Is Inflammation the Boogeyman?

On July 5, 2017, in Dr. Dino Pappas, Integrated Medicine, Pain, by Dr. Dino Pappas

Inflammation shouldn’t be feared but Chuck Norris should be!

Is Inflammation the Boogeyman?
Overview
A recent review of patient intake forms showed that a surge of patients presenting to the office taking anti-inflammatory medications, particularly the non-steroidals (NSAIDs). These medications include but are not limited to:
1. Aspirin (Bayer)
2. Ibuprofen (Motrin, Advil, Midol, Nuprin)
3. Naproxen (Aleve)
4. Diclofenac (Voltaren, Arthrotec)
5. Celecoxib (Celebrex)
6. Indomethacin (Indocin)
7. Meloxicam (Mobic)

This is speculation on my part, but worth noting that the recent trend I’m seeing of over prescription of NSAID’s could be a knee jerk reaction to the prescription opioid epidemic. The pendulum could have swung from NSAID’s to opioids and now back to NSAID’s. It’s also worth considering that this could just be the ebb and flow of clinical practice.

“Vitamin I”

As a humorous aside, we all know that patients swear they have a deficiency of “Vitamin I.” For those wondering if you missed a day in laboratory diagnosis class, no you didn’t. “Vitamin I” would be ibuprofen. We know how patients like to run to ibuprofen for their bumps, bruises, aches or pains.

This leads into the main point of the article. Is inflammation the boogeyman?

Recall from our basic science studies in pathology and physiology that inflammation has a role in the healing process. The important points without going into an in-depth scientific explanation that would sidetrack the reader from the purpose of the article are the following:
1. You can’t heal without inflammation.
2. Inflammation is one of the early phases of the healing process.
3. Inflammation and tissue self-healing appears to be an evolutionary adaptation and as such is an “innate” mechanism.
4. Anti-inflammatory medications alter the normal healing process.
5. It is still a bit controversial whether administration of prescription or over the counter anti-inflammatory medications early in the healing process for many musculoskeletal (MSK) conditions provides additional benefit over other treatment options including the conservative, non-drug, non-surgical treatments (manual therapy, acupuncture, rehab exercises or other therapeutic modalities), no treatment or placebo.

Stages of the Healing Response
It’s true that inflammation is part of the healing process. Millions or more years of evolution appear to have “hardwired” the inflammatory response into our DNA (16). Creating inflammation facilitates tissue and wound healing. This is not a trained response rather it is an automatic response to tissue trauma. This response appears to be naturally selected for survival purposes. The theory here is that inflammation helps both fight infection and heal our physical wounds increasing the chance for survival.

 

Depending on the source, there are 3-4 recognized phases of the healing process (1, 2, 17). The phases in sequential order are hemostasis/degeneration, inflammation, proliferation (tissue regeneration) and maturation (tissue remodeling).

Hemostasis occurs immediately after the initial injury. Hemostasis is the pooling of blood and fluid at the site of injury. This cascade of events causes tissue hypoxia (1). Lack of cellular exchange of nutrients leads to tissue degeneration or even necrosis.

Inflammation,the second phase, follows shortly after hemostasis.  The immune system triggers inflammatory cells to debride the area, get rid of metabolic waste products and reduce the chances for infection.

These events pave the way for the next phase, tissue proliferation. Growth of new tissue occurs slowly. Regrowth is highly linked to revascularization. Fresh blood flow brings in nutrients. Nutrients help lay the framework for what’s to come and that is development of tissue integrity and resiliency (2).

Healing tissue must undergo a period of maturation or remodeling. Remodeling is the final phase of the body’s innate healing response. The tissues solidify. Healing tissue is never histologically and functionally the same as pre-injury levels. Some degree of scarring is always present; however, the body does have an effective way of providing tissue that can resemble tissue prior to the injury. There is some overlap among phases of healing, but the main point here is that inflammation is clearly a precursor to later stages of the healing process.

This quick review then begs the following logical questions:
1. What are the consequences of altering the inflammatory process in acute/subacute MSK injuries with NSAIDs?
2. What serious risks are posed by over prescription and over consumption of NSAIDs?
3. When is inflammation generally considered to be bad?

Consequences of Altering the Inflammatory Process

Wound healing can be impacted by these things

It’s safe to say that Western Medicine has a high rate of prescription and utilization of NSAIDs for MSK pain syndromes. NSAID rates are particularly high in the sports medicine and sports performance settings (8, 9, 10, 11). Utilization is also high in the elderly. NSAIDs are readily accessible both over the counter and via simple prescription. Often, doctors, health care professionals, Dr. Mom and Dr. Dad don’t think twice about taking these drugs nor handing these to their children. NSAIDs do come with risks. Seldom talked about is the effect NSAIDs have on healing bone and soft tissues.

Bone

Callus formation can be impacted by NSAIDs. Long term use is not currently recommended.

Several studies have investigated the link between fracture healing and NSAIDs. Findings of the studies have been mixed (23, 24, 36). The consensus recommendation to date is that clinicians should treat NSAID’s as a risk factor for bone healing impairment in absence of robust evidence with the administration to be avoided in high risk patients (23, 25, 26, 37). High risk patients include diabetics, smokers, patients with autoimmune diseases that impact callus formation, patients on corticosteroid medications and in patients where bony fusion is the goal. The studies also indicate that short term utilization in the immediate days after the injury can provide an analgesic effect; however, prolonged utilization throughout the course of fracture or fusion healing would be more apt to delayed union or non-union (33). Delayed union or non-union jeopardizes the clinical outcome. More work clearly needs to be done in this area; however, basic science laboratory studies validate the clinical concern.

Soft Tissue
Research shows mixed results for anti-inflammatory drugs namely traditional NSAIDs and Cox-2 inhibitors for soft tissue healing. Some benefit has been described in the literature with improved tissue quality and outcomes; while, additional studies show no benefit. Yet other studies described delayed healing or altered tissue quality (18, 19, 27, 31, 32, 33, 34, 38). Contradictions abound.

Many studies are animal studies. Animal studies may not have direct translation into humans for a variety of reasons; however, the findings are a reason to take pause. In stark contrast, a recent Chinese study compared 3 NSAIDs utilized post surgically in arthroscopic surgical rotator cuff repairs. The study found that the three Cox inhibitors used were efficient and safe with no significant differences in side effects and no delayed tendon healing (38).

Studies that support utilization in soft tissue healing typically look at collagen formation, tensile strength and capability to adapt to load. One of the studies differentiated the effects of traditional NSAIDs from Cox-2 inhibitors on soft tissue healing with traditional NSAIDs showing promise in collagen synthesis and increased tensile strength in ligament healing when compared to the effects of Cox-2 inhibitors on ligament healing (33). Another study noted in animal models that Cox-2 inhibitors in tendons of lab rats had similar failure load rates, greater ability to handle tensile stress and reduced cross-sectional area indicative of less disorganized, degenerative tissue (31). The article suggests that Cox-2 inhibitors may have a role in prevention of tendon thickening which can be a sign of chronic tendinopathy.

Safety and efficacy of NSAIDs should be questioned. A systematic review and meta-analysis showed no major differences in soft tissue healing between Cox2-inhibitor drugs, traditional NSAIDs and tramadol for pain, restoration of function and swelling in acute soft tissue injuries of several areas of the body (5). The study concluded more work is needed in this area and additional methodology is needed to compare the risk of adverse events among the Cox-2 inhibitor medications and traditional NSAIDs.

Another study questions the efficacy of NSAIDs despite both widespread utilization with acute MSK injuries and some conferred benefit (19). The articles later notes that Cox-2 inhibitors do have beneficial anti-inflammatory effects and analgesic properties and appear to facilitate an earlier return to function after acute injury but questions utilization in response to experimental animal model studies showing impaired mechanical strength of bone, ligament and tendon. Impaired mechanical strength could negatively impact healing tissue and predispose to future injury. The study finishes by noting that the Cox-2 inhibitor rofecoxib increases adverse and potentially serious cardiovascular events, while traditional NSAIDs increases GI risks. Traditional NSAIDs are typically cheaper and equally effective as pain relievers.

It should be mentioned at this point that rofecoxib, better known as Vioxx, was removed from the market due to safety concerns in 2004 (19, 21). Another Cox-2 inhibitor, Bextra, (valdecoxib) was also pulled from the market in 2005 due to safety concerns. Concerns centered on increased adverse cardiovascular events and skin reactions (28).

One last study compares the effects of several analgesic and anti-inflammatory drugs on soft tissue healing in rat patellar tendons (34). The anagelsic options included celecoxib, valdecoxib, piroxicam, acetaminophen, ibuprofen, naproxen or control. The study found that the anti-inflammatory drugs and namely the selective and non-selective Cox inhibitors had higher rates of failure. The rat patellar tendons required less force to fail. It is theorized that the Cox inhibitors altered the biomechanical properties of collagen at the injury site.

Exercise Induced Inflammation and DOMS
The sports medicine and sports performance community largely accepts utilization of NSAIDs. The stated goals are reduction of inflammation, facilitation of recovery, and improved performance. Usage patterns typically start early in life with high school athletes, namely contact athletes showing strong utilization rates (10). Traditional over the counter NSAIDs such as ibuprofen and naproxen are typically abused in this demographic. NSAID use is also common in the endurance sports community of triathletes, bikers, swimmers and runners (8,9).

Two recent studies question the notion that NSAIDs affect inflammation and performance in athletes (6,7). No differences were noted in exercise induced inflammation markers, muscle damage or lipid peroxidation in a group given low dose Cox-2 inhibitors vs. a placebo. These studies indicate that sports medicine personnel, Dr. Mom and Dr. Dad may need to rethink the routine practice of administering NSAIDs to athletes who do not have an active acute or sub-acute injury and are training or competing with some mild/mild-moderate soreness.

Summary
1). Caution is strongly recommended when utilizing NSAIDs with bone healing.
2). There are mixed results with NSAID’s and Cox-2 inhibitors on healing soft tissue quality and clinical outcomes.
3). We should analyze and interpret these studies with caution as animal studies are frequently used. Animal studies do not necessarily translate to humans.
4). Potential for harm has been demonstrated particularly with long-term extended use scenarios.

Serious Side Effects

Vioxx and Bextra were removed from the US market some time ago (2004 & 2005) due to safety concerns.

Over consumption of NSAIDs has been linked to increased risk of heart attack, stroke, gastrointenstinal ulcers, heartburn, kidney damage, and liver damage. Recall that drugs such as Vioxx and Bextra were removed from the markets due to safety issues (21, 22). The makers of Vioxx (Merck) and Bextra (Pfizer) settled huge lawsuits for $4.85 billion and $2.3 billion respectively due to adverse events, scrupulous marketing tactics, routine recommendations for off label usage, fabrication of research in support of their products and ignoring early-warning concerns of increased risks of adverse reactions.

It’s shocking that many patients are unaware of the risks. It’s a bit more shocking that NSAIDs are often combined with other medications to contribute to GI symptoms (12). It’s also head scratching that physicians often do not prescribe the appropriate treatment regimen of a Cox-2 inhibitor or proton pump inhibitor with a traditional NSAID in those with known risk factors (13, 20). Cox-2 inhibitors along with a proton pump inhibitor showed the greatest reduction in GI symptoms. A Cox-2 inhibitor by itself was less likely to cause GI symptoms when compared to a traditional NSAID utilized with a proton pump inhibitor (14, 20). Use of an NSAID with a proton pump inhibitor or a Cox-2 inhibitor does not eliminate the chances for GI symptoms. It does reduce the risk.

Seniors appear to be the most vulnerable to GI side effects; therefore, preventative strategies should be strongly considered (15, 20).Seniors are a bit more susceptible to renal failure, hypertension and cardiac failure resulting from Cox-2 inhibitors (20). Cox-2 inhibitors have thrombotic potential especially with high doses or prolonged use. Interaction can occur with anticoagulant medications such as Warfarin (Coumadin) and heparin. Warfarin and heparin increase the risk of adverse cardiovascular events.

In summary
1). Patients at high risk of ischemic heart disease, stroke and renal failure should proceed with extreme caution if recommended a Cox 2-inhibitor.
2). Patients at high risk for GI events should use either Cox 2 inhibitors instead of traditional NSAID’s or concurrently take a proton pump inhibitor with the traditional NSAID.
3). In all cases, judicious use of all NSAIDs should occur following a comprehensive assessment of a patient’s health. Considerations should weigh the benefits vs. the risks.

Do NSAIDs Have a Role in Conservative MSK Treatment?
It is understood that the scope of practice for conservative care providers does not allow for prescription of medication including many of the NSAIDs. We can and do however see many patients in the office with questions on these drugs. It is always advised that patients check with the prescribing physician. It is always advised that the conservative care provider defer these questions back to the prescribing physician. That being said, I feel that we should at least have a working knowledge of actions, interactions and should be able to offer some general support to our patients.

NSAIDs do have a role in conservative MSK treatment. The strongest support appears to be in the acute traumatic and post-surgical populations (39, 40, 41, 42, 43, 44, 45, 46, 47, 48). Administration of NSAIDs namely Cox-2 inhibitors routinely cut down post-surgical use of narcotic medications. Administration of NSAIDs namely Cox-2 inhibitors independent of or in conjunction with narcotics routinely decreased pain more than non-usage. Best practice currently recommends short term utilization of a period of days to weeks for pain control. It is theorized that decreased pain may assist in the rehab setting in restoring range of motion, ADL tolerances and improving quality of life measures.

Conceptually, NSAIDs may also have a role in acute flare ups of chronic condition. Examples would be conditions such as osteoarthritis, rheumatoid arthritis, gout, psoriatic arthritis, lupus, etc. Best evidence indicates a trial of days to weeks to reduce pain and restore quality of life. The theory is get these patients over the hump quickly and then wean them off the medication if advised by their prescribing physician.

NSAIDs have a mixed role in cases of bone (facture and fusion) healing. There is conflicting evidence whether NSAIDs inhibit callus formation, fracture healing and clinical outcomes; therefore, caution is recommended due to absence of robust evidence. Widespread prescription is not recommended here.

Likewise, there is conflicting evidence that NSAIDs impair soft tissue healing. Some research does indicate that short term benefits may be provided; however, basic science laboratory studies indicate that the bone-tendon interface appears to be particularly susceptible to the effects of NSAIDs. Ligaments may also be susceptible. Judicious use of short term duration weighing benefits vs. risks is recommended.

NSAIDs do not appear to benefit athletes when compared with placebo in the realm of sports performance and recovery from delayed onset muscle soreness. Blood work has shown no changes in inflammatory markers. Additional measures like pain or sports performance markers have shown no significant changes vs. placebo. Best practice would be to avoid prescription of NSAIDs to this demographic in lieu of no conferred benefits with the potential for risk.

The last point to make here is concerning inflammation. Acute and sub-acute inflammation are actually part of the healing process. Chronic inflammation is not good for the body.  Chronic inflammatory conditions can lead to pathological changes to the tissue.  Medical providers at one point in time considered NSAID usage as a strong fit in this population; however, long term and continued usage of anti-inflammatory medications are still not recommended at the risk of adverse events spike.

Summary
The article started with a question. Is inflammation the boogeyman? I hope after reading this you think a bit differently about inflammation. Inflammation does play a critical role in our body. I hope that you take pause and re-evaluate your clinical practice patterns regarding inflammation and NSAIDs. Are you implementing the evidence to assist your patients or are you chasing the boogeyman?

About The Author

Dr. Dino Pappas, DC, MS, ATC, CSCS, Cert MDT, CKTP, ACP

Dr. Pappas is a chiropractic physician, certified athletic trainer and certified strength and conditioning specialist. He recently has moved from Tinley Park, IL to Austin, TX. His goal is to provide the Austin community of NW Hills with the best conservative orthopedic, sports medicine, rehabilitation and soft tissue based care possible. Dr. Pappas blends the best of physical medicine with the best of integrated medicine to help patients and athletes of all shapes and sizes. He utilizes tools such as chiropractic manipulation, soft tissue mobilization, functional movement based assessment, the McKenzie Method, strength training and conditioning, kinesiology taping, customized nutrition, diagnostic imaging and specialty laboratory testing when needed. Dr. Pappas’ clinical focus is sports medicine, conservative orthopedics, rehabilitation and integrated medicine. His sports medicine interests are endurance athletes, overhead athletes (pitchers, throwers, volleyball players and tennis players), contact sports athletes (football, rugby, lacrosse, field hockey, soccer and basketball) and Crossfit athletes. He has worked with athletes at all levels from professional to amateur.  He has provided sports medicine services to the University of Illinois, Indiana University, the Chicago White Sox, the Joliet Jackhammers minor league baseball team, the Windy City Thunderbolts minor league baseball team, Victor J. Andrew High School and Carl Sandburg High school.

On a personal noted, he reads and interprets the medical literature daily to stay abreast of cutting edge advances in his field. The doctor is an avid runner and aspiring triathlete having completed 5 marathons, 5 half marathons and numerous 5 and 10k races. He has goals of qualifying and competing in the Boston and New York Marathons, the Ironman in Kona, Hawaii, and climbing Mt. Kilimanjaro in Kenya, Africa. He recently completed the Pikes Peak Ascent, a half marathon to the 14,115 foot summit of Pikes Peak. He is currently training to complete the Go Ruck Tough Challenge as well as ruck Rim to Rim across the Grand Canyon. One day he hopes to serve his country as a team chiropractor for the United States Olympic teams and serve as a team chiropractor for a high level collegiate or professional sports team.

The doctor practices in the Northwest Hills area of Austin approximately 7 miles from downtown Austin, TX. The office is located within a multidisciplinary surgical hospital. His mantra is “Why Put Off Feeling Good?” He can be reached by email at drdinopappas@gmail.com or at 210-243-5734 (cell). Call 1-800-404-6050 to schedule an appointment with Dr. Pappas. ***

 

*** Disclaimer: The views and opinions above represent that of the author, Dr. Dino Pappas. They do not reflect the official policy or position of any agency or company that Dr. Dino Pappas may have a relationship or affiliation with. ***

References
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