There was a very interesting and perhaps paradigm-changing article that found that decreasing inflammation after acute low back pain may actually lead to more chronic pain (see acute pain not use antiinflam scitranmed2022 in dropbox, or 10.1126/scitranslmed.abj9954).
Review:
Human studies assessing inflammatory response:
-- 98 participants with acute low back pain (LBP) were assessed, half with resolved pain ("R" group) and half with persistent pain ("P" group).
-- transcriptional genetic changes were assessed in these patients, assessing all of the RNA in a cell, to see which of the cell's genes were active
-- initially patients reported substantial pain, with a mean pain score of 6.8 (range 4 to 10), from a scale of 0 to 10
-- there was no difference in the transcriptomes between the P or R groups at the initial encounter with acute pain, with elevated pathways related to immune cell activation and immune responses
-- at 3 months, there were >1700 differentially expressed genes detected in the R patients, and none in the P patients, suggesting that those whose pain resolved had an abundance of active biological processes associated with their recovery.
-- the R patients at 3 months had significant decreases in neutrophil as well as mast cell percentages, but increases in CD8 T cells and NK cells; the P group did not have any changes in blood cell type populations over time. ie, there was substantial down-regulation of neutrophil-specific genes in those who recovered from their pain; the P group maintained their inflammatory profile
-- genes affecting degranulation of neutrophils had the largest change in the R group in the 3-month assessment
-- these findings were replicated in a prospective cohort of patients with temporomandibular disorder (TMD), finding that there were similar findings in those with resolved pain (R) or persistent pain (P)
Mouse studies assessing physiology of pain:
-- mice were subjected to one of 3 injuries: chronic constriction injury of their sciatic nerve (CCI, reflecting myofascial injury), injection of nerve growth factor into the muscles of the lower back (NGF, reflecting neuropathic injury) or inflammatory injury using the cell-mediated immunity stimulator complete Freund's adjuvant (CFA)
-- all three injuries produced mechanical allodynia (eg wincing on touching the hind paw)
-- those given control injections of saline continued to have hypersensitivity 30 to 60 days later
-- those given the steroid dexamethasone had robust inhibition of allodynia from NGF by day six after injection, but the dexamethasone delayed the recovery to baseline after CCI (the overall pain episode duration was increased with the steroid by two-fold)
-- diclofenac (an anti-inflammatory NSAID) was compared to gabapentin, morphine, and peripherally injected lidocaine: all reduced allodynia right away, but diclofenac significantly prolonged the duration of the overall allodynia produced
-- two experiments were done which showed that neutrophils were responsible for these effects:
-- the researchers depleted neutrophils in mice with an antibody, finding prolonged administration of the antibody exacerbated the allodynia and prolonged its duration, similar to what they found with dexamethasone
-- injection of 2 neutrophil-released proteins prevented the development of allodynia
Human study of analgesic usage
-- they accessed the UK Biobank project, a large biomedical database and research resource with lots of genetic and health information from half a million UK participants, with data for the past 20 years
-- They evaluated the use of several analgesic drug classes, including NSAIDs, acetaminophen, and antidepressants in those with back pain
-- individuals with acute back pain had a 1.76-fold greater risk (p=3.9x10-5) of developing chronic back pain if they reported using NSAIDs, adjusting for age, sex, ethnicity, and time interval between measurements
-- neither acetaminophen nor antidepressants had an association with the development of chronic back pain
-- pain intensity (one of the predictors of chronic pain) was not assessed in the Biobank project, so they used the number of reported chronic pain body sites as a substitute of pain intensity (which has been found to correlate with pain intensity), and again there was a 1.67-fold greater risk, p=3.0x10-4.
Commentary:
-- low back pain is the most common reported chronic pain condition worldwide, with point prevalence of 18%, one-month prevalence of 31% , and one-year prevalence of 38%. It is a major cause of personal disability, with its attendant effects on personal function, self-esteem, ability to work/earning potential, family dynamics, and broad effects on the community and society overall.
-- chronic pain involves a complex interplay between the nervous and immune systems, peripherally and in the brain; and the presence of activated immune cells and glia is thought to contribute to the transition from acute to chronic pain
-- the effects of steroids (and NSAIDs) are complex and multiple. steroids affect essentially all of the hormonal systems in the body. NSAIDs have multiple effects, including salt retention, hypertension, heart disease, atrial fibrillation, kidney disease, substantial effects on the microbiome (see below), etc. So, these meds are much more than simply "anti-inflammatory". the above study did link the effects of early steroids/NSAIDs to their anti-inflammatory genetic changes, which is very helpful but not conclusive. also, many other interventions we do have anti-inflammatory effects:
-- BUT are the anti-inflammatory effects as profound in these therapies as with steroids/NSAIDs? do they produce the same genomic effect? do they lead to chronic pain in humans???
-- further comment on the effect of NSAIDs on the microbiome: there are pretty profound effects of NSAIDs on the composition of the gut microbiome (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426480/), and there is an intimate relationship between the gut microbiome and the brain, the gut/brain axis (see microbiome gut brain axis JClinInvest2015 in dropbox, or doi:10.1172/JCI76304), which shows that the gut microbiome can affect emotional behavior, stress- and pain-modulation, and brain neurotransmitters -- the study above found a few things:
-- people with acute low back pain who had resolution of their symptoms by 3 months had significantly decreased inflammation at that time, more than 1/2 of the genome changed expression, and these active biological processes that changed in those recovering from their acute pain were importantly targeting gene expressions for neutrophil activation, which was decreased in those who had resolved symptoms (those with persistent pain did not show any change in their inflammatory response)
-- these findings were largely replicated in those with temporomandibular disorders
-- in the mouse experiments they found that acute treatment of inflammation with either dexamethasone or diclofenac was effective at decreasing pain right away, but greatly prolonged the resolution of three different types of pain: neuropathic, myofascial, and especially inflammatory
-- there was a pivotal role of neutrophils in the pain process: steroids were associated with longer pain associated with earlier neutrophil depletion in the acute injury
-- the human population study from the UK Biobank found that NSAIDs used early was associated with back pain 2 to 6 years later. This was not true for antidepressants, gabapentin, or lidocaine.
so, many questions are raised by the above, if indeed these results are affirmed in other more specific studies:
-- should we just use acetaminophen for musculoskeletal pain and avoid anti-inflammatories?
-- is it okay to use short-term NSAIDs or steroids and not develop chronic pain?
-- what if acetaminophen does not work? I suspect that topical diclofenac raises the same potential problems as oral NSAIDs, but would be good to test that
-- what else could we use? it seems that several antidepressants may help (and seemed okay in the Biobank evaluation). what about gabapentinoids (though there are some mixed reviews on their effectiveness)? Perhaps even low dose opiates?? Acetaminophen with codeine? Tramadol? Maybe these would be better in the long-run if we can avoid chronic pain???? And these opiates seem to have lower but non-zero potential for addiction/opiate use disorders than the stronger ones (oxycodone, fentanyl...)
-- what about intra-articular or trigger point injected steroids? Does this increase chronic pain? There are cohorts followed with steroids vs saline (placebo) injections, as noted in http://gmodestmedblogs.blogspot.com/2022/05/knee-oa-does-pt-help.html. Could look at long term effects.
-- even lidocaine seems to have anti-inflammatory effects. So is chronic use of lidocaine patches not good???
-- sounds like we should not really be advising cold therapy for musculoskeletal injury and sticking with heat and acetaminophen?? And PT/exercise seems okay since exercise does not seem to decrease inflammation and has some positive long term effects (as in above sciatica study)
-- and, what about non-pharmacologic therapies????? some are anti-inflammatory, as noted above. But these may be much more benign than meds, both in the short- and long-term...
-- there are other issues with sustained chronic inflammation (as was found in above study in those who had chronic pain): there is a clear association (though not necessarily causal) between chronic inflammation and many of our prevalent disorders: for example, heart disease, diabetes, obesity, major depressive disorder. so, does pain prolongation by steroids/NSAIDs lead to more of these systemic diseases?
Limitations:
-- it would have been important to have genetic analysis at more time points in those with low back pain to see the graph of what happens to the inflammatory response and gene expressions over time, both in those given anti-inflammatory agents and those another agent that did not affect inflammation
-- and it would have been useful to have longer-term data in terms of chronic pain to assess changes in gene expression and inflammation (ie, more than 3 mopnths)
-- we do not have adequate randomized controlled trials to change our practice dramatically. these trials need to have patients with a variety of acute pains randomized to a variety of interventions (as noted above) to assess long-term outcomes
-- the strongest parts of the study above was an RCT on mice. but it turns out that we are not mice, and mouse data may or may not translate well to human clinical outcomes
-- the Biobank does not have lots of granular data. in the finding of an association between different meds in those with back pain, what meds were used at what doses and for how long? was there a different outcome based on these differences? and the Biobank did rely on patient reporting, which might have been inaccurate in some cases
-- This study does not comment on treatment of chronic pain, often associated with a chronic inflammatory state. so, the above by itself should not change management of chronic pain
so, a really intriguing study that could be a paradigm shift on how we treat patients with acute musculoskeletal pain. chronic pain is remarkably common (a 2021 report suggested 50.2 million people in the US, 20.5% of the population!!!!), is associated with profound individual and societal disruptions, has been a key component to our current opioid crisis (>108,000 deaths in 2021, and a large percentage of those with subsequent opioid use disorder start with pills, often those in their family's medicine cabinet). so, any new approaches that helps decrease the transition from acute musculoskeletal pain to chronic pain is sorely (!!) needed..... BUT there need to be lots more studies done comparing different approaches: which specific therapies, of the many that actually affect acute inflammation, are actually effective in preventing long-term pain?? Though it does sound like some things do make sense now: using acetaminophen/exercise as first line. keeping the muscles moving early on (including early PT), perhaps not using ice for acute pain...
geoff
If you would like to be on the regular email list for upcoming blogs, please contact me at gmodest@uphams.org
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Then go to "clinic", then to "clinical stuff" for articles, or go to https://www.dropbox.com/sh/nyle22q1fn6lkpk/AAB9B2hBj5Kw4gtrJAkI-UF8a?dl=0 for the powerpoint presentations
to get access to all of the blogs (2 options):
1. go to http://gmodestmedblogs.blogspot.com/ to see them in reverse chronological order
2. click on 3 parallel lines top left, if you want to see blogs by category, then click on "labels" and choose a category
3. or you can just click on the magnifying glass on top right, then type in a name in the search box and get all the blogs with that name in them
or: go to https://www.bucommunitymedicine.org/ , a website from the Community Medicine section at Boston Medical Center. This site does have a very searchable and accessible list of my blogs (though there have been a few that did not upload over the last year or two). but overall it is much easier to view blogs and displays more at a time.
please feel free to circulate this to others. also, if you send me their emails, i can add them to the listThere was a very interesting and perhaps paradigm-changing article that found that decreasing inflammation after acute low back pain may actually lead to more chronic pain (see acute pain not use antiinflam scitranmed2022 in dropbox, or 10.1126/scitranslmed.abj9954).
Review:
Human studies assessing inflammatory response:
-- 98 participants with acute low back pain (LBP) were assessed, half with resolved pain ("R" group) and half with persistent pain ("P" group).
-- transcriptional genetic changes were assessed in these patients, assessing all of the RNA in a cell, to see which of the cell's genes were active
-- initially patients reported substantial pain, with a mean pain score of 6.8 (range 4 to 10), from a scale of 0 to 10
-- there was no difference in the transcriptomes between the P or R groups at the initial encounter with acute pain, with elevated pathways related to immune cell activation and immune responses
-- at 3 months, there were >1700 differentially expressed genes detected in the R patients, and none in the P patients, suggesting that those whose pain resolved had an abundance of active biological processes associated with their recovery.
-- the R patients at 3 months had significant decreases in neutrophil as well as mast cell percentages, but increases in CD8 T cells and NK cells; the P group did not have any changes in blood cell type populations over time. ie, there was substantial down-regulation of neutrophil-specific genes in those who recovered from their pain; the P group maintained their inflammatory profile
-- genes affecting degranulation of neutrophils had the largest change in the R group in the 3-month assessment
-- these findings were replicated in a prospective cohort of patients with temporomandibular disorder (TMD), finding that there were similar findings in those with resolved pain (R) or persistent pain (P)
Mouse studies assessing physiology of pain:
-- mice were subjected to one of 3 injuries: chronic constriction injury of their sciatic nerve (CCI, reflecting myofascial injury), injection of nerve growth factor into the muscles of the lower back (NGF, reflecting neuropathic injury) or inflammatory injury using the cell-mediated immunity stimulator complete Freund's adjuvant (CFA)
-- all three injuries produced mechanical allodynia (eg wincing on touching the hind paw)
-- those given control injections of saline continued to have hypersensitivity 30 to 60 days later
-- those given the steroid dexamethasone had robust inhibition of allodynia from NGF by day six after injection, but the dexamethasone delayed the recovery to baseline after CCI (the overall pain episode duration was increased with the steroid by two-fold)
-- diclofenac (an anti-inflammatory NSAID) was compared to gabapentin, morphine, and peripherally injected lidocaine: all reduced allodynia right away, but diclofenac significantly prolonged the duration of the overall allodynia produced
-- two experiments were done which showed that neutrophils were responsible for these effects:
-- the researchers depleted neutrophils in mice with an antibody, finding prolonged administration of the antibody exacerbated the allodynia and prolonged its duration, similar to what they found with dexamethasone
-- injection of 2 neutrophil-released proteins prevented the development of allodynia
Human study of analgesic usage
-- they accessed the UK Biobank project, a large biomedical database and research resource with lots of genetic and health information from half a million UK participants, with data for the past 20 years
-- They evaluated the use of several analgesic drug classes, including NSAIDs, acetaminophen, and antidepressants in those with back pain
-- individuals with acute back pain had a 1.76-fold greater risk (p=3.9x10-5) of developing chronic back pain if they reported using NSAIDs, adjusting for age, sex, ethnicity, and time interval between measurements
-- neither acetaminophen nor antidepressants had an association with the development of chronic back pain
-- pain intensity (one of the predictors of chronic pain) was not assessed in the Biobank project, so they used the number of reported chronic pain body sites as a substitute of pain intensity (which has been found to correlate with pain intensity), and again there was a 1.67-fold greater risk, p=3.0x10-4.
Commentary:
-- low back pain is the most common reported chronic pain condition worldwide, with point prevalence of 18%, one-month prevalence of 31% , and one-year prevalence of 38%. It is a major cause of personal disability, with its attendant effects on personal function, self-esteem, ability to work/earning potential, family dynamics, and broad effects on the community and society overall.
-- chronic pain involves a complex interplay between the nervous and immune systems, peripherally and in the brain; and the presence of activated immune cells and glia is thought to contribute to the transition from acute to chronic pain
-- the effects of steroids (and NSAIDs) are complex and multiple. steroids affect essentially all of the hormonal systems in the body. NSAIDs have multiple effects, including salt retention, hypertension, heart disease, atrial fibrillation, kidney disease, substantial effects on the microbiome (see below), etc. So, these meds are much more than simply "anti-inflammatory". the above study did link the effects of early steroids/NSAIDs to their anti-inflammatory genetic changes, which is very helpful but not conclusive. also, many other interventions we do have anti-inflammatory effects:
-- BUT are the anti-inflammatory effects as profound in these therapies as with steroids/NSAIDs? do they produce the same genomic effect? do they lead to chronic pain in humans???
-- further comment on the effect of NSAIDs on the microbiome: there are pretty profound effects of NSAIDs on the composition of the gut microbiome (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7426480/), and there is an intimate relationship between the gut microbiome and the brain, the gut/brain axis (see microbiome gut brain axis JClinInvest2015 in dropbox, or doi:10.1172/JCI76304), which shows that the gut microbiome can affect emotional behavior, stress- and pain-modulation, and brain neurotransmitters -- the study above found a few things:
-- people with acute low back pain who had resolution of their symptoms by 3 months had significantly decreased inflammation at that time, more than 1/2 of the genome changed expression, and these active biological processes that changed in those recovering from their acute pain were importantly targeting gene expressions for neutrophil activation, which was decreased in those who had resolved symptoms (those with persistent pain did not show any change in their inflammatory response)
-- these findings were largely replicated in those with temporomandibular disorders
-- in the mouse experiments they found that acute treatment of inflammation with either dexamethasone or diclofenac was effective at decreasing pain right away, but greatly prolonged the resolution of three different types of pain: neuropathic, myofascial, and especially inflammatory
-- there was a pivotal role of neutrophils in the pain process: steroids were associated with longer pain associated with earlier neutrophil depletion in the acute injury
-- the human population study from the UK Biobank found that NSAIDs used early was associated with back pain 2 to 6 years later. This was not true for antidepressants, gabapentin, or lidocaine.
so, many questions are raised by the above, if indeed these results are affirmed in other more specific studies:
-- should we just use acetaminophen for musculoskeletal pain and avoid anti-inflammatories?
-- is it okay to use short-term NSAIDs or steroids and not develop chronic pain?
-- what if acetaminophen does not work? I suspect that topical diclofenac raises the same potential problems as oral NSAIDs, but would be good to test that
-- what else could we use? it seems that several antidepressants may help (and seemed okay in the Biobank evaluation). what about gabapentinoids (though there are some mixed reviews on their effectiveness)? Perhaps even low dose opiates?? Acetaminophen with codeine? Tramadol? Maybe these would be better in the long-run if we can avoid chronic pain???? And these opiates seem to have lower but non-zero potential for addiction/opiate use disorders than the stronger ones (oxycodone, fentanyl...)
-- what about intra-articular or trigger point injected steroids? Does this increase chronic pain? There are cohorts followed with steroids vs saline (placebo) injections, as noted in http://gmodestmedblogs.blogspot.com/2022/05/knee-oa-does-pt-help.html. Could look at long term effects.
-- even lidocaine seems to have anti-inflammatory effects. So is chronic use of lidocaine patches not good???
-- sounds like we should not really be advising cold therapy for musculoskeletal injury and sticking with heat and acetaminophen?? And PT/exercise seems okay since exercise does not seem to decrease inflammation and has some positive long term effects (as in above sciatica study)
-- and, what about non-pharmacologic therapies????? some are anti-inflammatory, as noted above. But these may be much more benign than meds, both in the short- and long-term...
-- there are other issues with sustained chronic inflammation (as was found in above study in those who had chronic pain): there is a clear association (though not necessarily causal) between chronic inflammation and many of our prevalent disorders: for example, heart disease, diabetes, obesity, major depressive disorder. so, does pain prolongation by steroids/NSAIDs lead to more of these systemic diseases?
Limitations:
-- it would have been important to have genetic analysis at more time points in those with low back pain to see the graph of what happens to the inflammatory response and gene expressions over time, both in those given anti-inflammatory agents and those another agent that did not affect inflammation
-- and it would have been useful to have longer-term data in terms of chronic pain to assess changes in gene expression and inflammation (ie, more than 3 mopnths)
-- we do not have adequate randomized controlled trials to change our practice dramatically. these trials need to have patients with a variety of acute pains randomized to a variety of interventions (as noted above) to assess long-term outcomes
-- the strongest parts of the study above was an RCT on mice. but it turns out that we are not mice, and mouse data may or may not translate well to human clinical outcomes
-- the Biobank does not have lots of granular data. in the finding of an association between different meds in those with back pain, what meds were used at what doses and for how long? was there a different outcome based on these differences? and the Biobank did rely on patient reporting, which might have been inaccurate in some cases
-- This study does not comment on treatment of chronic pain, often associated with a chronic inflammatory state. so, the above by itself should not change management of chronic pain
so, a really intriguing study that could be a paradigm shift on how we treat patients with acute musculoskeletal pain. chronic pain is remarkably common (a 2021 report suggested 50.2 million people in the US, 20.5% of the population!!!!), is associated with profound individual and societal disruptions, has been a key component to our current opioid crisis (>108,000 deaths in 2021, and a large percentage of those with subsequent opioid use disorder start with pills, often those in their family's medicine cabinet). so, any new approaches that helps decrease the transition from acute musculoskeletal pain to chronic pain is sorely (!!) needed..... BUT there need to be lots more studies done comparing different approaches: which specific therapies, of the many that actually affect acute inflammation, are actually effective in preventing long-term pain?? Though it does sound like some things do make sense now: using acetaminophen/exercise as first line. keeping the muscles moving early on (including early PT), perhaps not using ice for acute pain...
geoff
If you would like to be on the regular email list for upcoming blogs, please contact me at gmodest@uphams.org
to get access to all of the blogs (2 options):
1. go to http://gmodestmedblogs.blogspot.com/ to see them in reverse chronological order
2. click on 3 parallel lines top left, if you want to see blogs by category, then click on "labels" and choose a category
3. or you can just click on the magnifying glass on top right, then type in a name in the search box and get all the blogs with that name in them
or: go to https://www.bucommunitymedicine.org/ , a website from the Community Medicine section at Boston Medical Center. This site does have a very searchable and accessible list of my blogs (though there have been a few that did not upload over the last year or two). but overall it is much easier to view blogs and displays more at a time.
please feel free to circulate this to others. also, if you send me their emails, i can add them to the list
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