An observational study of the impact of genetic testing for pain perception in the clinical management of chronic non-cancer pain
Introduction
The perception of pain is a complex neuropsychosocial phenomenon that is notoriously difficult to measure objectively. An interplay of various factors – genetic, physiological, socioeconomic, geographic, stress, gender – contribute to the manner in which an individual both perceives and tolerates different types of pain. The subjective nature of pain perception is commonly measured in clinical care: patients are asked to rate their pain using a pain rating scale (e.g. Numeric Rating Scale or Visual Analog Scale), or questionnaire, such as the Brief Pain Inventory (Keller et al., 2004) or the McGill Pain Questionnaire (Grieve et al., 2015, Thimineur et al., 2004). These scales and questionnaires yield important but subjective data, and their validity is contingent upon accuracy of the patient's answers. Because a patient's perception of pain is a critical factor for clinicians to consider when prescribing treatments, the addition of objective information is essential to guide clinical decisions and may ultimately lead to better outcomes.
The evaluation of genetic variation is one such objective measurement that has been shown to play a part in pain perception (Belfer et al., 2015, Diatchenko et al., 2013, Diatchenko et al., 2006, Diatchenko et al., 2005, Slade et al., 2015, Tan et al., 2015, Wang et al., 2015). For example, a single nucleotide polymorphism (SNP) of catechol-O-methyltransferase (COMT), an enzyme that degrades catecholamines such as epinephrine, norepinephrine, and dopamine, was shown to modulate pain perception (Zubieta et al., 2003) by leading to a 3- to 4-fold reduction of COMT activity (Lachman et al., 1996, Lotta et al., 1995, Weinshilboum, 2006). Later, Diatchenko et al. (2005). identified 3 common COMT haplotypes composed of several SNPs in this gene that are associated with up to a 20-fold difference in COMT activity. Lower COMT enzymatic activity is correlated with higher sensitivity to painful stimuli and vice versa (Diatchenko et al., 2006).
COMT SNP variants have been examined in dozens of independent association studies of human pain (Andersen and Skorpen, 2009) and have been shown to be associated with several different pain conditions including musculoskeletal, orofacial, and postsurgical pain. Specifically, COMT variants are associated with altered cortical pain processing (Vossen et al., 2010), increased pain intensity (Jacobsen et al., 2012), and less favorable treatment outcomes (Dai et al., 2010, Jacobsen et al., 2010, Omair et al., 2012) in lower back pain; and interaction with orthodontic treatment (Slade et al., 2008), reduced efficacy of propranolol treatment (Tchivileva et al., 2010), and experimental pain sensitivity in temporomandibular joint dysfunction (Diatchenko et al., 2005). Several findings have also been reported for COMT variant associations with fibromyalgia: namely, increased pain level during elevated pain attention (Finan et al., 2011), thermal and pressure pain sensitivity (Martínez-Jauand et al., 2013), increased number of tender points (Cohen et al., 2009), and pain and positive affect interaction (Finan et al., 2010), fatigue, sleep disturbance, morning stiffness, and disability (Barbosa et al., 2012, Vargas-Alarcón et al., 2007).
Interestingly, COMT genetic changes have also been associated with pain catastrophizing (Finan et al., 2011) and psychological distress (Desmeules et al., 2012). Psychological traits that influence the perception of pain may predispose some individuals to exhibit pain disorders more severely than others, despite having similar prognoses or other physical similarities (Fernández-de-las-Peñas et al., 2013). Evidence that COMT-dependent pain is mediated by β-adrenergic receptors (Kline et al., 2015) has indicated therapies designed to target cognitive-affective behaviors – such as Cognitive Behavioral Therapy (CBT) (Carroll et al., 2015) – can be effective in modulating biological and learning processes relevant to symptom relief (Lonsdorf et al., 2010). Moreover, COMT-dependent pain disorders have shown promising response to β-adrenergic receptor antagonists, such as propranolol (Tchivileva et al., 2010), in peripheral, musculoskeletal pain. COMT modulation of catecholamines may also explain the analgesic effects of antidepressants versus opioids in pain management (Segall et al., 2012).
Despite the increasing evidence that the genetic component of pain is substantial (Nielsen et al., 2008, Norbury et al., 2007), genetic testing is not routine in clinical care. Therefore, this study was conducted in collaboration with physicians that currently use genetic testing to guide clinical decisions. The primary goals of this study were to evaluate how physicians use objective, genetic information related to pain perception in the clinical setting, and to evaluate patients' responses to treatment modifications when they occur. A secondary goal was to determine whether genetic predictions of pain perception were consistent with patients’ self-reported pain.
Section snippets
Material and methods
The data was collected in a prospective, longitudinal study that took place from April 30, 2015 until November 17, 2015. The study protocols 1JAN15-14CR and 1JAN15-20CR were reviewed, approved, and overseen by Solutions IRB, an institutional review board licensed by the U.S. Department of Health and Human Services, Office for Human Research Protections. the investigation was carried out in accordance with the latest version of the Declaration of Helsinki.
Demographics
Demographics, clinical features, and genetic testing scores of patients receiving the Pain Perception genetic test were collected and evaluated (Table 1). Genetic testing scores were categorized as low, moderate, or high in this analysis, with 41% of the patients having low pain perception, 31% having moderate pain perception, and 28% having high pain perception. Comparison with a larger cohort of patients (n = 4,480) that received this genetic test revealed these distributions were not
Case studies
In addition to aggregate data, case studies were collected to illustrate how physicians used genetic testing related to pain perception for clinical management. Each of the patients described below experienced therapeutic benefits after clinicians used the Pain Perception genetic profile results to guide their treatment.
Discussion
Evaluating a patient's pain perception is considered to be a crucial factor when making clinical decisions, whether for initiating treatment or evaluating the effectiveness of the ongoing plan of care (Coghill and Keefe, 2015, Huijnen et al., 2015, Keller et al., 2004). Treating chronic non-cancer pain patients comes with a significant risk of poor outcomes, particularly if the patients are being treated with opioids (Savage, 2009, Trescot et al., 2006). Having inaccurate information about pain
Conclusions
Genetic testing is an important component of personalized medicine. This study builds upon the substantial published research establishing the clinical validity of COMT haplotypes responsible for pain perception. Additional studies are warranted to discover more SNPs that affect pain perception, as well as phenotypic factors such as age, gender, or stress level that may contribute. Further research is required to evaluate the health economics impact of using genetic testing to objectively
Role of the funding source
This work was supported by Proove Biosciences, Inc.
Acknowledgements
The authors would like to acknowledge Daria Muller for analysis and interpretation of data and Lisa Davila for drafting and revising the manuscript. The authors also gratefully acknowledge all patients and physicians who agreed to take part in the study, without whose participation and cooperation this work would not have been possible.
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