Pain-evoked limitation of activities is one of the most costly morbidities of illness 1. Several studies have replicated the finding that bed rest or a decrease in activity may impair recovery from an acute back pain episode 2345. Clinical practice guidelines recommend early activity in the management of acute low back pain 67.

If decreased activity in the presence of back pain retards recovery, it may be important to understand why some patients decrease their activity more than others after a similar injury. Most of the relevant work to date has focused on psychological causes of reductions in motor activity in pain patients 89 paying relatively little attention to factors intrinsic to the motor system or direct connections with afferent pain systems. For example, Lethem et al 8 proposed the fear-avoidance model to explain a possible mechanism of inactivity and disability in patients with chronic musculoskeletal pain. According to this hypothesis, if an individual misinterprets back pain as a signal of reinjury or continued tissue damage, his fear of injury may cause him to systematically avoid movements that typically increase pain 10. The resulting inactivity may lead to deconditioning, contractures, and disability.

Psychological variables almost certainly explain some of the variation in the motor response to injury, but we propose that one should also examine the contribution of inter-individual differences in the wiring and neurochemistry of the motor system itself. Lund et al. 11 have proposed a plausible link from pain inputs to motor circuits, the "pain-adaptation model." In this model, pain afferent activity decreases activity of the muscle groups that move a joint in the pain-provoking direction and increases the activity of muscle groups that antagonize such movement. These motor adjustments reduce movement velocity and limit excursions, thereby protecting against pain.

One way to examine potential differences in motor control processes is to test for polymorphisms in genes encoding molecules that regulate motor systems. We and others have already been studying the association between short lists of candidate genetic polymorphisms and the severity of acute and chronic pain 121314 and pain-related mood change 15. Arrays of 500,000 or more single nucleotide polymorphisms are commercially available, making possible whole genome association studies in large cohorts of pain patients. It occurred to us that in cohorts where one had a good measure of motor function, one could use the same whole genome scan data to search for genes that predisposed to a greater decrease in activity, given similar injury and pain level. Many current spine pain studies will include enough data to make this possible, because a decade ago, leading spine researchers 16 agreed that studies should routinely incorporate either the Roland-Morris 17 or Oswestry Disability questionnaires 18, which question the patient about many motor functions.

We propose that there may be genetic polymorphisms that directly affect the motor system to cause a maladaptive level of guarding and hypoactivity. In preparation for our studies to test this hypothesis, we have examined the literature on motor systems to suggest some candidate genes. We previously proposed a method for prioritizing genetic polymorphisms for clinical studies in which pain intensity is the primary endpoint 19. We have adapted this into a method to prioritize polymorphisms that may contribute to reduction in movement in the presence of pain, and will describe this method and our resulting list of plausible candidate genes.

Our literature review showed that the genes for many molecules associated with motor control circuits have common polymorphisms. Such polymorphisms might conceivably contribute to excessive guarding shown by some patients with pain.

The present study of 14 of these candidate genes revealed an association of a GABA-A β1 subunit haplotype with the amount of motor limitation (Table 5). Two copies of the haplotype reduced movement limitation scores almost 30% compared with no copies. The nominal p value of 0.0025 is small enough to be interesting even if one corrects for the 22 haplotype blocks examined, yielding an overall p value = 0.055. If confirmed by subsequent studies, we would hypothesize that this variant of the gene serves as an "endogenous muscle relaxant", with greater GABAergic motor inhibitory activity that reduces spasm and permits more activities.

We cannot speculate about the specific biochemical mechanism by which this haplotype might affect motor function. The finding that the haplotype analysis was much more sensitive than single SNP analyses suggests that a movement-facilitating SNP that we did not directly test may be present on the haplotype we identified. Compared to other GABA receptors, the GABA-A receptor β1 subunit has been little studied 20, and there is no commonly used specific antagonist, agonist, or knockout mouse. The published literature states that benzodiazepine muscle relaxant effects are primarily mediated through GABA-A α2, α3, and α5 receptor subunits 21. However, interest in the β1 subunit is growing because of possible associations with autism 22 and bipolar disorder 23, so the gene may soon be better understood.

The nominally significant associations of two ADRA2C SNPs and a haplotype with motor limitation scores are not persuasive because of the modest size of the effect and the many genes tested. However, this gene is known to have common polymorphisms with strong effects on cardiovascular regulation and mood, such as a deletion affecting about 40% of chromosomes in African Americans 2425, not tested for in the current study of a Caucasian population. Alpha-2 adrenergic receptors mediate inhibition of motor tone at the spinal level 26, so this gene should be revisited in future studies.

Because of several limitations in our study methods, we consider these findings tentative. The first limitation is that the Roland-Morris scale items that we used are retrospective and subjective assessments of the patient's ability to carry out various movements of daily life. Moreover, we chose a subset of these items to represent changes in movement without any formal validation studies. Objective measures of motor function would have been more convincing, but these were not available for this cohort.

Secondly, we tested only 14 genes, chosen by an anatomical analysis the emphasized the final two or three neurons in the motor control pathway. Molecules influencing more rostral levels of control might also be candidates. For example, Kleim et al. 27 have reported a BDNF polymorphism to be associated with modified plasticity in the human motor cortex. A more thorough search could be done using a whole genome association array, but this would require a sample size in the thousands 23 to provide adequate power.

Thirdly, we would have been interested in searching for an interaction between gene effect and pain level on movement, similar to the gene, pain, and depression analysis we have done on the same cohort 15. For example, some polymorphic alleles might produce a major reduction in movement only in the presence of severe pain. However, this analysis was not appropriate in this case because the scale items mention both pain and various movements.

Finally, long-term decrease in movement is more directly relevant to the economic burdens of pain than the acute effects that we examined above. The analytical approach demonstrated above might also be used to search for effects of genes on a chronic decrease in movement. We chose to examine acute pain and movement data as an initial demonstration of this method for several reasons: (1) Almost all of our 290 patients who gave a DNA sample had pain at the baseline measurement, while a minority had persistent pain at one year or later time points. Sample size is crucial in screening multiple candidate genes 19. (2) A shorter time window in which patients are studied under similar methods and treated by the same clinicians may be more sensitive to genetic effects than a longer period during which many types of environmental variability overshadow gene effects. (3) The processes involved in chronic pain and movement limitation are probably more complex than acute pain, including deconditioning, muscle atrophy and contractures, chronic psychiatric morbidity, and occupational factors.

Although physicians commonly prescribe "muscle relaxants" such as cyclobenzaprine, carisoprodol, and methocarbamol for acute pain, the database supporting their effects on muscle and clinical usefulness is limited 28. Development of new treatments will require expansion of animal research on the neurochemical mechanisms of pain-related guarding. We propose that, as has been demonstrated in genetic studies of pain 14, genomic screens in humans may be useful in to prioritizing targets identified in animal studies.

We have illustrated a method to use routinely measured variables in musculoskeletal pain studies to screen for molecules that may be associated with the excessive pain-related decrease in movement that increases risk of chronic disability. After correction for multiple comparisons, we found a modestly significant association between a haplotype in the GABA-β1 receptor subunit with motor limitation scores. Replication of this finding and the use of such methods with larger samples or direct measures of movement 2930 might open up a new facet of the relationship between pain and movement.

GABA: Gamma-aminobutyric acid

GTP: Guanosine triphosphate

NIDCR: National Institute of Dental and Craniofacial Research

Drs. Max, Belfer, Wu, Kingman, Goldman, and Atlas are listed as coinventors on a patent application for the use of a diagnostic test for GCH1 polymorphisms to predict the level of chronic pain.

BKM carried out the review of motor neurochemistry, prioritized the polymorphisms, and cowrote the manuscript. MBM conceived of the project and analysis methods and cowrote the manuscript. TW did the statistical analyses, with advice of AK. CAH, IB, and CK carried out the genotyping. QY, CAH, and DG designed the genotyping array. DG provided senior scientific guidance on bioinformatics and genotyping issues. LGC provided advice on motor system physiology and clinical phenotype. SJA and RBK designed and carried out the original clinical study and advised on interpretation of the current analyses. All authors read and approved the final manuscript.