Has enough research been done on Ebola?

‘Has enough research been made on Ebola? What do you people think?‘

If we liken Ebola research to a race, it wouldn’t be a stretch to say that it’s barely off the starting block (1, 2, 3, 4, 5).

• Easy to diagnose Ebola? No.
• Easy to treat Ebola? No.
• Safe and effective vaccine against Ebola? No.

Notwithstanding that bleak background, the last Ebola outbreak from March 2014 until June 2016 in West Africa certainly accelerated research on it. For example, it stoked rapid development of commercial kits for Ebola diagnosis, several of which have now made it onto the WHO’s roster of approved test kits (6, 7).

While most of these diagnostic methods require sophisticated infrastructure, equipment and training, and thus can only be performed in reference laboratories, not at the patient’s bedside, a handful are rapid ones that can be done cheaply on site and most importantly, are quite sensitive as well as specific (8).

Situation is however a lot worse with respect to therapy with no single Ebola treatment as yet approved for humans, a major obstacle since its mortality rate remains quite high, ranging from 79% in the past to ~40% in the 2014-2016 West African outbreak (9).

Even something as seemingly simple as optimizing the standard of care may go a long way in reducing Ebola mortality rates. Such standard of care boils down to simple interventions as oral rehydration, electrolyte replacement, anti-symptomatics such as for fever, vomiting and diarrhea, adequate nutrition, timely treatment of accompanying infections such as malaria or bacterial infections (10). Point is even such a simple first step disease management approach didn’t exist for Ebola until this latest major outbreak.

Ebola outbreaks have been relatively rare and usually occur in remote regions, factors that make it very difficult to gather clinical efficacy data on experimental therapies since it’s next to impossible to conduct clinical trials in an outbreak setting (11). The FDA’s Animal Rule, Animal efficacy rule – Wikipedia, is meant to expedite therapies by relying mainly on animal model data, unlike the process by which therapies are usually approved for human use. Even so, getting approved therapies for a disease that shows up as outbreaks in remote regions is challenging.

Reliable point of care diagnostics and at least one or two safe, effective and relatively cheap therapies, one could say Ebola research reached commendable milestones when these become everyday realities. While the first goal appears within reach, that’s not the case with the second one.

Bibliography

1. http://www.who.int/ebola/22-5-17…

2. http://apps.who.int/iris/bitstre…

3. http://www.who.int/medicines/ebo…

4. http://www.who.int/immunization/…

5. http://www.who.int/immunization/…

6. Diagnostics

7. Ebola EUAL Status after PHEIC Termination

8. Mérens, A., C. Bigaillon, and D. Delaune. “Ebola virus disease: Biological and diagnostic evolution from 2014 to 2017.” Medecine et maladies infectieuses (2017).

9. 2014-2016 Ebola Outbreak in West Africa

10. Duraffour, Sophie, Denis Malvy, and Daouda Sissoko. “How to treat Ebola virus infections? A lesson from the field.” Current opinion in virology 24 (2017): 9-15. https://www.sciencedirect.com/sc…

11. Rojek, Amanda M., et al. “Regulatory and operational complexities of conducting a clinical treatment trial during an Ebola Virus Disease epidemic.” Clinical Infectious Diseases (2017). Regulatory and Operational Complexities of Conducting a Clinical Treatment Trial During an Ebola Virus Disease Epidemic | Clinical Infectious Diseases | Oxford Academic

https://www.quora.com/Has-enough-research-been-done-on-Ebola-What-do-you-think/answer/Tirumalai-Kamala

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Is the placebo effect very powerful?

Tags

Fabrizio Benedetti, Ted Kaptchuk

The https://en.wikipedia.org/wiki/Pl… effect is powerful enough to be the bane of the https://en.wikipedia.org/wiki/Ra… (RCT), https://en.wikipedia.org/wiki/Bi…, and really of modern medicine itself. A dynamic attribute since it can be seemingly manipulated at will, it maybe more accurate to call it the Placebo Response, as proposed by https://en.wikipedia.org/wiki/Fa…. Their considerable scientific and economic impact is evidence of the shadow placebo responses cast on all of medicine.

Answer highlights

• Placebo responses operate even for legitimate drugs and therapies.
• Placebos elicit beneficial responses even when patients take them knowingly.
• Placebo responses are becoming stronger, driving up drug development costs.
• How placebo responses could be leveraged to make medicine more effective, cheaper and safer.
• Examples that illustrate how just about anything to do with a Rx, colors, sizes, numbers, pills versus injections, even diligence in taking placebos, can trigger placebo response and influence its magnitude.

Longer answer for those interested in the details

Scientific Impact Of Placebo Responses

Placebo responses tend to be more pronounced in

• Patient-reported outcomes rather than those independently-assessed (1).
• Questionnaire- rather than clinical biomarker-based outcomes (2, 3).

No surprise since psychology is known to play an outsized role in pain and mental health conditions such as depression, which tend to lack objective diagnostic tests and are instead subjectively diagnosed on the basis of periodically revised, fuzzy questionnaires. Problem is most diseases lack biomarkers with proven therapeutic value.

However, even physiological attributes such as blood glucose levels entail placebo responses. Their concentrations in type II diabetes patients change commensurate to how their awareness of time is experimentally manipulated, lower and higher for those looking at clocks tweaked to run 2X slower or faster, respectively* (4). Blood glucose levels! Now that’s an objectively measured response. Already then, we can start to dimly discern the margins of modern biomedicine’s colossal problem. Unsubtly and arbitrarily splitting body (physiology) and mind (psychology) as a matter of course, it may not even be playing with a full deck since almost daily such new pieces of data force us to confront just how intertwined they actually are.

Placebo Responses: Outcome Of Expectation, Conditioning & Rx-Associated Communication/Ritual

Drugs and therapies are supposed to work specifically by targeting specific molecules and pathways involved in different diseases. Placebos, usually sugar pills, are supposed to mimic certain drug attributes. How? Three components working in tandem appear to explain not just how placebos work but also how placebo responses operate even for specific drugs and therapies.

Expectation is the outcome of learning, part of a general conditioning process of knowing one is getting Rx. The myriad components involved in getting Rx can be construed as Rx-associated communication/ritual (the physician, nurses, other care staff; are they warm, caring, supportive; do they explain what’s happening and what they’re doing; how much time they spend with the patient), etc.. Expectations and conditioning can mutually reinforce each other.

Paradigm shift lies in realizing placebo responses are ever-operational, even with legitimate drugs and therapies. Confused? The ‘open-hidden’ experiment design perfected by Benedetti’s team is not only clever but also groundbreaking because it reveals placebo response is an inherent part of response to medications and therapies.

In the original archetype of the ‘open-hidden’ experiment design (5), the powerful opioid painkiller https://en.wikipedia.org/wiki/Fe… was more effective when given openly by a doctor compared to being given secretly. Since then, the observation has been replicated in anxiety and Parkinson’s (6, 7). Knowingly getting a medication or therapy seems to set up expectations that make the medication or therapy more effective, i.e., by tapping Rx’s latent placebo response (8, See below from 9).

https://en.wikipedia.org/wiki/Te…, another leading placebo response researcher, has turned another conventional wisdom about placebos on their head. Giving patients placebos typically entails deception. Naturally this presents an ethical dilemma. If there are indeed bonafide benefits to placebos, how to reap them if doing so violates ethics?

Kaptchuk’s revolutionary idea is to turn this notion of secrecy on its head and to instead give placebos knowingly. Convention dictates knowingly taking placebos should blunt, even eliminate their benefit. Turns out to be not so. First for IBS (n=80, 10) then for lower back pain (n=97, 11), research on small patient groups shows knowingly taking a placebo in the context of an ongoing, supportive, caring, warm patient-physician relationship benefits patients. Rx-associated communication or ritual is a vital part of how placebo responses are triggered and sustained (12).

Economic Impact Of Placebo Responses

Decades-long evidence (13, 14, 15) suggests clinical trial placebo responses are becoming more powerful, especially for painkiller drug candidates (16) and especially in the US (17).

• Placebo responses in anti-depressant trials were twice as strong in the 2000s compared to those in the 1980s (18). Even more compelling is the observation that this improvement occurred not for the more subjective patient self-rating but rather for the comparatively more objective observer rating (1).
• Similar placebo response improvement when testing anti-psychotic drugs (19).
• Placebo response magnitude change may vary by disease since it increased more weakly from 1991 to 2005 in trials for bipolar disorder (20).

Why could placebo responses be strengthening?

• Could be simply because trials now last longer then they used to (21). Longer Rx-associated communication/ritual = Stronger Placebo responses.
• Over the same time period, drug advertisements have undergone a sea change. The US legalized direct-to-consumer prescription drug advertising in 1997, which also exists in New Zealand. One unanticipated consequence? Social conditioning may be strengthening placebo responses.

Consequences of stronger placebo responses

• Clinical trials are the necessary gatekeeper for new drug approvals. More powerful placebo responses increase the bar new drugs have to clear. No surprise new drug approvals have slowed down dramatically in recent years. Clearly some role there for the increasingly more powerful placebo responses.
• Publication bias predicates that ‘real’ placebo response in RCTs remains unknowable. Studies with a significant drug to placebo difference are more likely to get published. Published placebo responses are thus likely lower than in studies that never got/get published. Ergo, actual placebo responses may be even higher than those revealed by clinical trial results that do get published. If this is the case with new drug candidates, no wonder new drug approvals have declined steeply in recent years.
• One consequence of increasingly powerful placebo responses is a move away from the classic RCTs to newer designs such as comparative effectiveness research (CER) trials, which compare novel drugs to approved ones or to standard therapy, i.e., all participants get active Rx. Problem is such trials ‘increase the placebo response without being able to control for it‘ (9). Statistical analyses of such trials are also much challenging since they require showing the test compound is non-inferior to the standard Rx. As Enck et al point out (9, emphasis mine),

‘A non-inferiority trial tests the null hypothesis that the novel drug is inferior by the equivalence margin. If this null hypothesis is rejected, the novel compound can be regarded as clinically equivalent. This, on average, requires a fourfold larger sample size compared to classical RCTs and is one of the reasons why drug companies are increasingly concerned by the growing costs of drug development‘

How Placebo Responses Could Be Leveraged To Make Medicine More Effective, Cheaper & Safer

• Pigeonholing placebos and placebo responses as undesirable or hindrance is problematic. Placebos are supposedly inert substances that should do nothing yet they do. OTOH, even genuine medicines induce placebo responses which increase their effectiveness. A way to reconcile this seeming contradiction would be by viewing placebo responses as an inevitable part of a virtuous feedback loop between psychology and physiology.
• Expectations are outcome of learning, i.e., part of a conditioning process. Benefits of conditioning are well-known for allergies (22, 23) and nausea (24). See below from 9 how conditioning works.

• Maybe encouraging placebo responses could make modern biomedicine more effective (9) by
  • Reducing healthcare costs since patients could interchangeably take drugs and placebos, and still benefit.
  • Minimizing harm from drug side effects since patients would be taking lower doses of drugs.
• Now that would augur a true biomedical revolution. Conundrum is how to do this reproducibly since placebo’s evil twin, https://en.wikipedia.org/wiki/No…, lurks in the wings. Tapping the same pathways could yield harm just as easily as benefit and we simply don’t know enough about the feedback loops between psychology and physiology to manipulate them at will. For example, https://en.wikipedia.org/wiki/Na… can block analgesic (anti-pain) placebo response induced by opioid-driven but not non-opioid https://en.wikipedia.org/wiki/No… (NSAID) (25).

Placebo Responses: Research suggests placebo response magnitude depends on just about anything to do with Rx (26).

• Rx Appearance (27). A systematic 1996 review (28) found red, yellow and orange pills worked better as stimulants while blue and green pills worked better as tranquilizers. Out of 49 nervous system drugs, stimulants were more often red or orange while sedatives were more often green, blue or purple.
• Rx Frequency/number. A meta-analysis (29) of anti-duodenal ulcer RCTs found a difference in whether participants took 4 (51 trials) or 2 (28 trials) pills a day. After 4 weeks, 44% (805 of 1821) of those who took 4 placebo pills per day had healed duodenal ulcers compared to 36% (545 of 1504) of those who took 2, statistically a highly significant difference.
• Rx Form. A meta-analysis (30) of 22 trials found placebo injections (32%, 279 of 862 patients) to be more effective against migraine (feeling better one hour later) compared to placebo pills (26%, 222 of 865 patients), statistically a highly significant difference.
• Placebo-Taking Compliance Reduces Mortality Rates. BEST (Beta Blocker Evaluation of Survival Trial) participants (31) who took >75% of their prescribed placebos had significantly better outcomes (291 of 1038, 28%, died) compared to less compliant placebo-takers (55 of 136, 40%, died). A meta-analysis (32) of 21 RCT or cohort studies on conditions ranging from cancer-associated infections to heart attack to HIV found similar differences, lower mortality rates (4.3%, 581 of 13429 participants) for compliant placebo-takers compared to those less compliant (6.2%, 415 of 6204 participants).
• Influence of Doctors (8, 9, 12, See below from 33 using data from 34).

Placebo Responses: Age, Culture, Ethnicity, Gender, etc. Also Matter

However, hastily generalizing such results could also be in error.

• Different colors seem to matter differently in different countries, i.e., cultural differences are also at play (35).
• An Italian study found women responded more strongly to blue sleeping pills compared to men who preferred orange ones (36).
• Placebo injections may be more effective than pills at treating migraines in the US (33.6%, 151 of 449 patients for injections versus 22.3%, 25 of 112 patients for pills), not in Europe (25.1%, 80 of 318 patients for injections versus 27.1%, 182 of 670 patients for pills) (37).
• Meta-analysis of 100 old RCTs of https://en.wikipedia.org/wiki/H2… on https://en.wikipedia.org/wiki/Pe… found placebo effects that ranged from 6% in Brazil, ~20% in Denmark and the Netherlands to >60% in Germany (38).
• Again, would be wrong to conclude Germans are inherently more predisposed to strong placebo effects since the same analysis found them with among the lowest placebo effect for anti-hypertensive Rx.
• Rotation-induced nausea is a condition with well-established ethnic differences (24).

Even Surgeries Aren’t Immune To Placebo Responses

Unlike medications, especially for subjective symptoms such as pain, surgery is usually done for tangible reasons yet even it isn’t immune to placebo responses, some attributable to bonafide placebo response power and some attesting to the futility of certain prevalent and expensive surgical procedures.

• Back in the 1950s, ligating the internal mammary artery became a popular procedure to alleviate https://en.wikipedia.org/wiki/An…, the idea being restricting blood flow to a nearby region would improve supply going to the coronary arteries. Small placebo-controlled studies (39, 40) of this procedure found similar improvement (significantly less pain, lower nitroglycerine use) regardless whether patients got the ligation or just a skin incision.
• Highly cited placebo-controlled studies (41, 42) on surgical Rx for osteoporosis found no difference in improvement magnitude (modest pain score improvement, physical function) between patients who got either https://en.wikipedia.org/wiki/Pe… (n=38, 68) or sham Rx (n=40, 63).
• Highly cited placebo-controlled US-based studies (43, 44) on https://en.wikipedia.org/wiki/Os… found no difference in improvement magnitude between patients who got either arthroscopic debridement/ (https://en.wikipedia.org/wiki/Ar…), https://en.wikipedia.org/wiki/Ar… or simulated debridement (placebo, 3 small stab wounds in the knee). Even two years later, all patients had similar 6 point improvement on a 100 point scale that measured walking and bending. At the time these studies were done (1996-2002), 650,000 such arthroscopies were performed in the US each year, for an average cost of ~US $5000 each, obviously a colossal waste. An example of not the power of placebos but rather of uselessness of certain prevalent medical procedures.

* A preliminary study with few participants (n=47) that desperately needs replication. Also poor form to show data as Mean + Standard Error of the Mean (46). What that means is that actual variation within each group was much higher than what the authors chose to show, i.e., much more actual overlap between groups.

Bibliography

1. Rief, Winfried, et al. “Meta-analysis of the placebo response in antidepressant trials.” Journal of affective disorders 118.1 (2009): 1-8. https://www.researchgate.net/pro…

2. Hróbjartsson, Asbjørn, and Peter C. Gøtzsche. “Placebo interventions for all clinical conditions.” The Cochrane Library (2010). http://nordic.cochrane.org/sites…

3. Howick, Jeremy, et al. “Are treatments more effective than placebos? A systematic review and meta-analysis.” PloS one 8.5 (2013): e62599. http://journals.plos.org/plosone…

4. Park, Chanmo, et al. “Blood sugar level follows perceived time rather than actual time in people with type 2 diabetes.” Proceedings of the National Academy of Sciences (2016): 201603444. http://www.pnas.org/content/113/…

5. Benedetti, Fabrizio, et al. “Open versus hidden medical treatments: the patient’s knowledge about a therapy affects the therapy outcome.” Prevention & Treatment 6.1 (2003): 1a.

6. Colloca, Luana, et al. “Overt versus covert treatment for pain, anxiety, and Parkinson’s disease.” The Lancet Neurology 3.11 (2004): 679-684. https://www.researchgate.net/pro…

7. Benedetti, F., E. Carlino, and A. Pollo. “Hidden administration of drugs.” Clinical Pharmacology & Therapeutics 90.5 (2011): 651-661. http://www.isdbweb.org/app/webro…

8. Schedlowski, Manfred, et al. “Neuro-bio-behavioral mechanisms of placebo and nocebo responses: implications for clinical trials and clinical practice.” Pharmacological reviews 67.3 (2015): 697-730. http://pharmrev.aspetjournals.or…

9. Enck, Paul, et al. “The placebo response in medicine: minimize, maximize or personalize?.” Nature reviews Drug discovery 12.3 (2013): 191-204.

10. Kaptchuk, Ted J., et al. “Placebos without deception: a randomized controlled trial in irritable bowel syndrome.” PloS one 5.12 (2010): e15591. http://journals.plos.org/plosone…

11. Carvalho, Cláudia, et al. “Open-label placebo treatment in chronic low back pain: a randomized controlled trial.” Pain 157.12 (2016): 2766. https://www.ncbi.nlm.nih.gov/pmc…

12. Welch, John S. “Ritual in western medicine and its role in placebo healing.” Journal of Religion and Health 42.1 (2003): 21-33.

13. The New York Times, Daniel Goleman, August 17, 1993. http://www.nytimes.com/1993/08/1…

14. Silberman, Steve. “Placebos are getting more effective. Drugmakers are desperate to know why.” Wired Magazine 17 (2009): 1-8. http://www.southdevonacupuncture…

15. Tuttle, Alexander H., et al. “Increasing placebo responses over time in US clinical trials of neuropathic pain.” Pain 156.12 (2015): 2616-2626.

16. Vase, Lene, Martina Amanzio, and Donald D. Price. “Nocebo vs. placebo: The challenges of trial design in analgesia research.” Clinical Pharmacology & Therapeutics 97.2 (2015): 143-150.

17. Quartz, Akshat Rathi, October 16, 2015. https://qz.com/525995/why-the-pl…

18. Walsh, B. Timothy, et al. “Placebo response in studies of major depression: variable, substantial, and growing.” Jama 287.14 (2002): 1840-1847. http://211.103.242.133:8080/ziyu…

19. Leucht, S., et al. “How effective are second-generation antipsychotic drugs? A meta-analysis of placebo-controlled trials.” Molecular psychiatry 14.4 (2009): 429-447. http://www.nature.com/mp/journal…

20. Sysko, Robyn, and B. Timothy Walsh. “A systematic review of placebo response in studies of bipolar mania.” The Journal of clinical psychiatry 68.8 (2007): 1213-1217.

21. Quessy, Steve N., and Michael C. Rowbotham. “Placebo response in neuropathic pain trials.” Pain 138.3 (2008): 479-483.

22. Vits, Sabine, et al. “Cognitive factors mediate placebo responses in patients with house dust mite allergy.” PLoS One 8.11 (2013): e79576. http://journals.plos.org/plosone…

23. Bartels, Danielle JP, et al. “Role of conditioning and verbal suggestion in placebo and nocebo effects on itch.” PloS one 9.3 (2014): e91727. http://journals.plos.org/plosone…

24. Quinn, Veronica F., and Ben Colagiuri. “Placebo interventions for nausea: a systematic review.” Annals of Behavioral Medicine 49.3 (2015): 449-462.

25. Amanzio, Martina, and Fabrizio Benedetti. “Neuropharmacological dissection of placebo analgesia: expectation-activated opioid systems versus conditioning-activated specific subsystems.” Journal of Neuroscience 19.1 (1999): 484-494.

26. Enck, Paul, Sibylle Klosterhalfen, and Katja Weimer. “Unsolved, Forgotten, and Ignored Features of the Placebo Response in Medicine.” Clinical Therapeutics (2016).

27. Buckalew, Louis W., and Kenneth E. Coffield. “An investigation of drug expectancy as a function of capsule color and size and preparation form.” Journal of clinical psychopharmacology 2.4 (1982): 245-248.

28. De Craen, Anton JM, et al. “Effect of colour of drugs: systematic review of perceived effect of drugs and of their effectiveness.” Bmj 313.7072 (1996): 1624-1626. http://pubmedcentralcanada.ca/pm…

29. De Craen, Anton JM, et al. “Placebo effect in the treatment of duodenal ulcer.” British journal of clinical pharmacology 48.6 (1999): 853-860. https://www.researchgate.net/pro…

30. de Craen, Anton JM, et al. “Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos.” Journal of neurology 247.3 (2000): 183-188.

31. Pressman, Alice, et al. “Adherence to placebo and mortality in the Beta Blocker Evaluation of Survival Trial (BEST).” Contemporary clinical trials 33.3 (2012): 492-498. https://www.ncbi.nlm.nih.gov/pmc…

32. Simpson, Scot H., et al. “A meta-analysis of the association between adherence to drug therapy and mortality.” Bmj 333.7557 (2006): 15. http://www.bmj.com/content/bmj/3…

33. Moerman, Daniel E. “Edible symbols: The effectiveness of placebos.” Annals of the New York Academy of Sciences 364.1 (1981): 256-268.

34. Sarles, H., R. Camatte, and J. Sahel. “A study of the variations in the response regarding duodenal ulcer when treated with placebo by different investigators.” Digestion 16.4 (1977): 289-292.

35. Bhugra, Dinesh, et al. “Colour, culture and placebo response.” International Journal of Social Psychiatry 61.6 (2015): 615-617.

36. Cattaneo, Angelo D., Paolo E. Lucchelli, and Giorgio Filippucci. “Sedative effects of placebo treatment.” European Journal of Clinical Pharmacology 3.1 (1970): 43-45.

37. de Craen, Anton JM, et al. “Placebo effect in the acute treatment of migraine: subcutaneous placebos are better than oral placebos.” Journal of neurology 247.3 (2000): 183-188.

38. MOERMAN, DE. “GENERAL MEDICAL EFFECTIVENESS AND HUMAN-BIOLOGY-PLACEBO-EFFECTS IN THE TREATMENT OF ULCER DISEASE.” AMERICAN JOURNAL OF PHYSICAL ANTHROPOLOGY. Vol. 54. No. 2. DIV JOHN WILEY & SONS INC, 605 THIRD AVE, NEW YORK, NY 10158-0012: WILEY-LISS, 1981.

39. Cobb, Leonard A., et al. “An evaluation of internal-mammary-artery ligation by a double-blind technic.” New England Journal of Medicine 260.22 (1959): 1115-1118.

40. Dimond, E. Grey, C. Frederick Kittle, and James E. Crockett. “Comparison of internal mammary artery ligation and sham operation for angina pectoris∗.” The American journal of cardiology 5.4 (1960): 483-486.

41. Buchbinder, Rachelle, et al. “A randomized trial of vertebroplasty for painful osteoporotic vertebral fractures.” New England Journal of Medicine 361.6 (2009): 557-568. http://www.nejm.org/doi/pdf/10.1…

42. Kallmes, David F., et al. “A randomized trial of vertebroplasty for osteoporotic spinal fractures.” New England Journal of Medicine 361.6 (2009): 569-579. http://www.nejm.org/doi/pdf/10.1…

43. Moseley Jr, J. Bruce, et al. “Arthroscopic treatment of osteoarthritis of the knee: a prospective, randomized, placebo-controlled trial: results of a pilot study.” The American journal of sports medicine 24.1 (1996): 28-34.

44. Moseley, J. Bruce, et al. “A controlled trial of arthroscopic surgery for osteoarthritis of the knee.” New England Journal of Medicine 347.2 (2002): 81-88. https://www.researchgate.net/pro…

https://www.quora.com/Is-the-placebo-effect-very-powerful/answer/Tirumalai-Kamala

Has someone used a MeCbl treatment for patients or has been treated with MeCbl? What for and what were the outcomes?

Tags

Back and neck pain, Diabetic nerve pain, Herpes, MeCbl (Methylcobalamin)

What is MeCbl

• Discovered in 1962 (1) as a conezyme form of vitamin B12, MeCbl (methylcobalamin) acts as a methyltransferase cofactor.
• Methyltransferases are B12-dependent enzymes.
• They play important roles in amino acid metabolism.
• MeCbl helps covert homocysteine to methionine, important for DNA and protein methylation.

MeCbl uses in therapy
Other than to correct vitamin B12 deficiency, two important functions postulated: reduces circulating homocysteine (non-protein amino acid) and improves/restores nerve function.

• Too much homocysteine in circulation, hyperhomocysteinaemia, causes vascular problems (e.g. thickening of arteries), coronary artery disease and stroke.
  • MeCbl increases homocysteine consumption and lowers its circulating concentration to the normal range (4-15micromol/liter).
• Compared to other B12 analogs, MeCbl is most effectively taken up by neurons.
  • In rat studies, MeCbl helped myelin sheath regeneration and restored nerve function in neuropathy (2, 3).
  • Led to the idea that such effective delivery may make MeCbl more effective in human nervous system disorders.

How could MeCbl reduce pain?
No definite answers, only hypothesis. MeCbl may inhibit pain perception by increasing the availability of noradrenaline and 5-hydroxytryptamine.

Human study data for MeCbl therapy

• Cochrane reviews conducted under the auspices of the Cochrane Collaboration are systematic reviews of randomised controlled clinical trials.
• Cochrane reviews are considered the best quality reviews of clinical trials.
• What does a 2008 Cochrane review conclude about MeCbl for treating peripheral nerve pain (4)?
  • Total of 13 trials (n=741) on alcoholic or diabetic neuropathy.
  • Of these 13 trials, only one trial passed muster as being properly conducted and controlled.
  • See details in the following 2 figures.

This Cochrane review (4) excluded majority of MeCbl trials for diabetic neuropathy because they had methodological errors: either they weren’t randomised or they relied on improper diagnosis of neuropathy. Here is my summary of the excluded trials and Cochrane’s reasons for exclusion.

A more recent review (5) examined MeCbl for diabetic, and nonsepcific lower back and neck pain.

• It concludes that MeCbl Rx reduced diabetic neuropathy in some studies.
• However, my own analysis shows that this conclusion is incorrect.
• Rather, studies were either too small, not properly controlled or relied on self-reported symptoms for pain diagnosis.
• Cross-study comparisons not possible because they used different routes, doses, formulations and durations of Rx.
• Studies also relied on different methods for pain diagnosis and for assessing symptom reduction/changes.
• See details in the figure below.

Finally, another meta-analysis of MeCbl Rx for diabetic neuropathy (6) concluded that combination of MeCbl with prostaglandin E1 (PGE1) might work better. Qualified their conclusion by emphasizing that most studies were too small or had methodological problems (weren’t randomised/used improper diagnostic criteria/improper/inadequate outcomes measured). In other words, MeCbl+PGE1 might work for diabetic and other neuropathies but bigger and better designed studies are needed.

Review (5) of MeCbl trials for nonspecific lower back and neck pain suggests

• Oral MeCbl may not be effective.
• Injection MeCbl (either into skin or intramuscularly) may more effectively reduce pain compared to oral MeCbl.
• See details in the figure below.

One study on herpes-associated local neuralgia (nerve pain) (7):

• Compared skin (subcutaneous) injection versus oral MeCbl.
• Also compared to injection Lidocaine (a local anesthetic).
• Injections were 6 times a week/4 weeks.
• MeCbl injection was 1mg/2ml, Lidocaine injection was 2ml.
• Oral MeCbl was 0.5mg 3 times a day.
• Patients were also on antivirals (oral acyclovir or valaciclovir).
• Greater pain reduction with injection MeCbl.
• Patients on injection MeCbl took less oral analegsics (gabapentin/pregabalin/amititriptyline/oxycodone/tramadol) for their pain.
• See details in the figure below.

Another study (8) on intramuscular MeCbl for nonspecific lower back pain:

• Placebo controlled.
• Patients got 6 intramuscular injections over 2 weeks (on days 1, 3, 5 of each week).
• Got either 500micrograms of MeCbl or saline.
• Patients also took paracetamol as needed, up to a maximum of 3mg/day.
• Followed-up for 2 months after Rx start.
• Injection MeCbl worked best to reduce pain.
  • Self-reported pain responses and scores reduced most.
  • Paracetamol use reduced most.
  • OTOH, injection MeCbl also had greater injection site pain and hematoma (local swelling from bleeding).
• See details in the figure below.

Bottomline on MeCbl for pain reduction.

• Too few well-designed and controlled studies.
• Small study sizes are another limitation.
• More recent, better designed studies with better measured outcomes suggest
  • Injection MeCbl may be more effective compared to oral.
  • Little or no adverse effects from injection itself.
  • Combination regimens with other agents such as prostaglandin E1 (PGE1) might be more effective.

Bibliography

1. Guest, J. R., et al. “A methyl analogue of cobamide coenzyme in relation to methionine synthesis by bacteria.” (1962): 340-342.
2. Okada, Kiyoshi, et al. “Methylcobalamin increases Erk1/2 and Akt activities through the methylation cycle and promotes nerve regeneration in a rat sciatic nerve injury model.” Experimental neurology 222.2 (2010): 191-203.
3. Yamatsu, K., et al. “[Pharmacological studies on degeneration and regeneration of the peripheral nerves.(2) Effects of methylcobalamin on mitosis of Schwann cells and incorporation of labeled amino acid into protein fractions of crushed sciatic nerve in rats].” Nihon yakurigaku zasshi. Folia pharmacologica Japonica 72.2 (1976): 269-278.
4. Ang, Cynthia D., et al. “Vitamin B for treating peripheral neuropathy.” The Cochrane Library (2008). Page on update-software.com
5. Zhang, Ming, et al. “Methylcobalamin: a potential vitamin of pain killer.” Neural plasticity 2013 (2013). Methylcobalamin: A Potential Vitamin of Pain Killer
6. Deng, Houliang, et al. “Meta-analysis of methylcobalamin alone and in combination with prostaglandin E1 in the treatment of diabetic peripheral neuropathy.” Endocrine 46.3 (2014): 445-454.
7. Xu, Gang, et al. “A Single‐Center Randomized Controlled Trial of Local Methylcobalamin Injection for Subacute Herpetic Neuralgia.” Pain Medicine 14.6 (2013): 884-894. Page on painmuse.org
8. Chiu, C. K., et al. “The efficacy and safety of intramuscular injections of methylcobalamin in patients with chronic nonspecific low back pain: a randomised controlled trial.” Singapore medical journal 52.12 (2011): 868-873. Page on apamedcentral.org

https://www.quora.com/Has-someone-used-a-MeCbl-treatment-for-patients-or-has-been-treated-with-MeCbl-What-for-and-what-were-the-outcomes/answer/Tirumalai-Kamala