J Manipulative Physiol Ther. 2018 (May 26) [Epub] ~ FULL TEXT
James M. Whedon, DC, MS, Andrew W.J. Toler, MS, Justin M. Goehl, DC, MS, Louis A. Kazal, MD
Health Services Research,
Southern California University of Health Sciences,
OBJECTIVES: Mortality rates due to adverse drug events (ADEs) are escalating in the United States. Analgesics are among the drug classes most often associated with occurrence of an ADE. Utilization of nonpharmacologic chiropractic services for treatment of low back pain could lead to reduced risk of an ADE. The objective of this investigation was to evaluate the association between utilization of chiropractic services and likelihood of an ADE.
METHODS: We employed a retrospective cohort design to analyze health insurance claims data from the state of New Hampshire. After inversely weighting each participant by their propensity to be in their cohort, we employed logistic regression to compare recipients of chiropractic services to nonrecipients with regard to likelihood of occurrence of an ADE in an outpatient setting.
RESULTS: The risk of an ADE was significantly lower among recipients of chiropractic services as compared with nonrecipients. The adjusted likelihood of an ADE occurring in an outpatient setting within 12 months was 51% lower among recipients of chiropractic services as compared to nonrecipients (OR 0.49; P = .0002). The reported ADEs were nonspecific with regard to drug category in the majority of incidents that occurred in both cohorts.
CONCLUSIONS: Among New Hampshire adults with office visits for low back pain, the adjusted likelihood of an Adverse drug event (ADE) was significantly lower for recipients of chiropractic services as compared to nonrecipients. No causal relationship was established between utilization of chiropractic care and risk of an ADE. Future research should employ larger databases, rigorous methods to reduce risk of bias, and more sensitive means of identifying ADEs.
KEYWORDS: Adverse Drug Event; Adverse Drug Reaction; Chiropractic; Low Back Pain
From the Full-Text Article:
Adverse Drug Events
Adverse drug events (ADEs) are injuries that result from prescription drug interventions. Types of ADEs include medication errors, adverse or allergic reactions, and overdoses. Adverse drug events are associated with increased rates of disability, hospitalization and mortality, and may result from appropriate use of medications as well as overuse and misuse.  An analysis of 2 nationally representative probability sample surveys revealed that from 2005 to 2007 the highest incidence of ADEs occurred in outpatient settings and among patients aged 65 and older.  A systematic review reported a median prevalence rate for ADEs of 12.8% overall and 16.1% for elderly patients.  Mortality rates due to ADEs are escalating; the drug overdose death rate increased from 12.3 per 100,000 population in 2010 to 16.3 in 2015. 
Risk of an ADE Associated With Prescription Analgesia for Low Back Pain
A recent systematic review of pharmacologic therapies for low back pain found modest, short-term benefits for several types of medication used to treat low back pain, including acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids.  However, analgesics (particularly NSAIDs and opioids) are among the drug classes most often associated with occurrence of an ADE. [3, 6, 7]
Acetaminophen: Long thought to be safe and the most widely used nonopioid painkiller in the world, acetaminophen was recently reported to be associated with significant toxic effects (including hepatic and renal disease, gastrointestinal bleeding, and increased risk of myocardial infarction, stroke, and hypertension) particularly at higher doses. 
NSAIDs: An analysis of national survey data found that NSAIDs are the most commonly prescribed type of analgesic for older adults with chronic nonmalignant pain.  Nonsteroidal anti-inflammatory drugs offer effective analgesia for spinal pain, but carry increased risk of gastrointestinal reactions,  and a 100% increase in risk of heart failure.  The United States Food and Drug Administration has emphasized that patients using NSAIDs are also at added risk of a heart attack or stroke.  The safety of long-term use of NSAIDs is unknown. [13, 14]
Opioids: The safety of opioid analgesics is particularly concerning. Adverse effects of opioid therapy include depression, sexual dysfunction, myocardial infarction, addiction, and risk of death due to overdose. [13, 15] The risk of an ADE due to opioid use is alarmingly high and rapidly escalating; among 47,055 drug overdose deaths that occurred in 2014 in the US, 28,647(60.9%) involved an opioid.  Since 2000, the rate of death from drug overdoses involving opioids has increased 200%, and currently, nearly 50% of all opioid overdose deaths in the US involve a prescription opioid. 
Chiropractic Care: Nonpharmacologic Treatment for Low Back Pain
Many patients who are prescribed analgesic medications have low back pain ; among US adults prescribed opioids, 59% reported having back pain.  The American Geriatrics Society’s updated “Beers Criteria” for potentially inappropriate medication use in older adults encouraged “the use of nonpharmacological approaches when needed to avoid drugs that have a high risk of causing an adverse event.”  The Institute of Medicine has also recommended increased utilization of nonpharmacologic, integrative approaches, such as chiropractic care for patients with low back pain.  Recently published evidence-based clinical guidelines for management of both acute and chronic low back pain recommend nonpharmacologic therapies as first line treatment.  Chiropractic care of low back pain is both safe and effective; a recent systematic review and meta-analysis found that for treatment of acute low back pain, spinal manipulation, as performed by chiropractors, provides a clinical benefit equivalent to that of NSAIDs, with no evidence of serious harms.  A systematic review of the safety of chiropractic interventions found a low risk of serious adverse events, ranging from 1.56 to 2.68 events per 10000000 interventions. 
Nonpharmacologic chiropractic care, including spinal manipulation, may lead to reduced use of prescription drugs.  Pain relief afforded by chiropractic care may allow patients to use lower or less frequent doses of analgesics, leading to reduced risk of NSAID-induced bleeding, opioid overdoses, and other ADEs. However, evidence to support this hypothesis is sparse and conflicting. A randomized controlled trial of patients with acute low back pain treated with usual care, plus spinal manipulative therapy, vs usual care alone, found no difference between groups in analgesic consumption.  More recently, it was reported that the supply of chiropractors, as well as spending on chiropractic care, are inversely correlated with opioid prescriptions among younger Medicare beneficiaries.  Thus, increased availability and utilization of chiropractic services could lead to a reduction in prescriptions for analgesics and an associated reduction in risk of an ADE.
The objective of this investigation was to evaluate, among New Hampshire residents with low back pain, the association between utilization of chiropractic services and risk of an ADE. We chose New Hampshire because health claims data were readily available for research, and in 2015, New Hampshire had the second highest age-adjusted rate of drug overdose deaths in the US, a 31% increase from the previous year, and, at 34.3 per 100,000, more than double the national rate of 16.3 per 100000. [4, 26] We expected this study to generate the outcome that, among patients with low back pain, recipients of chiropractic care have a lower likelihood of an ADE as compared to nonrecipients. Such a finding could exert a positive impact on patient care by pointing to a strategy for reducing unnecessary risk for patients with low back pain.
With regard to likelihood of an ADE in an outpatient setting, we found impressive differences between recipients of chiropractic services and nonrecipients. However, it is important to note that the study design only allowed evaluation of correlation. It was not possible from the available data to infer whether or not utilization of chiropractic services actually reduced the likelihood of an ADE. An unmeasured confounder may be the underlying cause of the negative correlation between utilization of chiropractic services and occurrence of an ADE.
Despite the use of propensity scoring to equalize cohorts, the reported effect may have resulted from the cohorts being drawn from different populations. Differences in preferences regarding use of pharmaceuticals may have affected comparative risk of an ADE. A recent national survey found that 78% of adults preferred nonpharmacologic care over prescription drugs for treatment of pain, and those who had never seen a chiropractor were more likely to prefer pharmacologic therapies.  Use of medications (including drugs associated with increased risk of an ADE) is a modifiable health behavior, and it has been reported that utilization of integrative health services, such as chiropractic care, is associated with improved health behaviors. [31, 32] Changes in health behaviors related to clinical encounters may be attributed to the effects of treatments, provider support, or increased patient responsibility for health.  Rather than being caused directly by type of clinical encounter, differences in risk for an ADE may result from complex interactions between personal health behaviors and social and environmental determinants of health, as well as clinical care. Further evaluation of health behaviors between recipients and nonrecipients of chiropractic care may help to elucidate differences in risk for an ADE.
Certain limitations and threats to validity for this study must be acknowledged. In general, only a limited number of exposure variables were available for inclusion in propensity scoring and regression modeling. As noted in the discussion, patents’ self-selective stratification into pharmacologic and nonpharmacologic care pathways may be driven by unknown factors, including the onset, anatomic location, and severity of pain. Most of the diagnosis codes used to record ADEs were nonspecific with regard to drug category, and, in most cases where the type of drug reaction was specified, it appeared unlikely to be caused by a drug used to treat low back pain. The results contribute little evidence to suggest that utilization of chiropractic services leads to reduced use of analgesics, specifically. Furthermore, although our study population was restricted, the magnitude of the drug overdose problem in New Hampshire suggests that analysis of diagnosis codes specific for adverse events may have failed to capture a significant number of ADEs. Such codes may be less sensitive to actual rates of an ADE than previously reported,  and they may not be sufficiently sensitive to deliver externally valid results for specific drug classes, particularly with relatively small claims datasets. Finally, we were limited by the capacity of the dataset to support cohort assembly, as originally planned. Cohorts defined as primary care alone vs both chiropractic and primary care would have provided assurance that the cohorts were more comparable with regard to outpatient access to prescription medications.
These limitations point to the need for analysis of larger and more variable rich datasets that will facilitate use of more rigorous methods and allow establishment of the causal chain with higher resolution. Despite the inherent limitations of observational research with regard to causal inference, the scope of observational research datasets now available confers clear advantages over interventional designs for detection of uncommon adverse events. The results of this study should be interpreted as preliminary data that indicate the need for further observational research on comparative risk of an ADE and identify methodological elements that should be included in such research.
Among New Hampshire adults with office visits for low back pain, the adjusted likelihood of an ADE was 51% lower for recipients of chiropractic services as compared to nonrecipients. The results suggest that utilization of chiropractic care may be associated with reduced risk of ADEs; however, no causal relationship has been established. Future research on comparative risk of ADEs should employ larger databases; lengthier time periods for capturing outcomes; rigorous methods to reduce risk of bias; and more sensitive methods of identifying adverse events to enhance statistical power, sensitivity, and external validity.
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