Tag Archives: healing

Complications

NSAIDs And Fracture Healing Revisited – Yet Again!

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I’ve written so many posts about the use of non-steroidal anti-inflammatory drugs (NSAIDs) it’s practically getting old. To summarize, some old animal studies suggested that using NSAIDs during fracture healing could impair the process. However, human studies were not so convincing.

Over the years, there has been quite a bit of conflicting evidence. This generally means the association between healing and NSAID use is weak. However, after this period of time, we should have become aware of a significant cause/effect relationship.

The Eastern Association for the Surgery of Trauma recently released a practice management guideline regarding the use of NSAIDs for the treatment of acute pain after orthopedic trauma. They used a standard methodology to identify and analyze published research. They focused on human studies specifically relating to this drug class’s use in fractures. The group ultimately identified 19 pertinent research papers for analysis, 10 of which were prospective, randomized studies.

Here are the three questions they asked, with their answers:

  • Should NSAIDs be used in analgesic regimens for adult patients
    (≥18 years old) with traumatic fracture versus routine analgesic
    regimens that do not include NSAIDs to improve analgesia and
    reduce opioid use without increases in non-union and acute kidney
    injury rates? Although the quality of the studies for this question was low, EAST conditionally recommended using NSAIDs in pain control regimens. In the higher-quality studies in this group, there was no increased risk of non-union.
  • Should ketorolac be used in analgesic regimens for adult patients with traumatic fracture versus routine analgesic regimens that do not include ketorolac to improve analgesia and reduce opioid use without increasing non-union
    rates? This is the same question asked above, but with a specific drug rather than the class in general. The answer was basically the same.
  • Should selective NSAIDs (COX-2 inhibitors) be used in analgesic
    regimens for adult patients (≥18 years old) with traumatic fracture versus routine analgesic regimens that include non-selective NSAIDs to improve analgesia and reduce opioid use without increasing non-union rates?     COX-2 inhibitors are a subset of NSAIDs that are more selective in their action, blocking only the COX-2 receptor. Several years ago, there was a scandal regarding the COX-2 inhibitor rofecoxib (Vioxx). These selective drugs tended to have a higher incidence of cardiac complications. The manufacturer covered up this fact for several years, resulting in many unneeded deaths before it was removed from the market. The only COX-2 inhibitor available in the US is celecoxib. Only a few studies were performed using this drug during bone healing. There were not enough to make a recommendation.

Bottom line: EAST made conditional recommendations for using NSAIDs in general and ketorolac specifically in adults with fractures. “Conditional” only means that the authors did not have a consensus. Some voted to strongly recommend, and the remainder to conditionally recommend. There were no votes to recommend against their use.

The use of NSAIDs should complement a well-thought-out opioid regimen, which should also be combined with other non-narcotic medications and appropriate mobilization and therapy.

Reference: Efficacy and safety of non-steroidal anti-inflammatory
drugs (NSAIDs) for the treatment of acute pain after orthopedic trauma: a practice management guideline from the Eastern Association for the Surgery of Trauma and the Orthopedic Trauma Association. Trauma Surg Acute Care Open. 2023 Feb 21;8(1):e001056. doi: 10.1136/tsaco-2022-001056. PMID: 36844371; PMCID: PMC9945020.

Complications

The Impact Of NSAIDs On Fracture Healing

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In my last post I discussed some of the basic effects of NSAIDs on bone healing. Now let’s see if theory applies to practice.

In 2003, several papers brought to light possible interactions between these drugs and fracture healing. Specifically, there were questions about these drugs interfering with the healing process and of increasing the number of delayed unions or nonunions. But once again, how convincing were these papers, really?

It would seem to make sense that NSAIDs could interfere with bone healing. The healing process relies heavily on the regulation of osteoblast and osteoclast function, which itself is regulated by prostaglandins. Since prostaglandins are synthesized by the COX enzymes, COX inhibitors like the NSAIDs should have the potential to impair this process. Indeed, animal studies in rats and rabbits seem to bear this out.

But as we have seen before, good animal studies don’t always translate well into human experience. Although a study from 2005 suggested that NSAID administration in older patients within 90 days of injury had a higher incidence of fracture nonunion, the study design was not a very good one. It was equally likely that patients who required these drugs in this age group may have been at higher risk for nonunion in the first place.

A meta-analysis of human studies was performed in 2011. Out of 558 potential studies, only 5 met criteria review. (This is yet another reminder of the sheer amount of sub-par research out there.) The authors found that short-term use (< 14 days) of normal dose NSAIDS was not associated with non-union. High doses of ketorolac (> 120mg/day) and diclofenac sodium (> 300mg total) did have an association. But remember, this does not show causation. There are many other factors that can impede healing (smoking, diabetes, etc).

A study from 2016 examined the effect of ketorolac administration on fracture healing in patients undergoing repairs of femoral and tibial fractures. It did not find an association between non-union and ketorolac, but did find one with smoking. Unfortunately, the study was small (85 patients given ketorolac, 243 controls without it). It probably does not have the statistical power to detect any difference with the NSAID. A power analysis was not provided in the methods section.

Bottom line: Once again, the animal data is clear and the human data less so. Although there are theoretical concerns about NSAID use and fracture healing, there is still not enough solid risk:benefit information to abandon short-term NSAID use in patients who really need them. NSAIDs can and should be prescribed in patients with short-term needs and simple fractures, and consider COX-1 specific drugs like ketorolac while your patient is in the hospital. And we do have some evidence that high-dose NSAIDs may have some impact, so stick to the usual doses for just as long as they are needed for pain management.

References:

  1. Effects of nonsteroidal anti-inflammatory drugs on bone formation and soft-tissue healing. J AM Acad Orthop Surg 12:139-43, 2004.
  2. Effect of COX-2 on fracture-healing in the rat femur. J Bone Joint Surg Am 86:116-123, 2004.
  3. Effects of perioperative anti-inflammatory and immunomodulating therapy on surgical wound healing. Pharmacotherapy 25:1566-1591, 2005.
  4. Pharmacological agents and impairment of fracture healing: what is the evidence? Injury 39:384-394, 2008.
  5. High dose nonsteroidal anti-inflammatory drugs compromise spinal fusion. Can J Anaesth 52:506-512, 2005.
  6. Nonsteroidal Anti-Inflammatory Drugs and Bone-Healing: A Systematic Review of Research Quality. JBJS Rev 4(3), 2016.
  7. High-dose ketorolac affects adult spinal fusion. Spine 36(7):E461-E468, 2011.
  8. Ketorolac administered in the recovery room for acute pain management does not affect healing rates of femoral and tibial fractures. J Orthop Trauma 30(9):479-482, 2016.
Complications

NSAIDs And Bone Healing: How Do They Impact It?

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The arguments about whether NSAID administration has any effect on bone healing continues to be argued by our orthopedic and spine surgery colleagues. In the early days of research in this area (about 20 years ago) there were concerns in animal models that there might be a problem. Apparently lots of rats and bunnies were suffering from fractures in those days.

But physiologically, how could NSAIDS do this? Here’s a simplified diagram of how the bone healing process works.

First, an acute injury occurs and macrophages and other cells move into the area to start the inflammatory process. COX-2 receptors are highly expressed on these cells, resulting in an increase in prostaglandin E2 (PGE2) production.

PGE2 then promotes proliferation of stem cells that differentiate into osteoblasts, which in turn begin forming bone to repair the injury.  In theory, if PGE2 is reduced in the healing area there is the possibility that bone formation may be impaired, leading to non- or malunion or refracturing.

Administration of NSAIDs can block COX-1 and COX-2 receptors throughout the body. This serves to decrease prostaglandin production and hence reduces inflammation and pain. Doesn’t it follow that giving these drugs should be bad for bone formation in patients with fractures?

Not so fast! There are a number problems with this argument. First, not all NSAIDs are created alike. Here is a chart that shows where the primary focus of COX inhibition is with some common NSAIDs.

Note how the common over-the-counter drugs affect both COX-1 and COX-2, yet there are some that are more selective. So the choice of drug may be relevant.

And we can’t assume that an in vitro effect in a Petri dish of cells actually carries over into the in vivo world. Many researchers rely initially on animal models to study drug effects in vivo. Predictions based on studies of rats and bunnies frequently do not pan out in humans.

We are left with only a theory based on an understanding of the basic mechanism of bone healing. Tune in to my next post where I discuss the research that’s been done in this field and whether it actually translates into human bone healing or not.

Complications

NSAIDs And Fracture Healing Revisited

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Over the years, I’ve commented several times on the “myth” of NSAIDs causing problems with fracture healing. I still hear occasional comments from my orthopedic colleagues cautioning against the use of these drugs in patients who have had fracture repairs.

But is it true?  In 2003, several papers brought to light possible interactions between these drugs and fracture healing. Specifically, there were questions about these drugs interfering with the healing process and of increasing the number of delayed unions or nonunions. But once again, how convincing were these papers, really?

It would seem to make sense that NSAIDs could interfere with bone healing. The healing process relies heavily on the regulation of osteoblast and osteoclast function, which itself is regulated by prostaglandins. Since prostaglandins are synthesized by the COX enzymes, COX inhibitors like the NSAIDs should have the potential to impair this process. Indeed, animal studies in rats and rabbits seem to bear this out.

But as we have seen before, good animal studies don’t always translate well into human experience. Although a study from 2005 suggested that NSAID administration in older patients within 90 days of injury had a higher incidence of fracture nonunion, the study design was not a very good one. It was equally likely that patients who required these drugs in this age group may have been at higher risk for nonunion in the first place.

A meta-analysis of human studies was performed in 2011. Out of 558 potential studies, only 5 met criteria review. (This is yet another reminder of the sheer amount of sub-par research out there.) The authors found that short-term use (< 14 days) of normal dose NSAIDS was not associated with non-union. High doses of ketorolac (> 120mg/day) and diclofenac sodium (> 300mg total) did have an association. But remember, this does not show causation. There are many other factors that can impede healing (smoking, diabetes, etc).

A study from 2016 examined the effect of ketorolac administration on fracture healing in patients undergoing repairs of femoral and tibial fractures. It did not find an association between non-union and ketorolac, but did find one with smoking. Unfortunately, the study was small (85 patients given ketorolac, 243 controls without it). It probably does not have the statistical power to detect any difference with the NSAID. A power analysis was not provided in the methods section.

Bottom line: Once again, the animal data is clear and the human data less so. Although there are theoretical concerns about NSAID use and fracture healing, there is still not enough solid risk:benefit information to abandon short-term NSAID use in patients who really need them. NSAIDs can and should be prescribed in patients with short-term needs and simple fractures. But we now have evidence that high-dose NSAIDs may have some impact, so stick to the usual doses for just as long as they are needed for pain management.

References:

  1. Effects of nonsteroidal anti-inflammatory drugs on bone formation and soft-tissue healing. J AM Acad Orthop Surg 12:139-43, 2004.
  2. Effect of COX-2 on fracture-healing in the rat femur. J Bone Joint Surg Am 86:116-123, 2004.
  3. Effects of perioperative anti-inflammatory and immunomodulating therapy on surgical wound healing. Pharmacotherapy 25:1566-1591, 2005.
  4. Pharmacological agents and impairment of fracture healing: what is the evidence? Injury 39:384-394, 2008.
  5. High dose nonsteroidal anti-inflammatory drugs compromise spinal fusion. Can J Anaesth 52:506-512, 2005.
  6. Nonsteroidal Anti-Inflammatory Drugs and Bone-Healing: A Systematic Review of Research Quality. JBJS Rev 4(3), 2016.
  7. High-dose ketorolac affects adult spinal fusion. Spine 36(7):E461-E468, 2011.
  8. Ketorolac administered in the recovery room for acute pain management does not affect healing rates of femoral and tibial fractures. J Orthop Trauma 30(9):479-482, 2016.
General

Trauma Mythbusters: NSAIDs And Fracture Healing

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Trauma hurts like hell. Over the years, we’ve developed quite a few ways of combating this pain. A number of drug classes have been developed to reduce it. One of the more common non-narcotic drug classes are the NSAIDs. As I’ve mentioned before, every drug has dozens of effects. Drug companies market a particular medication based on one of the predominant effects. All the others are considered side effects.

NSAIDs are not unique; they have lots of side effects as well. In 2003, several papers brought to light possible interactions between these drugs and fracture healing. Specifically, there were questions about these drugs interfering with the healing process and of increasing the number of delayed unions or nonunions. But once again, how convincing were these papers, really?

It would seem to make sense that NSAIDs could interfere with bone healing. This  process relies heavily on the regulation of osteoblast and osteoclast function, which itself is regulated by prostaglandins. Since prostaglandins are synthesized by the COX enzymes, COX inhibitors like the NSAIDs should have the potential to impair this process. Indeed, animal studies in rats and rabbits seem to bear this out.

But as we have seen before, good animal studies don’t always translate well to human experience. Although a study from 2005 suggested that NSAID administration in older patients within 90 days of injury had a higher incidence of fracture nonunion, the study design was not a very good one. It is equally likely that patients who required these drugs in this age group may have been at higher risk for nonunion in the first place.

In fact, there are no large, prospective randomized studies that have explored the effect of short-term or long-term NSAID administration on fracture repair. But there have been several smaller studies that showed absolutely no effect on nonunion with short-term administration of this drug class. Yet the dogma that leads us to avoid giving these drugs persists.

A recent analysis looked at the quality of the published research, both for and against NSAID usage in fracture patients. They used the Coleman Methodology Score, which evaluates study size and type, mean followup, detailed description of treatment, subject selection, outcomes, and outcome assessment. The maximum score was 100. 

Here are the factoids:

  • There were 4x as many total subjects in the “NSAIDS are okay” papers than in the “avoid NSAIDS” papers
  • The quality of the “NSAIDS are okay” papers were significantly higher than “avoid NSAIDS” group (59 vs 40)
  • Interestingly, the “avoid NSAIDS” papers are cited twice as often
  • All of the reviews ended with my pet peeve catch phrase “further (good) research is needed”

Bottom line: Once again, the animal data is clear but the human data is not. Although there are theoretical concerns about their use, there is not enough solid risk:benefit information to abandon short-term NSAID use in patients who really need them. NSAIDs can and should be prescribed in patients with short-term needs and simple fractures.

References:

  1. Effects of nonsteroidal anti-inflammatory drugs on bone formation and soft-tissue healing. J AM Acad Orthop Surg 12:139-43, 2004.
  2. Effect of COX-2 on fracture-healing in the rat femur. J Bone Joint Surg Am 86:116-123, 2004.
  3. Effects of perioperative anti-inflammatory and immunomodulating therapy on surgical wound healing. Pharmacotherapy 25:1566-1591, 2005.
  4. Pharmacological agents and impairment of fracture healing: what is the evidence? Injury 39:384-394, 2008.
  5. High dose nonsteroidal anti-inflammatory drugs compromise spinal fusion. Can J Anaesth 52:506-512, 2005.
  6. Nonsteroidal Anti-Inflammatory Drugs and Bone-Healing: A Systematic Review of Research Quality. JBJS Rev 4(3), 2016.