EFFECTS OF ANALGESIA ON BONE HEALING 1

Perioperative Use of Analgesia Effects on Bone Healing

Rachel Garcia, Dale Wolford, Clayton Gingher, Jordan Malavong, Nick Boyce

04/09/2020

NURS 3749: Nursing Research

Dr. Valerie O’Dell

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Abstract

The purpose of this research was to determine if the current course of treatment of nonsteroidal

anti-inflammatory (NSAID) medications and opioids in the perioperative period for orthopaedic

patients inhibits their bone healing. The research used was pulled from ten sources, majority

being quantitative studies. As with anything in medicine there are varying results depending on

factors used in a study. The type of medication, dosage used, and time span studied have all

been proven to affect the results of research done. Therefore, with new studies with different

parameters there is always new information coming to light, evidence supporting previous

studies, or even evidence calling into question previously confirmed standards of practice. This

just goes to show that in the medical field care of patients can never become stagnant because if

it does then the patients, outcomes, and quality of life can suffer. While there are some

conflicting reports, most confirmed that NSAIDs and opioids used in the perioperative period do

in fact inhibit bone healing.

Perioperative Use of Analgesia Effects on Bone Healing

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Introduction

In order to address the question of whether perioperative use of analgesia effects on bone

healing, ten sources from OhioLINK databases were reviewed. These quantitative studies

covered multiple animal and human experiments to help determine the effect nonsteroidal anti-

inflammatory (NSAID) and opioid medications had on bone healing. Principles of bone

biochemistry, a variety of NSAIDs, morphine, advances in modern medicine through evidence

based practice, and a possible solution will all be discussed.

Advances in Modern Medicine Through Evidence Based Practice

For the entire history of surgery, the quest to find a pain relieving agent that would not

only perform the job of alleviating pain, but also result in the best patient outcomes has been

successful in some respects and troublesome in others. If you were to travel back in time and

discuss medicine with a surgeon in the 19th century, aspects of surgery that we take for granted

today would be absent in his practice. To ponder the leaps of innovation in the relative short

time of 200 years that we have achieved is nothing short of mind boggling. Today we stand with

high survival rates, lower chances of infections, and overall better medicinal practices than ever

before in history. With all the noted advances in modern medicine, it is not perfect; through trial,

error, and peer review, modern medicine can continue to evolve to accommodate for best patient

outcomes through evidence-based practice.

One of the examples of evidence-based practice involves the healing time and nonunion

rate of surgeries on bone (internal fixation and other corrective surgeries), in relation to what

medicines are given in the postoperative period. In a large study in which over 300,000 cases of

fractures were examined by a team of physicians, some of the major factors of bone nonunion

were identified. According to Steen (2016), “… the most powerful risk factor (for bone
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nonunion) was use of nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids. Other pain

medications, such as opioids alone, and anticonvulsants, with or without benzodiazepines, were

moderately strong positive risk factors…” (p. 4). Patients that took NSAIDs or opioids in the

postoperative period were shown to have a positive correlation with a longer recovery time and

increased incidence of malunion or nonunion. This, in the cases of malunion or nonunion, likely

leads to another surgery which exposes the patient to all the risks that surgery entails. In all

cases, this leads to increased time until the patient is able to return to all of their regular activities

of daily life which is in itself a negative patient outcome.

As healthcare professionals, patient care and positive outcomes are of utmost importance

in all levels of care. Evidence-based practice is essential in finding solutions to result in better

patient care as well as positive patient outcomes.

Principles of Bone Biochemistry

When a patient enters the hospital due to an injury the most optimal goal is to provide

them with the best possible care in the quickest amount of recovery time. This goal however

must be delivered with an acceptable level of recovery so that the patient is at a low risk for

readmission to the hospital. To ensure you are providing quality care and actually lowering

recovery time an extensive amount of research and trials must be done. In this case, research has

been done on the effects of analgesics and how they interact with the healing of bones. To

understand how analgesics could affect bones you need to know the chemical components

behind them and what exactly can increase or decrease their rate of resorption. In this case one of

the biggest factors that affects bone metabolism/resorption are calciotropic hormones specifically

parathyroid hormone, vitamin D and Calcitonin. In bone resorption, the first two weeks are

considered to be the most vital times for proper healing. In this study, observations were
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recorded in the bone resorption rate involving bone grafts and how analgesics could affect them.

According to the study involving healing time with bone grafts, “during the 1st week of bone

healing steroid medications, cytotoxic agents and nonsteroidal anti-inflammatory medications

can have harmful effects” (Kalfas, 2001). This study helps show us the many different systemic,

local and chemical factors that can affect bone healing. It also gives us great insight to the

biochemistry behind bones and what actually is being hindered or increased due to analgesics.

Nonsteroidal Anti-Inflammatory Drugs and Bone Density

NSAIDs are very popular drugs used for many purposes in both the hospital and home

today. They have a wide variety of many helpful actions for a patient such as reducing pain,

decreasing fever, preventing blood clots and helping lower inflammation. When it comes to bone

resorption/metabolism, NSAIDs have shown to have more detrimental effects than benefits. In a

study done with animals during their perioperative phase of bone healing measurements were

recorded on the amount of recovery with bone density, strength, stiffness and osteoblast. In this

section of the study specifically they measured the amount of recovery in bone density when

treating a fracture with diclofenac. According to Beck (2005), “ bone density in these animals,

regardless of the length of diclofenac treatment, was reduced by approximately 34%” (p. 573).

This study finding helps give us more insight to find out what other effects may be caused by

nonsteroidal anti-inflammatory drugs on bone resorption. It also helps us realize that possibly

treating a patient with NSAIDs for inflammation due to a bone fracture is causing a decrease in

recovery time and providing inadequate healing placements.

Nonsteroidal anti-inflammatory drugs (NSAIDs) have a wide variety of uses for

countless conditions. They are frequently used over the counter, but other uses exist. Common

over the counter NSAIDs are prescribed by physicians for multiple reasons but often prescribed
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postoperatively. There are many well documented studies on multiple NSAIDs regarding their

effect on bone healing.

Studies that show a relationship between the bone healing process and NSAIDs have

many different factors that can influence a change in their results. An evidence-based systematic

review done in 2016 explored the differences between a group of studies that were covering this

topic. The researchers took 12 clinical studies and analyzed their quality and relevant factors.

They then outline the factors such as Coleman Methodology score, publication date, use of

sources, anatomical region, and their recommendation of the use of NSAIDs.

The article expressed that different factors affect the results of the studies but most

studies said to avoid NSAIDs (7/12 studies). These studies also did not have orthopaedic doctors

for all of the authors and had a lower average for the modified coleman score (they noted that it

was not a significant difference in score average). They also mentioned that the scores did not

correlate with a chronological publish date trend on both sides of the argument. The researchers

stated, “unfortunately, there was no correlation between modified Coleman Methodology Score

and year of publication, which suggests that the quality of research in this area has not improved

in the past decades” (Marquez-Lara et al., 2016, para. 14). In addition to those findings, the

researchers concluded that “the great variability in the interpretation of the available evidence

appears to suggest that NSAIDs may affect bone-healing, but that this effect depends on the type,

dose, timing, and length of exposure” (Marquez-Lara et al., 2016, para. 31). This gives us a real

sense of the quality of information that is available on this topic. It can be concluded that much

more research needs to be done to get a definitive answer about the use of NSAIDs during the

bone healing process.

Indomethacin
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Indomethacin is used to relieve pain, inflammation, and joint stiffness. It is used in many

different conditions but specifically in arthritis, gout, bursitis, and tendonitis. In order to study

the effect of this medication on bone healing, an experiment involving rats was done. In these

experiments the researchers studied the healing of fractures in the limbs and spines of rats.

According to the study with rat radial and ulnar fractures, “their results demonstrated a

statistically significant drug- and dose-related impairment of fracture healing at all levels of

indomethacin dosage” (Harder & An, 2003). The results of the studies across the board were all

very similar in that they demonstrated inhibited bone healing in some way to the NSAID treated

group.

Ibuprofen

Ibuprofen is a pain reliever that acts by blocking the body's production of certain

substances that cause inflammation therefore, decreasing inflammation, pain and fever. There

were two studies done specifically where researchers studied the effects of using ibuprofen on

rats with tibial fractures and surgically created grooves and holes in the temporomandibular joint.

Both experiments came to the result that ibuprofen affected the rats bone healing after suffering

the fractures and alteration to the temporomandibular joint. In the study of the healing and

remodeling of bone and cartilage on the temporomandibular joint they came to the result, “that

ibuprofen had an inhibitory effect on the healing of bone and cartilage, perhaps by impairing the

remodeling process of the bone” (Harder & An, 2003).

A Favorable Solution

As mentioned previously, patients who took NSAIDs or opioids during their

postoperative recovery period had higher incidences of increased recovery time as well as

complications such as malunion and nonunion. It is scientifically proven that NSAIDs delay
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bone healing, so it is required that an alternative solution be found to relieve postoperative

swelling in patients that have had surgeries to resolve broken bones. Promising advances are

being made regarding this very problem as evidenced by a 2018 study examining Ketorolac as an

alternative to NSAIDs. According to McDonald (2018):

In comparison when investigating time to union and healing rates in femoral shaft and

tibial shaft fractures, Donohue et al found ketorolac administration had no effect on time

to union or healing rates. Specifically, in the treatment of fractures, time to healing and

union rates are better in patients receiving ketorolac than other nonsteroidal

anti-inflammatory drugs (NSAIDs). (p. 10)

Although ketorolac is categorized as an NSAID, it did not inhibit bone growth in that particular

study. With those results, it seems that the administration of ketorolac in patients that underwent

surgery for broken bones experienced the anti-inflammatory properties that NSAIDs provide

without the negative bone union inhibiting side effects.

Ketorolac

Ketorolac is very similar to ibuprofen and other NSAIDs in that it works by reducing

hormones that cause inflammation and pain. It is most often used for the short-term treatment of

moderate to severe pain. Studies involving ketorolac have been done on rats with spinal fusions

as well as a study with humans who had undergone a spinal fusion from L4 to the sacrum. The

rat study results supported all the previous studies examining NSAIDs inhibitory role in bone

healing. The human study showed, “a statistically significant difference, with nonunion being

approximately five times more likely in the ketorolac-treated group compared with the group of
EFFECTS OF ANALGESIA ON BONE HEALING 9

patients that did not use NSAIDs postoperatively” (Harder & An, 2003). This study also

revealed to researchers that there was an increase of nonunion in patients that were both male

and female and smokers and nonsmokers. Due to the findings of this human experiment, the

researchers came to the conclusion, “that the inhibitory effects of postoperative ketorolac

administration on spinal fusion are at least equivalent and potentially greater than the well-

established inhibitory effect of smoking” (Harder & An, 2003). Prior to this study there was

hardly any clinical evidence proving the effect NSAIDs had on bone healing, however, after this

study there was now a correlation proving its effect clinically and not just in animal and in vitro

studies.

COX-2 Inhibitors

COX-2 inhibitors are a newer type of NSAID, they are becoming more widely used

because they selectively block the COX-2 enzyme unlike older NSAIDs that blocked the action

of COX-1 and COX-2 enzymes. This selective blocking allows for a lower risk of causing ulcers

of the stomach or intestine. With these newer medications there have also been experiments

done with rats to determine their effect on bone healing. One of the main studies involved

femoral fractures in rats that were treated with either a COX-2 inhibitor, ibuprofen or no

medication. This experiment proved to researchers that, “initial results demonstrate that COX-2

inhibitors, much like traditional NSAIDs, have a detrimental effect on bone healing in animal

models” (Harder & An, 2003). This was evident by the group being treated with the COX-2

inhibitor showed that those rats more often had a nonunion of their fractures. However, a

separate study in 2005 involving patients undergoing spinal fusion surgery yielded different

results.
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In this study 80 patients undergoing spinal fusion surgery were divided into two equal

groups. One group received Celecoxib, (a COX-2 inhibitor) one hour before surgery and every

twelve hours post-op for five days. The other group received a placebo during this same

schedule. As expected pain scores were rated lower more consistently throughout therapy for the

group receiving Celecoxib. “There was no difference between the Celecoxib group and the

placebo group with regard to the incidence of nonunion at the time of the one-year follow up”

(Reuban, Scott, Ekman, and Evan, 2005). This study shows that COX-2 inhibitors are effective

at reducing pain, cause less GI effects, and do not inhibit bone fusion. The reason that this study

may differ from the previous study is that this study used a short term, limited amount of COX-2

inhibitors. This idea is supported by another study that suggests that COX-2 inhibitors may be

effective in relieving pain without inhibiting bone healing in limited use. “Concerning modern

selective anti-COX-2 agents the literature is inconclusive, with their action on fracture healing

probably being time- and dose-dependent” (Boursinos, Karachalios, Poultsides, and Malzios,

2009). This study also supported that COX-2 inhibitors have reduced GI effects unlike traditional

NSAIDs.

Morphine

The current main course of treatment postoperatively is opioid analgesics; therefore, this

study was done to determine the effect morphine has on fracture healing. Chrastil, Sampson,

Jones and Higgins (2013) explained:

Opioid use in medicine and in particular the orthopaedic population continues to rise

dramatically in the United States. Greater than 80% of orthopaedic patients are prescribed

some form of opioid analgesic in the perioperative or fracture care period morphine
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administration impaired the rate of callus maturation and delayed final osseous union (p.

4077).

The researchers decided to perform this experiment to see the effect morphine had on rats with

stabilized femur fractures. The results of this study concluded, just as with the NSAIDs, that the

group of rats treated with morphine showed a decreased amount of bone healing than the control

group. This reinforces the fact that the current course of pain management in the perioperative

period may need to be reevaluated due to the evidence proving the negative effects of NSAIDs

and morphine on bone healing.

Another study has been done that reinforces this trend. Researchers found that opioids

delay bone healing when a study was done that contains a sample of rabbits who had their spines

fused. In their study, they make a reference to the study that was done on rats by Chrastil,

Sampson, Jones and Higgins. They note that the trend has been marked by that study but spinal

fusions have not been tested. According to Jain et al. (2018):

There is evidence that opioids downregulate osteoblasts in vitro, and a previous study

found that morphine delays the maturation and remodeling of callus in a rat femur

fracture model. However, the effect of opioids on healing of spinal fusion has not been

investigated before. (p. 1659)

In this study, the researchers took a total sample of twenty-four adult white rabbits which

all underwent a bilateral L5-L6 posterolateral spinal fusion. The control group only received

perioperative pain control if needed. The opioid group, on the other hand, received transdermal

fentanyl 4 weeks preoperatively and 6 weeks postoperatively. The animals were then euthanized

after the 6 week mark after the operation. The animal's spinal fusion was then analyzed through
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“manual palpation, plain radiographs, microcomputed tomography (microCT), and histology”

(Jain et al., 2018).

By the end of the 6 week period, there were 12 control specimens and only 11 opioid

specimens available for testing. The researchers found that the opioids took a toll on the rabbits

bone healing. “Three-dimensional microCT morphometry found that the fusion mass in the

opioid group had a lower bone volume (p=.09), a lower trabecular number (p=.02), and a higher

trabecular separation (p=.02) compared with the control group” (Jain et al., 2018). Although

they found this trend, it is important to note that some of the fusion scores were not different.

They found that the manual palpation, radiographs and microCT were not out of statistical

standards.

The researches soon concluded that opioid analgesics do delay bone healing

postoperatively. They noted that their findings were just the tip of the iceberg when it comes to

researching this trend. Most interestingly, they mention the need to study the dose-duration

relationships that cause the delay in bone healing. Their conclusion read:

Systemic opioids led to an inferior quality fusion mass with delay in maturation and

remodeling at 6 weeks in this rabbit spinal fusion model. These preliminary results lay

the foundation for further research to investigate underlying cellular mechanisms, the

temporal fusion process, and the dose-duration relationship of opioids responsible for our

findings. (Jain et al., 2018, p. 1668)

Conclusion

When analyzing resources to determine if use of analgesia in the perioperative period

affects bone healing there were some varying opinions. However, these differences were
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generally based on studies done with different medications, dosages, and lengths of time studied.

The overwhelming majority did stand to prove that use of most NSAIDs and opioids do in fact

inhibit bone healing in the postoperative phase.

References

Beck A., Salem K., Krishak G., Kinzl L., Bischoff M., Schmelz A. (2005). Nonsteroidal

Anti-Inflammatory Drugs (NSAIDs) in the Perioperative Phase in Traumatology and

Orthopedics Effects on Bone Healing. Operative Orthopedics and Traumatology, 17(6),

569-578. Retrieved from https://eps.cc.ysu.edu:8443/login?

url=https://search.ebscohost.com/login.aspx?

direct=true&AuthType=ip,uid&db=mnh&AN=16369754&site=ehost-live&scope=site
EFFECTS OF ANALGESIA ON BONE HEALING 14

Boursinos, L.A., Karachalios, L., Poultsides, K.N., Malizos. (2009). Do steroids, conventional

non-steroidal anti-inflammatory drugs and selective COX-2 inhibitors adversely affect

fracture healing. Journal of Musculoskeletal and Neuronal Interactions, 9(1), 44-52.

Chrastil, J., Sampson, C., Jones, K. B., & Higgins, T. F. (2013). Postoperative Opioid

Administration Inhibits Bone Healing in an Animal Model. Clinical Orthopaedics and

Related Research®, 471(12), 4076–4081. doi: 10.1007/s11999-013-3232-z

Harder, A. T., & An, Y. H. (2003). The Mechanisms of the Inhibitory Effects of Nonsteroidal

Anti-Inflammatory Drugs on Bone Healing: A Concise Review. The Journal of Clinical

Pharmacology, 43(8), 807–815. doi: 10.1177/0091270003256061

Jain N., Himed K., Toth J., Briley K., Phillips, F., Khan S. (2018). Opioids delay healing of

spinal fusion: a rabbit posterolateral lumbar fusion model. The Spine Journal, 18(9),

1659-1668. doi: https://doi.org/10.1016/j.spinee.2018.04.012

Kalfas, I. (2001). The Principles of Bone Healing. The Journal of Neurosurgery, 10 (4), 1-4.

doi: https://doi.org/10.3171/foc.2001.10.4.2

Marquez-Lara A., Hutchinson I., Nuñez F., Smith T., Miller A. (2016). Nonsteroidal Anti-

Inflammatory Drugs and Bone-Healing. Journal of Bone and Joint Surgery, 4(3), doi:

10.2106/JBJS.RVW.O.00055

McDonald, E., Winters, B., Nicholson, K., Shakked, R., Raikin, S., Pedowitz, D. I., & Daniel, J.

N. (2018). Effect of Postoperative Ketorolac Administration on Bone Healing in Ankle

Fracture Surgery. Foot & Ankle International, 39(10), 1135–1140.

https://doi.org/10.1177/1071100718782489
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Reuben, Scott, S., Ekman, Evan, F. (2005). The Effect of Cyclooxygenase-2 Inhibition on

Analgesia and Spinal Fusion. The Journal of Bone and Joint Surgery, 87(3), 536-542.

doi:10.2106/JBJS.D.02283

Zura, R., Ze Xiong, Einhorn, T., Watson, J. T., Ostrum, R. F., Prayson, M. J., Rocca, G. J. D.,

Mehta, S., McKinley, T., Zhe Wang, Steen, R. G., Xiong, Z., Della Rocca, G. J., &

Wang, Z. (2016). Epidemiology of Fracture Nonunion in 18 Human Bones. JAMA

Surgery, 151(11), 1–12. https://eps.cc.ysu.edu:2144/10.1001/jamasurg.2016.2775

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