeptical to go one step further and conclude that:
- The percieved effectiveness of SMT compared to other treatments is due to a placebo effect which is likely to be strong with a therapy involving touch, cracking bones, etc.
- The effects of different types of SMT are all similar because these interventions are little more than theatrical placebos.
- Since these placebos can cause consideraable harm, their risk/benefit balance is not positive.
- Because their risk/benefit balance fails to be positive, SMT cannot be recommended as a treatment in routine care.
So-called alternative medicine (SCAM) is, according to the authors of this paper, gaining popularity among patients experiencing pain, alongside traditional treatments. Their survey aimed to explore the views of pain clinicians and researchers on SCAM interventions.
An anonymous, online survey was distributed to 46 223 authors who had published pain-related research in MEDLINE-indexed journals. The survey included multiple-choice questions and open-ended sections to gather detailed opinions.
A total of 1024 participants responded, most identifying as either pain researchers (43.59%) or both researchers and clinicians (39.88%). Many held senior positions (61.55%). Among the SCAM modalities, mind-body therapies such as meditation, yoga, and biofeedback were viewed as the most promising for pain prevention, treatment, and management, with 68.47% of participants endorsing these approaches. While a majority (43.89%) believed that most SCAM therapies are safe, only 25.55% expressed confidence in their effectiveness. There was broad agreement on the need for more research into SCAM therapies, with 45.88% agreeing and 42.53% strongly agreeing that further investigation is valuable. Additionally, many respondents supported the inclusion of SCAM training in clinician education, either through formal programs (46.40%) or supplementary courses (52.71%). Mind-body therapies received the most positive feedback, while biofield therapies were met with the most skepticism.
The authors concluded that these findings highlight the interest in SCAM among pain specialists and emphasize the need for more research and education tailored to this area.
It is not often that I come across an article that makes me laugh out loud. Here are some of the reasons for my amusement:
- Since when is 44% a majority?
- In fact, the majority of respondents seems not to believe that SCAM is safe;
- only 26% were confident that SCAM is effective, yet we are made to believe that “many respondents supported the inclusion of SCAM training in clinician education”.
The biggest laugh needs to go to the response rate of this survey: 46 223 people received the questionnaire and 1024 responded to it! This gives a response rate of just over 2%! and seems to indicate that the vast majority of pain researchers are not bothered about SCAM. If that is so, should we not adjust the conclusion accordingly? Perhaps something like this would fit the data much better:
These findings highlight the disinterest in SCAM among pain specialists and emphasize that no more research and education tailored to this area are required.
Constipation is characterized by persistent difficulty in defecating. It is a common disorder in the community particularly affecting the elderly and those with intellectual disabilities and neuropsychiatric disorders. It can also be caused by numerous medications including analgesic, antidepressant, antihypertensive and anticholinergic agents. It may be asymptomatic or it may produce abdominal pain/cramps, bloating, nausea and anorexia progressing to urinary incontinence and fecal impaction, or paradoxical diarrhea due to overflow.
This review demonstrated that constipation may also kill you. A wide range of mechanisms associated with constipation may result in death including:
- bowel obstruction,
- stercoral colitis with ulceration,
- perforation and peritonitis,
- respiratory compromise,
- abdominal compartment syndrome,
- venous thrombosis with pulmonary thromboembolism.
Moreover, constipation may exacerbate pre-existing diseases and treatments such as laxative and enemas may be lethal. The autopsy examination of a case with constipation and megacolon should take into account all of the pre-existing conditions, as well as the possibility of underlying disorders such as Hirschprung disease. Review of the decedent’s medical and drug history and level of supportive care will be important. Toxicological evaluations may be useful.
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Constipation is defined as having fewer than three bowel movements per week or experiencing difficulty in passing stool. The condition is common and often difficult to treat. WebMD recommends diet and lifestyle changes, such as:
- Drink an extra two to four glasses of water a day, unless your doctor tells you to limit fluids for another reason.
- Try warm liquids, especially in the morning.
- Add fruits and vegetables to your diet.
- Eat prunes and bran cereal.
- Exercise most days of the week. When you move your body, the muscles in your intestines are more active, too.
- Don’t ignore the urge to poop. Listen to your body when it’s telling you it’s time to go.
- Eat foods with probiotics such as yogurt and kefir.
- Skip processed meats, fried foods, and refined carbs such as white bread, pasta, and potatoes. You can eat lean meats such as poultry and low-fat dairy products.
- Keep a food diary and make a note of any foods that constipate you.
- Adjust how you sit on the toilet. Raising your feet, leaning back, or squatting may make it easier to poop.
- Take an over-the-counter fiber supplement (Metamucil®, MiraLAX®, Citrucel® or Benefiber®). Start with a small amount at first.
- Avoid reading or using your phone or other devices while you’re trying to move your bowels.
- Drink less alcohol and caffeinated drinks, which can make you dehydrated.
- Talk to your doctor about bowel training. It can help train your body to pass stool shortly after breakfast every morning.
- Don’t rush when going to the bathroom. Give yourself time to relax, which can help your digestive muscles relax.
- Talk to your doctor about any medications that could be causing your constipation.
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Because conventional options are often not as successful as hoped, many sufferers turn to so-called alternative medicine (SCAM). But is SCAM really a solution?
A recent review found that “acupuncture or electroacupuncture and herbal medicine are effective in treating
constipation, whereas findings on massage and moxibustion are inconclusive.” Our own assessment [‘Oxford Handbook…’ (2008)] of the evidence disagrees and rated as follows:
- Beneficial: Psyllium
- Likely to be beneficial: abdominal massage, biofeedback, fibre
- Unknown effectiveness: acupuncture, aloe vera, ayurvedic medicine, meditation, Padma Lax, probiotics, herbal tea.
Whichever way we turn it, constipation is a more serious condition than many of us think, and neither conventional healthcare nor SCAM are convincingly successful in helping those who suffer from it.
This double-blind, randomized, placebo-controlled trial compared the effects of individualized homeopathic medicinal products (IHMPs) and placebo after 4 months of intervention in patients with chronic low-back pain (LBP).
- the small sample size might have the result unreliable;
- the marginal level of statistical significance;
- the fact that 5+5+8+13=31 and not 30;
- the fact that the study originated from India where hardly any negative studys of homeopathy see the light of day;
- the fact that allmost all of the many authors of this paper are affiliated with homeopathic institutions;
- the existance of a strangely similar study that has recently reported largely negative results.
Tuina, or Tui Na is based on the notion that imbalances of the life-force, qi, can cause blockages or imbalances that lead to symptoms and illness. Tuina massage is similar to acupressure in that it targets specific acupoints. Practitioners use fingers to apply pressure to stimulate these points.
Some people suggest that Tuina might benefit diabetic peripheral neuropathy (DPN), but the evidence is inconclusive. This review evaluated its clinical efficacy and safety for DPN treatment.
Ten databases were searched, covering the period from their inception to February 21, 2024. Relevant data were extracted from studies meeting the inclusion criteria, and a meta-analysis was conducted using RevMan
5.3 software.
A total of 24 randomized controlled trials (RCTs) involving 1,989 participants were included. Patients in the experimental group received Tuina in addition to routine treatments and nursing of DPN. Patients in the control group received routine treatments and nursing of DPN, including health education, dietary guidance, blood sugar control, and oral vitamin B or mecobalamin.
The meta-analysis showed that, compared to various control therapies, Tuina demonstrated a higher overall clinical efficacy rate and improved Toronto Clinical Scoring System (TCSS) scores, indicating that Chinese Tuina may provide benefits beyond conventional treatment. Furthermore, improvements were observed in the motor and sensory nerve conduction velocities (MNCV and SNCV) of certain specific nerves, such as the common peroneal nerve, sural nerve, and ulnar nerve. Although the differences in MNCV and SNCV of the tibial and median nerves were not statistically significant, the overall improvement in clinical outcome supports the notion that Tuina is superior to conventional treatment.
The authors concluded that Chinese Tuina therapy is a safe and effective treatment option for DPN. It can alleviate clinical symptoms and improve the MNCV of the common peroneal nerve as well as the SNCV of the sural and ulnar nerves. Its efficacy in the tibial and median nerves remains unconfirmed, highlighting a need for future large-scale, high-quality RCTs.
There are several reasons why I cannot accept the conclusion that Tuina is effective for DPN, e.g:
- All the RCTs were of the notorious A+B vs B design that – as discussed ad nauseam on this blog – does not control for placebo effects and thus never generate negative results.
- None of the RCTs were single or double blind which means that expectation and therapist influence would have impacted on the findings.
- All of the studes originate from China; we have often discussed why such studies are notoriously unreliable. Funding for the review was supported by the National Key Research and Development Program of China and Jilin Provincial Natural Science Foundation Project.
- Most of the studies are published in journals and/or laguages that are not accessible to non-Chinese readers.
- None of these serious limitations are discussed by the review authors.
I REST MY CASE
