Most practitioners are aware that there is considerable variability in the pain experience reported by different people. Variability is a key characteristic of acute pain in response to noxious stimuli; we each have our own ‘pain threshold‘. It is also characteristic of chronic pain associated with injury or disease, even when the underlying tissue disorder is essentially identical. A notable example is phantom limb pain in amputees. Some amputees report essentially no phantom limb pain at all, while in others, severe disabling pain lasts a lifetime. Reamputation usually fails to relieve phantom limb pain, suggesting that factors associated with the patient are the underlying cause, not details of the surgery Citation[1].
Individual differences in pain response are traditionally attributed to psychosocial and cultural factors, personality, personal inclination and upbringing (i.e., environmental factors). New evidence, however, indicates that genetic factors contribute as much to individual pain response as environment and upbringing Citation[2]. Why should a pain professional be interested to know that pain experience is affected by genes? There are basically four reasons.
Stigma
First, people who report having severe pain in the absence of easily observed signs of injury or disease are often stigmatized as weak in character, or malingerers. They may even be suspected of trying to cheat ‘the system‘; of exaggerating their complaints to garner sympathy from family and friends, and undeserved benefits from employers, insurance companies and the government. Such stigmatization is usually unfair, it undermines self image and is likely to add considerably to the patient‘s distress and suffering (and to that of his/her loved ones). For the pain professional, stigma is almost always harmful to efforts at reducing pain. Knowledge, of the therapist and the patient, that one person may have much more pain than another, not because of a character flaw, but for genetic reasons, is sure to provide comfort. If it‘s the luck of the genetic draw, it‘s not your fault! It should be noted that this benefit does not require actual knowledge of the pain genes involved or even knowledge that, in the specific patient at hand, excessive pain is indeed due to bad luck in the genetic draw. The simple knowledge that science has shown that genes count can reassure your patient. It can also provide him/her with a response to tormentors and maybe even help you, as a pain professional, to take the patient‘s problem more seriously. This knowledge is an easy gift you can give your patient as he sets out on his journey to pain relief.
Diagnosis, prognosis & guidance
A ‘pain gene‘ is a gene for which there are polymorphisms (variations in the DNA base-pair sequence) that affect the expression of the gene‘s protein product, or its function, in a way that affects pain response. Typically, the polymorphism amounts to a single letter difference in the sequence of As, Ts, Gs and Cs that make up the gene. Such single base-pair differences are called single nucleotide polymorphisms (SNPs). Several dozen SNPs that might affect the amount of pain that an individual suffers have already been identified. Although we are not there yet, it is fairly straightforward to identify from a simple blood or saliva sample whether an individual patient carries one or more pain-related SNPs that might account for exacerbated pain. In addition, it can be anticipated that, in the future, results of such lab tests will assist in the medical diagnosis of the underlying pain condition, and the prognosis. Such information may even guide treatment.
One example comes from recent work from the author‘s research group Citation[3]. We began with inbred mice in which one mouse strain consistently develops neuropathic pain behavior after a standard nerve lesion and another doesn‘t. Cross-breeding males and females of the two strains brought us to the conclusion that a gene of major effect was involved. Subsequent application of a set of modern analytical tools eventually allowed us to identify the gene in question. It is a gene called Cacng2, known to code for the γ-subunit of voltage-sensitive Ca2+ channels. Cacng2 had previously been implicated in epileptogenesis but not in neuropathic pain.
Virtually all mouse genes have a homolog in the human genome and Cacng2 is no exception. The human version of the Cacng2 gene is called CACNG2. Having determined the importance of polymorphisms in this gene for neuropathic pain in mice we asked whether it might also have a role in neuropathic pain in humans. This was checked by comparing SNPs in this gene using DNA obtained from a blood sample in 549 women who had undergone a complete or partial mastectomy due to breast cancer. Among these women, 215 reported persistent neuropathic pain in the chest wall and 334 did not. We found that if a particular woman had the bases A-C-C at three particular adjacent SNPs in the base-pair sequence of their CACNG2 gene, this would predict, with a fair likelihood, that she will develop chronic postoperative pain (OR: 1.7 on a baseline likelihood of nearly 40%). The increased chance is sufficiently large that it could be a factor in the decision on which surgical procedure to choose, or at least to inform the surgeon that special care is needed to minimize nerve injury during the procedure. The experimental results need to be reproduced independently by other investigators using additional cohorts of women before CACNG2 genotyping can be introduced into clinical practice. But this type of application probably has the potential to be used in the not too distant future. Further in the future, the genetic study of pain response could lead to gene-based therapy.
Pharmacogenetics & individualized medicine
A third arena in which pain genetics could make a difference is in predicting which patients are likely to respond to which analgesic drugs. This capability is called ‘pharmacogenetics‘. Like pain itself, response to therapeutic options varies among individuals and a good deal of the variability is thought to be due to genes. Pharmacogenetics promises a new era of individualized pain medicine in which the choice of drugs will be tailored to the specific patient, providing increased efficacy with decreased unwanted side effects.
Discovery of novel pain mechanisms
Research on pain genetics has already begun to contribute to the understanding of pain mechanisms and will probably continue to do so. Past experience indicates that this will ultimately lead to improved pain medicine. Indeed, pain genetics has a special potential to uncover novel and unexpected insights into pain; insights that might not be achieved by a step-by-step pursuit of conventional pain physiology. This is because, if done right, the genetic approach permits a broad and unbiased scan of genes and gene-related pain mechanisms; a perspective that is independent of our current knowledge on how pain works.
Pain genetics is still in its infancy. However, the basis for expecting substantial future pay-offs in terms of new understanding and medical applications is firm. Such pay-offs could lie in two different directions. First, genes are waiting to be found for which individual variations cause (or at least predispose to) diseases that may be painful. Such ‘disease susceptibility genes‘ have already been documented for Type 2 diabetes, migraine headache, a variety of peripheral neuropathies, temporomandibular joint disorder, rheumatoid arthritis, and even low back pain and sciatica Citation[4–7]. Even more interesting, however, are genetic polymorphisms, such as CACNG2, that predispose to more or less pain given the same precipitating injury or disease. Such ‘pain susceptibility genes‘ may not contribute to a better understanding of a particular disease. However, they will very likely provide unique insights into the neural mechanisms of the pain experience that is caused by disease and answer the question of why some people develop severe pain, while others don‘t.
Financial & competing interests disclosure
The author has no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
References
- Sherman R , DevorM, Casey Jones DE, Katz J, Marbach JJ. Phantom Pain. Plenum, NY, USA, 1–264 (1996).
- Mogil JS . The genetics of pain. In: Progress in Pain Research and Management. IASP Press, Seattle, WA, USA, 1–349 (2004).
- Nissenbaum J , DevorM, SeltzerZ et al. Susceptibility to chronic pain following nerve injury is genetically affected by CACNG2. Genome Res. 20 , 1180–1190 (2010).
- de Vries B , FrantsRR, FerrariMD, van den Maagdenberg AM. Molecular genetics of migraine. Hum. Genet.126 , 115–132 (2009)
- Diatchenko L , NackleyAG, TchivilevaIE, ShabalinaSA, MaixnerW. Genetic architecture of human pain perception. Trends Genet.23 , 605–613 (2007)
- Fischer TZ , WaxmanSG. Familial pain syndromes from mutations of the NaV1.7 sodium channel. Ann. NY Acad. Sci.1184 , 196–207 (2010)
- Olsen MB , JacobsenLM, SchistadEI et al. Pain intensity the first year after lumbar disc herniation is associated with the A118G polymorphism in the opioid receptor mu-1 gene: evidence of a sex and genotype interaction. J. Neurosci. 32 , 9831–9834 (2012).