Pregabalin for Sciatica - NEJM

[oreosandsake]

http://www.nejm.org/doi/full/10.1056/NEJMoa1614292?query=featured_home&

Trial of Pregabalin for Acute and Chronic Sciatica
Stephanie Mathieson, M.Chiro., Christopher G. Maher, Ph.D., Andrew J. McLachlan, Ph.D., Jane Latimer, Ph.D., Bart W. Koes, Ph.D., Mark J. Hancock, Ph.D., Ian Harris, Ph.D., Richard O. Day, M.B., B.S., M.D., Laurent Billot, M.Sc., M.Res., Justin Pik, M.B., B.S., Stephen Jan, Ph.D., and C.-W. Christine Lin, Ph.D.

N Engl J Med 2017; 376:1111-1120March 23, 2017DOI: 10.1056/NEJMoa1614292

BACKGROUND
Sciatica can be disabling, and evidence regarding medical treatments is limited. Pregabalin is effective in the treatment of some types of neuropathic pain. This study examined whether pregabalin may reduce the intensity of sciatica.


METHODS
We conducted a randomized, double-blind, placebo-controlled trial of pregabalin in patients with sciatica. Patients were randomly assigned to receive either pregabalin at a dose of 150 mg per day that was adjusted to a maximum dose of 600 mg per day or matching placebo for up to 8 weeks. The primary outcome was the leg-pain intensity score on a 10-point scale (with 0 indicating no pain and 10 the worst possible pain) at week 8; the leg-pain intensity score was also evaluated at week 52, a secondary time point for the primary outcome. Secondary outcomes included the extent of disability, back-pain intensity, and quality-of-life measures at prespecified time points over the course of 1 year.


RESULTS
A total of 209 patients underwent randomization, of whom 108 received pregabalin and 101 received placebo; after randomization, 2 patients in the pregabalin group were determined to be ineligible and were excluded from the analyses. At week 8, the mean unadjusted leg-pain intensity score was 3.7 in the pregabalin group and 3.1 in the placebo group (adjusted mean difference, 0.5; 95% confidence interval [CI], −0.2 to 1.2; P=0.19). At week 52, the mean unadjusted leg-pain intensity score was 3.4 in the pregabalin group and 3.0 in the placebo group (adjusted mean difference, 0.3; 95% CI, −0.5 to 1.0; P=0.46). No significant between-group differences were observed with respect to any secondary outcome at either week 8 or week 52. A total of 227 adverse events were reported in the pregabalin group and 124 in the placebo group. Dizziness was more common in the pregabalin group than in the placebo group.


CONCLUSIONS
Treatment with pregabalin did not significantly reduce the intensity of leg pain associated with sciatica and did not significantly improve other outcomes, as compared with placebo, over the course of 8 weeks. The incidence of adverse events was significantly higher in the pregabalin group than in the placebo group. (Funded by the National Health and Medical Research Council of Australia; PRECISE Australian and New Zealand Clinical Trials Registry number



Sciatica was defined in this trial as radiating pain into one leg below the knee, accompanied by nerve-root or spinal-nerve involvement as indicated by the presence of at least one of the following clinical features: dermatomal leg pain, myotomal weakness, sensory deficits, or diminished reflex, as determined by the trial clinician.

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[ampaphb]

So I read this the other day, and the first things that jumped out at me were that

1) the lead author is a chiro
2) only one of the 12 authors was an MD
3) the vast majority of the authors are PTs

 

[bedrock]

So I read this the other day, and the first things that jumped out at me were that

1) the lead author is a chiro
2) only one of the 12 authors was an MD
3) the vast majority of the authors are PTs

good point. You have to wonder about their motivation.

Still for acute sciatica, I use gabapentin or other cheap generics as no time to play insurance games with lyrica. However for chronic sciatic, its a nice option to have lyrica.

 

[lobelsteve]

Maybe my inherent bias from seeing patients with acute radic respond to the medication at 75mg bid over several years of care was wrong. Or the study was crap.
14 pills for free, no insurance requirement to trial. Gets them to home exercise vs PT, can save them from TFESI.

 

[drusso]

Maybe my inherent bias from seeing patients with acute radic respond to the medication at 75mg bid over several years of care was wrong. Or the study was crap.
14 pills for free, no insurance requirement to trial. Gets them to home exercise vs PT, can save them from TFESI.

I took it once for 2 days after a complicated dental procedure and it worked. But maybe my "fibromyalgianess" was just acting up or I had a conflict of interest since my mutual fund invests in Pfizer stock and therefore I can't be counted upon as a reliable reporter of my own experience.

 

[oreosandsake]

just trying to stimulate discussion..

I actually rarely use pregabalin vs gabapentin. not sure how much better it really is. ? first dose effect. also great campaign by Pfuzzy to get it approved for every indication under the sun

i have had a lot ladies say they gained 15 lb in 1 month on pregabalin after the first month

 

[ampaphb]

just trying to stimulate discussion..

I actually rarely use pregabalin vs gabapentin. not sure how much better it really is. ? first dose effect. also great campaign by Pfuzzy to get it approved for every indication under the sun

i have had a lot ladies say they gained 15 lb in 1 month on pregabalin after the first month

Oddly Neurontin does not seem to have a similar effect, despite Lyrica being a gabapentin prodrug.

 

[oreosandsake]

Oddly Neurontin does not seem to have a similar effect. Lyrica is a gabapentin prodrug

Sent from my SAMSUNG-SM-G930A using SDN mobile

Which is why I stick with gabapentin. That and its dirt cheap. Also feel like lot of range to titrate... tho the dose response curve starts to flatten out at 2000mg per day

 

[epidural man]

Which is why I stick with gabapentin. That and its dirt cheap. Also feel like lot of range to titrate... tho the dose response curve starts to flatten out at 2000mg per day

I think this is an absorption issue.

If you take it QID or more, I think the response curve continues.

 

[jadedphysiotherapist]

So I read this the other day, and the first things that jumped out at me were that

1) the lead author is a chiro
2) only one of the 12 authors was an MD
3) the vast majority of the authors are PTs

Irrelevant unless tampering and fudging of data is found. Skepticism cannot trump empiricism.

PhDs (the majority) have the best skillset in creating experimentation rather than a study done by all MDs, all chiros, all PTs, etc.

Attack and appraise the structure.

It was randomized, double blinded, there was a placebo group, n values were solid and close to each other for treatment and control groups. Outcome measure scores were adjusted. Pregabalin had higher pain ratings at the first time point and at followup after mean score adjustment. Assessment was at the 95th percentile CI. Sciatica was explicitly defined.

Almost double the amount of adverse events from the pregabalin group, one including dizziness. That is a lot. Whether that is due to simply a medication side effect or from the pain experienced from the patients I'm not sure. I don't have access to full article and don't know how "adverse effects" is defined in this context which may be an unfair conclusion here.

There is no significant difference according to the data and this made it to NEJM. With a worst case scenario of the data it doesn't seem that subjective mean pain ratings would've fluctuated from anywhere near 2 differences on a pain rating and pregabalin already had a higher rating from the start.

Cons: The P values are awful. At least the second one. The first isn't great but the complexity of subjective pain scores has something to do with this I'm sure. I do not know the exclusion criteria.

Public Health Perspective:
-The waste of pharmaceutical use this implies is astounding.
-Are the adverse effects a fatality concern or is it other symptoms that pharma will try to fix with marketing of other Rx that treat the new symptoms....similar to the 6 o clock drug ad meant to fix opioid induced constipation.
-This would have to be compared to data demonstrating outcomes from patients utilizing therapy techniques for exercises that target flexion, extension, or lateral flexion techniques for strengthening....in order to strengthen musculature that pull on the spine and decrease pain symptoms radiating down the leg. Other interventions to compare would be postural education, decreasing activity exacerbating the symptoms with a tx progression back to the movement pattern, or neurodynamics. Widescale data on that is difficult to compare given pains subjectivity.
-manipulation if suggested by chiropractic should be avoided as an "alternative" since adjusting one segment doesn't exist to my knowledge and this isn't "low back pain" which does receive an acute alleviation of symptoms actually. Longterm is a different story
-Pharma will never want any studies to get funded with these researchers ever again.
-This supports conservative competition in the pain field for Rx vs. Tx although this study didn't involve Tx as an intervention group so a definite statement of one over the other is unfair here.....unless we're talking economics.

Kudos to the resident facilitating discussion. Hope this doesn't tread on too many toes within this thread and discussion.

 

[ampaphb]

Irrelevant unless tampering and fudging of data is found. Skepticism cannot trump empiricism.

PhDs (the majority) have the best skillset in creating experimentation rather than a study done by all MDs, all chiros, all PTs, etc.

Attack and appraise the structure.

Yes yes, investigator bias never impacts study outcomes ...

Also, am I the only one who is still offended by the notion that one additional year of training earns a PT a "PhD"

 

[jadedphysiotherapist]

Yes yes, investigator bias never impacts study outcomes ...

Also, am I the only one who is still offended by the notion that one additional year of training earns a PT a "PhD"

If there isn't a trail showing tampering then all you can do is appraise it critically. This is with anything. This would be like me saying MDs were in the clinical trial research for prazosin to show that it produced X effect......so I'm going to ignore X effect regardless of study design simply because a contributor makes a living off of Rx.


I think you have a fundamental misunderstanding of what a clinical doctorate and a research doctorate are.

MD is a clinical doctorate. PharmD, DPT, OD etc. although those are specified in allied health scope.

If the researchers have a PhD, they spent four years doing graduate coursework to demonstrate ability to pick a research field and spend a career adding to that knowledge base. Usually they are completing postdocs to compete and add as resume fillers until a professor spot appears. If these researchers had a physical therapy background then they completed a terminal clinical degree pathway and then returned to school for the four year PhD training pathway (although good researchers can complete it in 3 but that would throw off the universities graduation and supply and demand dynamics so it's kept at 4). Sometimes extended out to 6

Rehab has many people who were clinicians return to school for a research career. It isn't "adding a year" to get a PhD. The clinical rehab field increased a year in timelength for a terminal 3 year degree. Mentorship is not yet required (residency) as it is with medical specialties

 

[ampaphb]

A DPT is obtained 3 years after college

Industry-sponsored research is not accorded similar weight to research done by independent investigators.

There's a guy in Paducah, KY who claims that, lidocaine's duration of action is weeks to months.

If Carragee produces a study about discography, you can be sure of the outcome will be negative.

You're a fool if you don't incorporate investigator bias into your overall impression of a study

 

[jadedphysiotherapist]

A DPT is obtained 3 years after college

Sent from my SAMSUNG-SM-G930A using SDN mobile

...yes, and a PhD is obtained four years after college. You're comparing a clinical degree to a research degree.

 

[DOctorJay]

and now, this...
Home

 

[jadedphysiotherapist]

A DPT is obtained 3 years after college

Industry-sponsored research is not accorded similar weight to research done by independent investigators.

There's a guy in Paducah, KY who claims that, lidocaine's duration of action is weeks to months.

If Carragee produces a study about discography, you can be sure of the outcome will be negative.

You're a fool if you don't incorporate investigator bias into your overall impression of a study

You edited this. Just noticed. I agree you incorporate. Just don't dismiss. Talk to the physician who was involved in the study for probably the least possibility of bias. If it were predominantly chiropractic, then I would be very skeptical especially since they directly compete with physicians while those with the physical therapy backgrounds would've been collaborating with physicians most likely

........You're example makes me scared to go to the dentist now guh! 🙁

 

[jadedphysiotherapist]

A DPT is obtained 3 years after college

Industry-sponsored research is not accorded similar weight to research done by independent investigators.

There's a guy in Paducah, KY who claims that, lidocaine's duration of action is weeks to months.

If Carragee produces a study about discography, you can be sure of the outcome will be negative.

You're a fool if you don't incorporate investigator bias into your overall impression of a study

Do you have a preference for industry sponsored research or independent? Or is it more of whoever is producing research relevant to your field at that time of publication and you don't have a predilection towards one?

^This is just curiosity

 

[ampaphb]

Industry-sponsored research is bought and paid for. Studies that don't reflect well on the sponsor are typically buried, so that the company is not harmed by the results. Investigators do not wish to bite the hand that feeds them.

So do I have a preference? I do - I prefer research independent of bias

Sent from my SAMSUNG-SM-G930A using SDN mobile

 

[epidural man]

and now, this...
Home

oh crap.

I often joke I got my medical degree online. I guess I can't do that anymore since one can actually do that.

 

[Ducttape]

here are my questions/concerns:

- if memory serves correctly, NEJM while seeming to sound very impressive, tends to carry a significant amount of COI.

- second, why are there no MDs as second or third authors? the dearth of MDs from a clinical standpoint is unusual. and especially for NEJM. why would the apparently 1 trial clinician be listed 8th?

- why were there 124 adverse events in the placebo group?

- what was the baseline that all patients started with (i dont have access to the full article either).
my only question is, if the average pain for all patients was 8, and there was pain reduction across the board from 8 to 3 with placebo and lyrica, then im not sure that one can say that lyrica doesnt help...


ADDENDUM: with a little digging, more becomes clear.

this is an australian corporation that does research studies. the George Institute is primarily made up of researchers that apparently then find some trial clinician to do research on.

Pregabalin in addition to usual care for sciatica (PRECISE)
http://www.georgeinstitute.org/projects/pregabalin-in-addition-to-usual-care-for-sciatica-precise
they do have many many sponsors ie project funders: Project funders
Pfizer is not one of them, btw.

 

[jadedphysiotherapist]

here are my questions/concerns:

- if memory serves correctly, NEJM while seeming to sound very impressive, tends to carry a significant amount of COI.

- second, why are there no MDs as second or third authors? the dearth of MDs from a clinical standpoint is unusual. and especially for NEJM. why would the apparently 1 trial clinician be listed 8th?

- why were there 124 adverse events in the placebo group?

- what was the baseline that all patients started with (i dont have access to the full article either).
my only question is, if the average pain for all patients was 8, and there was pain reduction across the board from 8 to 3 with placebo and lyrica, then im not sure that one can say that lyrica doesnt help...


ADDENDUM: with a little digging, more becomes clear.

this is an australian corporation that does research studies. the George Institute is primarily made up of researchers that apparently then find some trial clinician to do research on.

Pregabalin in addition to usual care for sciatica (PRECISE)
they do have many many sponsors ie project funders: Project funders
Pfizer is not one of them, btw.

NEJM is still the highest impact journal in existence tho, correct? At least for clinical implementation? Well....I know others get more specific dependent on discipline and subfield but from the broad standpoint of general medical practice, it's pure science is to Nature as clinical practice is to NEJM

 

[epidural man]

NEJM is still the highest impact journal in existence tho, correct? At least for clinical implementation? Well....I know others get more specific dependent on discipline and subfield but from the broad standpoint of general medical practice, it's pure science is to Nature as clinical practice is to NEJM

impact factor doesn't mean quality factor.

In my opinion, they publish a ton of crap.

 

[drpainfree]

NEJM is still the highest impact journal in existence tho, correct? At least for clinical implementation? Well....I know others get more specific dependent on discipline and subfield but from the broad standpoint of general medical practice, it's pure science is to Nature as clinical practice is to NEJM

have NOT read a single paper out of NEJM since med school, even when it was free...

irrelevant information, mostly

 

[DrCommonSense]

So I read this the other day, and the first things that jumped out at me were that

1) the lead author is a chiro
2) only one of the 12 authors was an MD
3) the vast majority of the authors are PTs

When did Chiros start getting to publish in the NEJM?

Medicine really has started to deteriorate into some kind of weird place in the last 10 years or so.

I mean you literally have clowns like Chou recommending all kinds of alternative quackery such as Subluxation, Thai Chi, Yoga, etc as "high value" these days with literally ZERO evidence.

Now we have Chiros doing "studies" in top medical journals.

 

[DrCommonSense]

Irrelevant unless tampering and fudging of data is found. Skepticism cannot trump empiricism.

PhDs (the majority) have the best skillset in creating experimentation rather than a study done by all MDs, all chiros, all PTs, etc.

Attack and appraise the structure.

It was randomized, double blinded, there was a placebo group, n values were solid and close to each other for treatment and control groups. Outcome measure scores were adjusted. Pregabalin had higher pain ratings at the first time point and at followup after mean score adjustment. Assessment was at the 95th percentile CI. Sciatica was explicitly defined.

Almost double the amount of adverse events from the pregabalin group, one including dizziness. That is a lot. Whether that is due to simply a medication side effect or from the pain experienced from the patients I'm not sure. I don't have access to full article and don't know how "adverse effects" is defined in this context which may be an unfair conclusion here.

There is no significant difference according to the data and this made it to NEJM. With a worst case scenario of the data it doesn't seem that subjective mean pain ratings would've fluctuated from anywhere near 2 differences on a pain rating and pregabalin already had a higher rating from the start.

Cons: The P values are awful. At least the second one. The first isn't great but the complexity of subjective pain scores has something to do with this I'm sure. I do not know the exclusion criteria.

Public Health Perspective:
-The waste of pharmaceutical use this implies is astounding.
-Are the adverse effects a fatality concern or is it other symptoms that pharma will try to fix with marketing of other Rx that treat the new symptoms....similar to the 6 o clock drug ad meant to fix opioid induced constipation.
-This would have to be compared to data demonstrating outcomes from patients utilizing therapy techniques for exercises that target flexion, extension, or lateral flexion techniques for strengthening....in order to strengthen musculature that pull on the spine and decrease pain symptoms radiating down the leg. Other interventions to compare would be postural education, decreasing activity exacerbating the symptoms with a tx progression back to the movement pattern, or neurodynamics. Widescale data on that is difficult to compare given pains subjectivity.
-manipulation if suggested by chiropractic should be avoided as an "alternative" since adjusting one segment doesn't exist to my knowledge and this isn't "low back pain" which does receive an acute alleviation of symptoms actually. Longterm is a different story
-Pharma will never want any studies to get funded with these researchers ever again.
-This supports conservative competition in the pain field for Rx vs. Tx although this study didn't involve Tx as an intervention group so a definite statement of one over the other is unfair here.....unless we're talking economics.

Kudos to the resident facilitating discussion. Hope this doesn't tread on too many toes within this thread and discussion.

I am actually surprised NEJM would publish this data considering it is a journal that is usually very opaque in their "data" accumulation coupled with usually being a ***** for big pharma with most of their editorial board being "consultants" for Pfizer, Merck, etc.

NEJM is so dishonest it won't allow other scientists access to primary data on their "articles", leading to clear dishonesty that can't be scrutinized.

How did NEJM respond when we tried to correct 20 misreported trials?

 

[DrCommonSense]

If there isn't a trail showing tampering then all you can do is appraise it critically. This is with anything. This would be like me saying MDs were in the clinical trial research for prazosin to show that it produced X effect......so I'm going to ignore X effect regardless of study design simply because a contributor makes a living off of Rx.


I think you have a fundamental misunderstanding of what a clinical doctorate and a research doctorate are.

MD is a clinical doctorate. PharmD, DPT, OD etc. although those are specified in allied health scope.

If the researchers have a PhD, they spent four years doing graduate coursework to demonstrate ability to pick a research field and spend a career adding to that knowledge base. Usually they are completing postdocs to compete and add as resume fillers until a professor spot appears. If these researchers had a physical therapy background then they completed a terminal clinical degree pathway and then returned to school for the four year PhD training pathway (although good researchers can complete it in 3 but that would throw off the universities graduation and supply and demand dynamics so it's kept at 4). Sometimes extended out to 6

Rehab has many people who were clinicians return to school for a research career. It isn't "adding a year" to get a PhD. The clinical rehab field increased a year in timelength for a terminal 3 year degree. Mentorship is not yet required (residency) as it is with medical specialties

How can we determine that "trail" of tampering considering NEJM won't released primary data of their articles to independent scientists?

How did NEJM respond when we tried to correct 20 misreported trials?

 

[joshmir]

Here's the main issue with this study...

It looks at pain relief at 8 weeks or 52 weeks after randomization

While 8 weeks is important, the majority of people will improve with their sciatica in 8 weeks

Nobody believes Lyrica *changes* the underlying cause, nor does it alter sciatica pain in the medium or long-term after one has been taking it; it alters it *when the lyrica is at a reasonable serum level*, just like an opiate or an NSAID

The important thing is, at weeks 1-3, when they had severe pain, and weeks 4-7 when they had moderate pain, did the lyrica improve their quality of life during those weeks? That's when its needed most; by 8 weeks most people are better; its a silly study design

8 weeks gives you time to find an ideal dose, with a balance of effect and side effect, so its somewhat useful, but this study really misses the boat, and provides nothing new, and NEJM should be ashamed for publishing it

an assessment of the "area under the curve" for the first 8 weeks of pain would be much more useful

 

[Liontale]

Your study is very useful.
It helps new people who want to know how to handle sciatica.

 

[viralstu]

You are correct.

 

[viralstu]

Also, I want to know some simple home remedies for sciatica.
If possible, please let me know.