Neuropathic Pain Medications – review & metanalysis of 229 studies






This review was done by many of the best pain specialists from all over the world. You will not find answers in that large review if neuropathic pain has already failed tricyclic antidepressants (Elavil, amitriptyline, Norpramin desipramine, others), gabapentin (Neurontin), pregabalin (Lyrica), lidocaine, capsaicin, or opioids. That is the current paradigm. A new paradigm – glial modulators  – that I discuss on this site, may or may not give relief.


A member of the International Association for Study of Pain, IASP, published a brief critique of that comprehensive review of 229 trials of medications for neuropathic pain published in Lancet Neurology February 2015. The critique is posted below, done by a member of the Neuropathic Pain Special Interest Group, NeuPSIG.



To understand the metanalysis of these 229 trials, you need to understand the simple concept of number needed to treat, NNT.


NNT is an estimate of “the number of patients that need to be treated in order to have an impact on one person.”


The smaller the number, the more effective the drug. Example, NNT of 7.2 for gabapentin means you need to treat  7.2 people before a response. If 3, need to treat 3 before a response.


Barsook (Harvard, ref. below) reviewed ketamine studies in 2009:  “they did show a level of efficacy (of ketamine) based on NNT that equals or betters most drug trials for this condition.”



“NeuPSIG has just published an up to date systematic review on the effectiveness of pharmacotherapy in Lancet Neurology. They have negotiated with the journal to make it available beautifully open access. You can download it for free here.”

Neil O’Connell, Brunel University London


“This is a comprehensive review, containing 229 trials of the full range of pharmacological agents using robust methods, to synthesize, summarise and make value judgements about the quality of the available evidence. So what are the take home messages?”


“Using a primary outcome of achieving at least 50% pain relief trial outcomes were described as “generally modest”. The number of patients needed to treat with the drug compared to a placebo for one more person to achieve this outcome ranged from a relatively rosy 3.6 (95% confidence interval 3 to 4.4) for tricyclic antidepressants such as amitryptiline, 4.3 (95%CI 3.4 to 5.80 for strong opioids to a less impressive 7.2 (95%CI 5.9 to 9.21) for gabapentin, and 7.7 (6.5 to 9.4) for pregabalin (often sold under the brand-name Lyrica). It’s interesting, at least to me, how much better the older more traditional agents seem to have fared compared on effectiveness to the more modern (and commonly more expensive) agents although the safety and tolerability of gabapentin seems superior.”


“The spectre of publication bias also raises its head. The reviewers carefully took a number of routes to try to unpick this notoriously difficult issue and estimate that there has been overall a 10% overstatement of treatment effects. Published studies reported larger effect sizes than did unpublished studies. This is not a problem restricted to the field of pain trials. It is a burning issue across the world of clinical trials. It is very important because if we fail to base our clinical recommendations on the totality of relevant evidence (because some data are hidden from us) we are in danger of mis-estimating the benefits and the harms and as a result patients are put at risk. If you think that is pretty important then there are ways that you can help. Check out the All-Trials campaign.”


“Overall what does this mean? Many drugs are effective but not as effective as we would wish them to be. No pharmacological agent really impresses and for any drug the most probable outcome is failure to produce 50% pain relief. There are various potential reasons for this. The first is that the drugs may only be moderately or marginally effective, another is that neuropathic pain includes quite a mixed bag and our ability to accurately diagnose and to target drugs to specific mechanisms in the clinic is currently fairly poor.”


“The NeuPSIG review team formulate a number of recommendations for revision of their clinical guideline for managing NP pain, balancing the benefits, harms, costs and strength of the evidence.”

  • a strong recommendation for use and proposal as a first-line treatment in neuropathic pain for tricyclic antidepressants, serotonin-noradrenaline reuptake inhibitors, pregabalin, and gabapentin;


    • a weak recommendation for use and proposal as a second line treatment for lidocaine patches, capsaicin high-concentration patches, and tramadol; and a weak recommendation for use and proposal as third line for strong opioids and botulinum toxin A. Topical agents and botulinum toxin A are recommended for peripheral neuropathic pain only.


“This email [from IASP’s NeuPSIG] is also published as a blogpost at”




Finnerup NB, Attal N, Haroutounian S et al. Pharmacotherapy for neuropathic pain in adults: a systematic review and meta-analysis. Lancet Neurol. 2015;14:2:162-73.





Glial modulators – another paradigm


From my January 2012 brief review of publications on ketamine, only one of a handful of glial modulators, this author says reviews “show a level of efficacy based on NNT that equals or betters most drug trials for this condition.



Ketamine and chronic pain – Going the distance, David Barsook, Director, P.A.I.N. Group, Massachusetts General, McLean and Children’s Hospitals, Harvard Medical School, Boston, MA;


This paper covers essential points not mentioned by many, thus quoted at length below:


Our current therapeutic armamentarium is quite limited in terms of analgesic efficacy in controlled trials. Some would argue that the small efficacy (both at a population level and the magnitude of change in VAS score) this is related to the fact that we need to consider mechanistic approaches to chronic pain subgroups. However, patients and clinicians find themselves in a position of “what to do now”.


Ketamine, brain function and therapeutic effect – neuroprotective or neurotoxic


With the onset of chronic pain (including CRPS) a number of changes in brain function occur in the human brain including but not limited to: (1) central sensitization ; (2) functional plasticity in chronic pain and in CRPS; (3) gray matter volume loss in CRPS ; (4) chemical alterations ; and (5) altered modulatory controls. Such changes are thought to be in part a result of excitatory amino acid release in chronic pain. Excitatory amino acids are present throughout the brain and are normally involved in neural transmission but may contribute to altered function with excessive release producing increased influx of calcium and potentially neural death. Here lies the conundrum the use of an agent that potentially deleteriously affect neurons that may already be compromised but may also have neuroprotective properties by mechanisms that include reducing phosphorylation of glutamate receptors resulting in decreased glutamatergic synaptic transmission and reduced potential excitotoxicity . Alternatively, ketamine may affect glia regulation of glutamate and inhibit glutamate release within glia. However, by whatever mechanism ketamine acts on CRPS pain, there does seem to be a dose/duration effect in that longer doses at levels tolerated by patients seem to prove more effective in terms of the duration of effects.


So what could be happening in the brain and what is required to alter brain systems and reverse the symptomatic state? Ketamine may diminish glutamate transmission and “resets” brain circuits, but it seems that a minimal dose and/or duration of treatment is required. Alternatively, ketamine may produce neurotoxicity and damage or produce a chemical lesion of affected neurons. These two issues are important to be understood in future trials. Reports from patients who have had anesthetic doses have included prolonged pain relief for many months. While the authors did not address issues such as the effect of dosing duration or repetitive dosing at say 6weeks, they did show a level of efficacy based on NNT that equals or betters most drug trials for this condition.”




As a community we have a major opportunity to define the efficacy and use of a drug that may offer more to CRPS (and perhaps other) patients than is currently available. This is clearly an opportunity that needs urgent attention and a number of questions remain to be answered. For example, is ketamine more effective in early stage disease? How does ketamine provide long-term effects? Further controlled trials evaluating dose, duration, anesthetic vs. non-anesthetic dosing are needed. Few of us really understand what it is like to suffer from a chronic pain condition such as CRPS. Ketamine therapy may be a way forward that can be brought into our clinical practice through further controlled studies that will allow for appropriate standards for use in patients.





The material on this site is for informational purposes only, and is not a substitute for medical advice,

diagnosis or treatment provided by a qualified health care provider.



Please understand that it is not legal for me to give medical advice without a consultation.

If you wish an appointment, please telephone my office.



For My Home Page, click here:  Welcome to my Weblog on Pain Management!


Be the change you wish to see – or walk away. Money at NIH



A Turning Point


$$$$$ MONEY $$$$$


at NIH


May not come this way again


NIH developing

5-year NIH-wide Strategic Plan




Donate to organizations, below

They can provide feedback to NIH via the

RFI Submission site




John C. Liebeskind, 1935 – 1997, distinguished scholar and researcher, past president of the American Pain Society, had the radical idea that pain can affect your health.


Research decades ago by an Israeli team at UCLA and others had shown “that pain can accelerate the growth of tumors and increase mortality after tumor challenge.” Decades ago Professor Liebeskind lectured all over the country: Pain kills.


He wrote an editorial in 1991, summarizing a life’s work:


“Pain and stress can inhibit immune function.”



Quoting John Bonica, the father of modern pain management, he wrote:


“Bonica has long argued that the term ‘chronic benign pain’ (used in distinction to pain associated with cancer) is seriously misleading.  Chronic pain is never benign, he contends; “it is a ‘malefic force’ that can devastate its victims’ lives and even lead to suicide.”



Liebeskind continues, “It appears that the dictum ‘pain does not kill,’ sometimes invoked to justify ignoring pain complaints, may be dangerously wrong.”


Pain mediates immune function




  Opioids mediate the suppressive effect of stress on natural killer cells,


 published in 1984, immune system.


Alcohol increases tumor progression, 1992, immune system.


It used to be news.

He did not live to see change.


People just want to go on doing what they’re doing.

They want business as usual.



After 1991, we saw the great discoveries of neuroinflammation, pioneered by Linda Watkins, PhD, the early understanding of the innate immune system, its involvement in chronic pain and depression, and a few weeks ago, a British team showed neuroinflammation in teens with early signs of schizophrenia and DNA markers.



Major Depression has the same neuro-inflammation found in chronic pain, often responding to same medications, in particular glial modulators – immune modulators. Now, perhaps early schizophrenia will respond to glial modulators, reducing inflammation seen on scan in teens, before they become homeless and burned out by antipsychotic drugs


Inflammation out of control destroys neurons


Fire on the brain



We must be the change we wish to see


It’s not just the Bern. It’s been starting. Forces are finally coming together. We want change. It’s been too much. Too long.


We won’t take it anymore.


I figure if I tell you about it, you might just mention it to someone to pass it on. That is all. One small action may lead to change. Activate inputs to the NIH strategic plan.



~ Action needed ~


Prices of drugs becoming unaffordable

No new drugs for pain or major depression

Research to repurpose existing drugs

Expose the politics destroying our compounding pharmacies


Above all

The #1

Major Priority:

Request NIH to solicit priority call for research on

Glial modulators of the

Innate immune system





Glia modulate

chronic pain, major depression

and almost every known disease


Glia are your innate immune system


Inflammation kills




 Stress kills. Inflammation kills.



Pain kills


In the 1970’s, Professor Liebeskind and an Israeli team at UCLA injected cancer cells to two groups of rats that had sham surgery. Cancer spread much faster and killed far sooner in the group with poor treatment of surgical pain.



~ Pain kills ~


He lectured all over the country


Forty five years ago



I’m gonna be dead before I see this country do anything but unaffordable opioids and the magical ineffective trio of gabapentin, Lyrica, Cymbalta to treat chronic pain. The devastating, blind, nationwide emphasis does nothing to address the cause: inflammation, the innate immune system gone wild.



Innate immune system in action


Untreated pain suppresses the hormone systems too.


Untreated depression – same inflammation kills lives.


Where’s the money?


We are the change we wish to see. It’s pitiful I am so lazy. Suddenly, too late, we may need something, but, aha, no new drugs in the pipeline.




~ Make a joyful cry to NIH ~


They are soliciting input from professional societies


If your condition has failed all known drugs for pain or major depression, then make a joyful cry to NIH, now, before they give away all that nice new $$$$$money$$$$$.



Follow and join


American Pain Society



International Association for Pain

celebrating 40 years of pain research



Reflex Sympathetic Dystrophy Syndrome Association

help for CRPS/RSD  




The key to CRPS/RSD pain will apply to all forms of chronic pain, in particular the most difficult form, neuropathic pain. RSDSA funds research into all forms of chronic pain, not only Complex Regional Pain Syndrome (CRPS/RSD). Their scientific board members are not funded by opioid money.





what is the annual cost of care

as fraction of GDP

for the growing population of Americans on opioids

for one year, for lifetime?



People are dying from prescription opioids and those who need them find they don’t work well enough. Prescriptions opioid costs must be a huge fraction of the medical costs in the United States GDP. You are required  to see a doctor every single month each year, often lifelong, just for one opioid, 12 months a year x 30 years x tens of millions of people and increasing – a growth industry. Not even counting $600 a day for the opioid, what the cost of monthly visits for 30 years? Not counting the army of DEA, FDA, CDC agents watching the opioids like a hawk. We all have to be sharp, addiction is growing. Addiction aside, deaths from prescription opioids are shaking up the CDC forcing urgent change this coming month.




Opioids do not work well for chronic pain

We need better

It’s not just the $600/day price

They just don’t work






Raise a joyful noise at NIH now or write back at us readers with comments and better suggestions. Tell others what you’d like to see. Which politicians do you know would be most interested in this at national levels and organizations?


You may never see this change unless you do it now. Other forces will get this new money.



Turning point now

May not return



We are at a turning point and we will fail to catch the sail that’s coming fast to carry all research money in their shiny big stem cell direction. They never look back.



There is so many medications we can use today, FDA approved drugs that can be re-purposed and applied to recent cutting edge science. Someone must pay to do the work to study this.



Re-purpose old drugs



Stanford just showed a popular generic drug improved recovery of stroke paralysis in mice to begin at 3 days rather than 30. Old drug, new purpose, of course more years of testing to confirm in humans. Brilliant team applying new science.



NIH to solicit a

Special Invitation

for 30 good protocols to

repurpose old drugs



Hundreds of old drugs, already approved, could be involved in mechanisms we have recently learned about. Speak up or money will go to shiny new stem cells. None for chronic pain or major depression. No company will find this profitable – it must be funded by NIH. A popular generic sleeping pill can bring astonishing return from stroke paralysis.



Congress has not opened this new money to NIH in many long years. How often will there be extra money?






Lawrence A. Tabak, D.D.S., Ph.D.
Principal Deputy Director, NIH, solicits you to

Review the NIH Strategic Initiative Plan and their

Request for Information (RFI) and the NIH website

and provide your feedback via the RFI Submission site



This is for “stakeholder organizations (e.g., patient advocacy groups, professional societies) to submit a single response reflective of the views of the organization/membership as a whole. We also will be hosting webinars to gather additional input. These webinars will be held in early to mid-August.




Be the change you wish to see

Donate to those organizations

to solicit the change you wish to be




Happy New Year


There’s money at NIH







The material on this site is for informational purposes only.

It is not a substitute for medical advice, diagnosis or treatment provided by a qualified health care provider.

Relevant comments are welcome.

If any questions, please schedule an appointment with my office.

This site is not for email.


For My Home Page, click here:  Welcome to my Weblog on Pain Management!





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