Biomarkers – or to be more precise, the research into their discovery – have recently received a lot of attention. This is not only reflected by an increasing number of working groups or meetings regarding the topic, but also the sheer number of publications (more than 500,000) tells its own story. Why is it that scientists and clinicians alike regard this as such an important topic worth spending money, time and potentially careers on? At least in part, the overwhelming interest might be rested on the current revitalization of an old concept in medicine – personalized healthcare, but undeniably also because of recent breathtaking advances in diagnostic technology.
Most readers today, when asked what biomarkers are, would probably answer with a term belonging to ‘omics‘ research: genomics, metabonomics or proteomics. Although that takes them straight to one of the most prosperous and best known branches in biomarker research, they have not provided a concise definition of what biomarkers are. Is there such a definition?
The Biomarkers Definitions Working Group Citation[1] defined biological markers (biomarkers) as “A characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.” However, this definition has been criticized as being too broad and the Ninth European Federation of Pharmaceutical Sciences Conference on Optimising Drug Development recommended a seven-point mechanistic classification of biomarkers Citation[2].
| ▪ | Type 0: Genotype or phenotype; | ||||
| ▪ | Type 1: Concentration; | ||||
| ▪ | Type 2: Target occupancy; | ||||
| ▪ | Type 3: Target activation; | ||||
| ▪ | Type 4: Physiological measures or laboratory tests; | ||||
| ▪ | Type 5: Disease process; | ||||
| ▪ | Type 6: Clinical scales. | ||||
This classification outlines some of the aims or purposes of biomarkers usage. They are thus intended to improve pharmaceutical research (drug development) and aid clinical care (personalized medicine).
In drug research the discovery of more specific biomarkers is hoped to improve the identification of potential drug targets and to characterize clearer end points to verify drug efficacy and treatment success. Consequently, it is not only expected that there will be a reduction in participant numbers in clinical trials but also a shortening of trial length, allowing a quicker introduction of new therapies into clinical practice.
Furthermore, the use of biomarkers would enable drug companies on the one hand to prevent expensive drug failures, but also to avoid the unnecessary labeling of compounds as ineffective Citation[3]. In daily practice clinicians need biomarkers to aid diagnosis, enable accurate estimates about disease progress and prognosis, as well as to help stratify patients to the best-suited treatments Citation[4]. In addition, especially in pain medicine, scientists hope that biomarkers will help the development of new classes of drugs that not only alleviate symptoms, but also possess disease-modifying properties Citation[5].
These essentially represent the aims and hope the medical community as a whole project into biomarker research. But where does pain, especially acute pain, research fit into this stratagem and what have we achieved so far?
Pain research in general is currently undergoing a smooth but significant paradigm shift, away from animal experiments and more towards research in humans. The reasons are manifold and include an increasing unwillingness of western societies to consent to animal studies, improved tools that allow more detailed insight into the human body, as well as recognized anatomical and physiological differences between humans and laboratory animals that are seen as the cause for the frustratingly little success in the translation of results from the bench to the bedside Citation[6].
At present, pain researchers mainly focus on the identification of type 0 biomarkers (genotype or phenotype) from the classification previously described. However, use of type 6 biomarkers (clinical scales and questionnaires) has been a domain of pain medicine since long before this classification was developed.
As a matter of fact, verbal, numerical and visual analog scales as well as pain questionnaires such as the McGill Pain Questionnaire or the Brief Pain Inventory, to name a few, are such vital parts of every pain clinic and clinical study that their inclusion into a classification of biomarkers seems surprising Citation[7]. Nevertheless, they are the unsurpassed backbone of our clinical and scientific diagnostic armament, despite their increasingly recognized shortcomings.
The use of questionnaires is predominantly the remit of chronic pain medicine. However, despite some of them reaching a fair level of sophistication with good discriminative properties between pain modalities, they are time consuming and subjective. By contrast, in acute pain, the focus tends to be on the assessment of pain intensity. Rating scales for this purpose are generally straightforward and robust, but hampered by large interpatient variability. Moreover, similar easy-to-use assessment tools for the use in patients at the extremes of age, with cognitive deficits or inabilities to express themselves, are still lacking Citation[8]. However, the simplicity, robustness and low associated costs puts type 6 biomarkers at such an advantage, that scientists should be encouraged to develop them further, even though, in technology-dominated times, this seems a futile endeavor to many people.
At present, most areas in medicine are concerned with research into type 0 biomarkers. Phenotyping in chronic pain has recently made some progress through the formal standardization of quantitative sensory testing protocols Citation[9]. This enables clinical scientists to analyze neuropathic pain patients with regards to their somatosensory characteristics, allowing a systematic comparison between different neuropathic pain subtypes and phenotypes of healthy persons. Results so far are promising and it looks like distinct neuropathic somatosensory phenotypes are emerging Citation[10]. Quantitative sensory testing has also been used to assess the risk of patients with and without a history of pain, to develop chronic postoperative pain. Increased areas of secondary hyperalgesia, for instance, have been shown to correlate with higher rates of chronic postoperative pain Citation[11].
The method used for pain phenotyping that has recently seen the most technical progress and subsequently led to an entire new era in pain research is functional MRI. It is capable of detecting small changes in regional blood flow and is therefore an indirect measure of neuronal activity Citation[12]. With its help, scientists can now determine the brain areas that are activated during the processing of nociceptive signals Citation[13]. Interestingly, many results were obtained from volunteer studies employing acute pain models Citation[14]. However, with the advent of voxel-based morphometry, it is now also possible to assess cortical thickness or gray matter volume changes in response to chronic pain, and diffusion tensor imaging allows the estimation of white matter connectivity Citation[15]. This, in the future, might lead to more fascinating discoveries about the state of networks during pain processing. Therefore, research into neuronal and network activity patterns together with the determination of brain morphology changes, as seen in certain chronic pain states, might result in the development of imaging-based biomarkers, both in acute and chronic pain Citation[16].
Finally, the search for biomarkers in pain is, like in many other fields, now increasingly concerned with ‘omics‘ research. Here, a vast array of molecules usually sampled from all kinds of body fluids is analyzed simultaneously to possibly allow geno- and pheno-typing of specific pain entities. Genomics, proteomics and metabonomics, among others, are the proponents of this novel and attractive research.
Genomics theoretically enables scientists to analyze the activity of thousands of gene transcripts at the same time and hence develop an idea about the activation of the genetic machinery in response to nociceptive stimuli or as part of entire pain pathways Citation[17]. Conversely, proteomics and metabonomics provide the ability to directly measure the (end)products of anabolic or catabolic processes on a cellular level. There are promising results emerging with regards to pain medicine, both from a generalized approach investigating chronic conditions with a prominent pain component, such as rheumatoid arthritis Citation[18], and also at a more specific level with complex regional pain syndrome patients demonstrating differences in the metabolic profile of urine samples compared with healthy controls Citation[19]. However, after a period of high hopes, the so far overall unsatisfactory results in biomarker research have caused groups across all specialties to realize the potential shortcomings of their techniques. In genomics, huge variations in the human genome pose a significant problem for the generation of homogenous group samples.
In addition, incomplete mathematical analytical models hamper metabonomics, while the lack of consensus over data processing negatively affects progress of modern imaging Citation[17,20].
Nevertheless, the recent advances in technology offer pain research new and exciting possibilities, when used judiciously. Chronic, and especially acute, pain scientists should feel encouraged in contributing to the discovery of biomarkers in an attempt to help develop much needed new therapeutic strategies.
Financial & competing interests disclosure
C Bantel is supported by Higher Education Funding Council for England (HEFC-E). H Laycock is supported by the London Deanery. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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References
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