a level of pain that completely incapacitates one individual may cause only a minor annoyance in another . characterizing the genetic factors affecting susceptibility to chronic pain could lead to novel treatment or prevention strategies , which are desperately needed . a recent paper by costigan et al . the authors performed a multi - dimensional analysis using rat gene expression and human genetic association that identified a new genetic factor affecting susceptibility to chronic pain . this study   was initiated by analysis of gene expression changes within rat dorsal root ganglia obtained after nerve damage was induced in three different models of chronic pain . the mrna for a potassium channel alpha subunit ( kcns1 ) was constitutively expressed in sensory neurons , but was downregulated after three types of nerve injury in these models . other studies have successfully identified a human genetic susceptibility factor on the basis of a candidate gene emerging from analysis of a rodent model . costigan and colleagues   therefore examined snp alleles within the human homolog ( kcns1 ) in five independent cohorts ( two with chronic low back pain , two after limb amputation and one after mastectomy ) that have a high incidence of chronic pain . in four of the five cohorts studied , there was a significant association of the val allele at a nonsynonymous snp ( rs734784 , val / ile ) with increased risk for chronic pain . for example , homozygous val / val individuals had a 2.4-fold increased relative risk of failing to achieve pain improvement 1 year after back surgery . the proportion of individuals without phantom limb pain after leg amputation was 45% in those without the val allele , but fell to 22% in val / val homozygotes . among healthy volunteers that were subjected to multiple experimental pain stimuli , although experimental studies demonstrating an allelic effect were not presented , which is a substantial limitation of this study , these results   make it likely that kcns1 alleles contribute to susceptibility to chronic pain . although kcns1 by itself does not have potassium channel function when tested in heterologous expression systems , its expression has been shown to modulate the currents formed by other channels [ 3 - 5 ] . voltage - gated potassium channels have important effects on neuronal function , including altering the resting membrane potential and the shape and frequency of the action potential . similarly , gain - of - function mutations in the nav1.7 sodium channel cause syndromes associated with increased pain sensitivity . chronic pain has a huge impact on our society , and its treatment is a major driver for the increasing cost of health care . an estimated 76 million people in the us have chronic pain , which costs the us public over $ 100 billion per year . approximately 25% of chronic pain is neuropathic ( caused by nerve damage ) , which is characterized by spontaneous pain that is burning or stabbing in nature . this can develop after limb amputation , mastectomy or lower back injury , or in individuals with a long history of diabetes . although multiple kinds of treatment can be used , they often have limited efficacy , and chronic pain is often managed by administration of opioids ( morphine and related synthetic compounds , including hydrocodone ) . the increased focus on pain management resulted in a six - fold increase in the per capita sales of prescription opioid medications in the us between 1997 and 2006 . hydrocodone - acetaminophen is prescribed over 100 million times per year in the us , which is far more than any other medication , including lipid - lowering and blood - pressure - lowering agents . this has led to a dramatic increase in the incidence of opioid misuse , emergency room visits due to opioid analgesic poisoning , and fatal opioid overdose . prescription opioids have now surpassed marijuana as the drug that is most commonly abused among the newly initiated . because of the enormity of this public health problem , we desperately need new approaches for the prevention or treatment of chronic pain conditions . it is likely that genetic discoveries can lead to new approaches for chronic pain , because genetic discoveries have catalyzed new approaches for related clinical conditions . for example , haplotype - based computational genetic analysis has identified causative genetic factors affecting analgesic medication   and inflammatory pain responses , and it has identified four genes affecting narcotic drug responses [ 11,14 - 16 ] in mice . the latter genetic discovery generated a new treatment strategy for preventing narcotic drug withdrawal symptoms , which was shown to be effective in humans . moreover , the variable response to multiple classes of analgesic medications among inbred mouse strains was shown to be due to genetic variation within a genetic locus ( kcnj9 ) that also encodes a potassium channel ( girk3 ) . hopefully , characterizing the functional role of kcns1 in neuronal responses and pain perception , and the impact of the allelic differences , could lead to new approaches for treatment of chronic pain . although the tractability of kcns1 ( or other potassium channels ) as a therapeutic target remains to be determined , small molecules targeting potassium channels have been produced ( reviewed in ) , and one has attenuated neuropathic pain in animal models . although the kcns1 val allele explains only a small percentage of the total variance ( 4.6 to 7.8% ) in the chronic pain endpoints in the cohorts studied , the identification of an initial genetic factor for chronic pain is an important achievement for two reasons . first , it shows that genetic factors can be identified for this condition , and this study provides a template for subsequent studies . second , it is likely that a greater percentage of the genetic susceptibility to chronic pain can be explained by combining this genetic factor with other subsequently identified factors . moreover , pain is a subjective sensory symptom ; it is difficult to measure ; and there are substantial psychological and emotional components that contribute to the perception of pain . it has recently been found that there are different subtypes of chronic pain , which are distinct from the causative disease ( diabetic neuropathy , radicular back pain and so on ) . it is likely that genetic factors determine whether a chronic pain syndrome will develop and the specific subtype that emerges after exposure to a triggering cause . thus , the impact of a single genetic factor could be much larger if a specific pain subtype is examined relative to that measured in a large cohort of individuals with different types of chronic pain . beyond finding new drug targets , identification of genetic factors affecting susceptibility to chronic pain syndromes could be the lever that drives advances in this difficult clinical area . a genetic risk factor could have a substantial impact on clinical practice because individuals at increased risk for developing a chronic pain syndrome could be identified before a surgical procedure or immediately after a traumatic incident . the genetic information could be used to develop proactive methods for prevention of chronic pain syndromes , enabling interventions to be targeted to the high - risk subset . because of the great inter - individual variation in the response to painful stimuli and to analgesic drugs , knowledge of genetic risk factors could enable better stratification of chronic pain patients or aid in the selection of the appropriate therapy . rather than focusing on the disease that is etiologically associated with the chronic pain , study   is hopefully one of the first of many subsequent genetic studies that could lead to entirely new ways to approach chronic pain syndromes . clearly , the clinical and research communities have a long way to go before genetically targeted therapies for chronic pain become a reality . however , kcns1 ( or other channels ) could perhaps become the next target for a new class of analgesics that are selectively used in the 20% of the population that are homozygous for the val alleles of kcns1 . the day might soon come when we no longer think of ' chronic pain ' as a single clinical entity , but have the tools to characterize the specific ' channelopathy ' that underlies the clinical presentation and targeted treatments for each subgroup . gp is a professor and mz is the director of statistical research in the department of anesthesia at stanford university medical school .
a recent publication that combined rat gene expression data and a human genetic association study has identified the first genetic risk factor for chronic pain in humans . in four of 
 the five cohorts studied , there was a significant association of an allele within a gene ( kcns1 ) encoding a potassium channel ( kv9.1 ) with an increased risk for chronic pain . 
 identification of genetic risk factors for chronic pain could catalyze new advances in this difficult clinical area that has become a major public health problem . 
 genomic - medicine - based advances for chronic pain could include the development of a mechanism - based classification system for chronic pain , new treatment options , improved methods for treatment selection and targeted prevention strategies for high - risk individuals .