Do motor control genes contribute to interindividual variability in decreased movement in patients with pain?

BACKGROUND: Because excessive reduction in activities after back injury may impair recovery, it is important to understand and address the factors contributing to the variability in motor responses to pain. The current dominant theory is the "fear-avoidance model", in which the some patients' heightened fears of further injury cause them to avoid movement. We propose that in addition to psychological factors, neurochemical variants in the circuits controlling movement and their modification by pain may contribute to this variability. A systematic search of the motor research literature and genetic databases yielded a prioritized list of polymorphic motor control candidate genes. We demonstrate an analytic method that we applied to 14 of these genes in 290 patients with acute sciatica, whose reduction in movement was estimated by items from the Roland-Morris Disability Questionnaire. RESULTS: We genotyped a total of 121 single nucleotide polymorphisms (SNPs) in 14 of these genes, which code for the dopamine D2 receptor, GTP cyclohydrolase I, glycine receptor alpha1 subunit, GABA-A receptor alpha2 subunit, GABA-A receptor beta1 subunit, alpha-adrenergic 1C, 2A, and 2C receptors, serotonin 1A and 2A receptors, cannabinoid CB-1 receptor, M1 muscarinic receptor, and the tyrosine hydroxylase, and tachykinin precursor-1 molecules. No SNP showed a significant association with the movement score after a Bonferroni correction for the 14 genes tested. Haplotype analysis of one of the blocks in the GABA-A receptor beta1 subunit showed that a haplotype of 11% frequency was associated with less limitation of movement at a nominal significance level value (p = 0.0025) almost strong enough to correct for testing 22 haplotype blocks. CONCLUSION: If confirmed, the current results may suggest that a common haplotype in the GABA-A beta1 subunit acts like an "endogenous muscle relaxant" in an individual with subacute sciatica. Similar methods might be applied a larger set of genes in animal models and human laboratory and clinical studies to understand the causes and prevention of pain-related reduction in movement.

A clinical genetic method to identify mechanisms by which pain causes depression and anxiety.

BACKGROUND: Pain patients are often depressed and anxious, and benefit less from psychotropic drugs than pain-free patients. We hypothesize that this partial resistance is due to the unique neurochemical contribution to mood by afferent pain projections through the spino-parabrachial-hypothalamic-amygdalar systems and their projections to other mood-mediating systems. New psychotropic drugs for pain patients might target molecules in such brain systems. We propose a method to prioritize molecular targets by studying polymorphic genes in cohorts of patients undergoing surgical procedures associated with a variable pain relief response. We seek molecules that show a significant statistical interaction between (1) the amount of surgical pain relief, and (2) the alleles of the gene, on depression and anxiety during the first postoperative year. RESULTS: We collected DNA from 280 patients with sciatica due to a lumbar disc herniation, 162 treated surgically and 118 non-surgically, who had been followed for 10 years in the Maine Lumbar Spine Study, a large, prospective, observational study. In patients whose pain was reduced >25% by surgery, symptoms of depression and anxiety, assessed with the SF-36 Mental Health Scale, improved briskly at the first postoperative measurement. In patients with little or no surgical pain reduction, mood scores stayed about the same on average. There was large inter-individual variability at each level of residual pain. Polymorphisms in three pre-specified pain-mood candidate genes, catechol-O-methyl transferase (COMT), serotonin transporter, and brain-derived neurotrophic factor (BDNF) were not associated with late postoperative mood or with a pain-gene interaction on mood. Although the sample size did not provide enough power to persuasively search through a larger number of genes, an exploratory survey of 25 other genes provides illustrations of pain-gene interactions on postoperative mood--the mu opioid receptor for short-term effects of acute sciatica on mood, and the galanin-2 receptor for effects of unrelieved post-discectomy pain on mood one year after surgery. CONCLUSION: Genomic analysis of longitudinal studies of pain, depression, and anxiety in patients undergoing pain-relieving surgery may help to identify molecules through which pain alters mood. Detection of alleles with modest-sized effects will require larger cohorts.

The effect of surgical and nonsurgical treatment on longitudinal outcomes of lumbar spinal stenosis over 10 years.

OBJECTIVES: To assess the relative effect of initial surgical and nonsurgical treatment on longitudinal outcomes of patients with lumbar spinal stenosis over a 10-year follow-up period. DESIGN: A prospective observational cohort study. SETTING: Enrollment from community-based specialist practices throughout Maine. PARTICIPANTS: One hundred forty-four patients with lumbar spinal stenosis who had at least one follow-up: 77 initially treated surgically and 67 initially treated nonsurgically. INTERVENTION: Initial surgical or nonsurgical treatment. MEASUREMENTS: Clinical data were obtained at baseline and outcomes followed at regular intervals over 10 years with mailed questionnaires including patient-reported symptoms of back pain, leg symptoms, back-specific functional status, and satisfaction. Longitudinal data were analyzed using general linear mixed models. In addition to treatment (initial surgical or nonsurgical care), time period, and the interaction between treatment and time, the models included baseline score, patient age and sex, and a time-varying general health status score. The effects of these covariates in explaining differences between treatment groups were also examined. The effect of subsequent surgical procedures was assessed using different analysis strategies. RESULTS: The 10-year rate of subsequent surgical procedures was 23% and 38% for patients initially treated surgically and nonsurgically, respectively, and the overall 10-year survival rate was 69%. Patients undergoing initial surgical treatment had worse baseline symptoms and functional status than those initially treated nonsurgically. For all outcomes and at each time point, surgically treated patients reported greater improvement in symptoms and functional status and higher satisfaction scores, indicative of better outcomes, than nonsurgically treated patients. However, the relative magnitude of the benefit diminished over time such that the relative differences for low back pain and satisfaction were no longer significant over long-term follow-up (both P=.08 for treatment effect between 5 and 10 years after controlling for covariates). Regardless of initial treatment received, patients undergoing subsequent surgical procedures reported less improvement in outcomes over time than patients who did not undergo subsequent procedures, but the relative differences between treatment groups were similar in analyses that controlled for outcomes after subsequent procedures. CONCLUSION: After controlling for covariates, patients initially treated surgically demonstrated better outcomes on all measures than those initially treated nonsurgically. Although outcomes of initial surgical treatment remained superior over time, the relative benefit of surgery diminished in later years, especially for low back pain and satisfaction. Patients undergoing subsequent surgery had worse outcomes regardless of initial treatment received, but excluding them did not change overall treatment group comparisons. The analytical methods described may be helpful in the design and analysis of future studies comparing treatment outcomes for patients with lumbar spinal stenosis.

Criteria for approximating certain microgravity flow boiling characteristics in Earth gravity.

The forces governing flow boiling, aside from system pressure, are buoyancy, liquid momentum, interfacial surface tensions, and liquid viscosity. Guidance for approximating certain aspects of the flow boiling process in microgravity can be obtained in Earth gravity research by the imposition of a liquid velocity parallel to a flat heater surface in the inverted position, horizontal, or nearly horizontal, by having buoyancy hold the heated liquid and vapor formed close to the heater surface. Bounds on the velocities of interest are obtained from several dimensionless numbers: a two-phase Richardson number, a two-phase Weber number, and a Bond number. For the fluid used in the experimental work here, liquid velocities in the range U = 5-10cm/sec are judged to be critical for changes in behavior of the flow boiling process. Experimental results are presented for flow boiling heat transfer, concentrating on orientations that provide the largest reductions in buoyancy parallel to the heater surface, varying +/-5 degrees from facing horizontal downward. Results are presented for velocity, orientation, and subcooling effects on nucleation, dryout, and heat transfer. Two different heater surfaces were used: a thin gold film on a polished quartz substrate, acting as a heater and resistance thermometer, and a gold-plated copper heater. Both transient and steady measurements of surface heat flux and superheat were made with the quartz heater; only steady measurements were possible with the copper heater. R-113 was the fluid used; the velocity varied over the interval 4-16cm/sec; bulk liquid subcooling varied over 2-20 degrees C; heat flux varied over 4-8W/cm(2).

Longer distal motor latency predicts better outcomes of carpal tunnel release.

The association of preoperative median nerve distal latencies with surgical outcomes of carpal tunnel release is unclear. A total of 109 surgically treated workers with carpal tunnel syndrome across the state of Maine completed questionnaires assessing preoperative levels of symptom and functional limitations and general physical health (SF-12). A second questionnaire assessed the 6-month postoperative outcomes of symptom severity, functional limitations, and satisfaction with surgery. Univariate analyses indicated that longer preoperative distal motor and sensory latencies were associated with less postoperative levels of symptom, less postoperative functional limitations, and more satisfaction with surgery. The associations persisted in multiple linear regression analysis; however, better general health preoperatively was a better predictor of favorable outcomes. The results suggest that workers with prolonged preoperative distal motor latencies and who are in good general health preoperatively have a higher rate of successful carpal tunnel release surgery.

Do osteopathic physicians differ in patient interaction from allopathic physicians? An empirically derived approach.

Colleges of osteopathic medicine teach osteopathic principles, which provide a different approach to and interaction with patients than principles taught in allopathic medical schools. The authors examined whether osteopathic primary care physicians' interactions with patients reflect the principles of osteopathic medicine when compared with allopathic physicians' interactions. The principles of osteopathic medicine were adapted to elements that could be measured from an audio recording. This 26-item index was refined with two focus groups of practicing osteopathic physicians. Fifty-four patient visits to 11 osteopathic and 7 allopathic primary care physicians in Maine for screening physicals, headache, low back pain, and hypertension were recorded on audiotape and were dual-abstracted. When the 26-item index of osteopathic principles was summed, the osteopathic physicians had consistently higher scores (11 vs. 6.9; P = .01) than allopathic physicians, and visit length was similar (22 minutes vs. 20 minutes, respectively). Twenty-three of the 26 items were used more commonly by the osteopathic physicians. Osteopathic physicians were more likely than allopathic physicians to use patients' first names; explain etiologic factors to patients; and discuss social, family, and emotional impact of illnesses. In this study, osteopathic physicians were easily distinguishable from allopathic physicians by their verbal interactions with patients. Future studies should replicate this finding as well as determine whether it correlates with patient outcomes and satisfaction.

Orientation and related buoyancy effects in low-velocity flow boiling.

This work is an extension of experimental results reported previously, which might provide design guidance for approximating certain aspects of the flow boiling process in microgravity but taking place in Earth gravity. In that research the buoyancy effects on the bubble dynamics were minimized by the imposition of a liquid velocity parallel to a flat heater surface in the inverted horizontal position, or nearly horizontal (within +/-5 degrees ), thus holding the heated liquid and vapor formed close to the heater surface. For the fluid used, liquid velocities in the range U= 5-10 cm/s were judged to be critical for changes in the behavior of the flow boiling process. Using the hydraulic diameter of the rectangular duct used, with the heater surface embedded in one side, this velocity range gives rise to flow Reynolds numbers on the order of 4400-8800. It was subsequently judged to be of interest to extend the range of orientation of the flat heater surface relative to gravity to the full circular range of 0-360 degrees, in increments of 45 degrees, and the results of this work are presented here. A solid massive copper heater with a gold-plated boiling heat transfer surface 19 x 38 mm in size, previously used for critical heat flux measurements with boiling, provided a near-uniform surface temperature. Only steady measurements of heat flux and surface temperature were possible with the copper heater. R-113 was the fluid used; the velocity was varied over the interval of 4-28 cm/s; bulk liquid subcooling was varied over 5-11 degrees C; and heat flux varied over 0-10 w/cm(2).

Symptoms of distress as prospective predictors of pain-related sciatica treatment outcomes.

Prior studies evaluating predictors of pain-related outcomes following treatment for sciatica have been limited by methodological problems, including retrospective study design, use of unvalidated outcome measures, and short-term follow-up periods. Despite these limitations, some reports have suggested that symptoms of psychological distress may predict individual differences in pain treatment-related outcomes (e.g., higher levels of depressive and anxious symptomatology are associated with greater pain and disability after treatment). In this study, we sought to determine whether acute symptoms of depression and anxiety were prospectively associated with treatment outcomes over a 3-year follow-up period in surgically treated and non-surgically treated patients with sciatica. Patients were recruited from the practices of community-based physicians throughout the state of Maine, and underwent in-person baseline assessments, with mailed follow-up questionnaires at 3, 6, 12, 24, and 36 months. Study outcomes included patient-reported symptoms of pain and disability. For each outcome variable, we examined whether baseline mood (i.e., mood assessed prior to the initiation of treatment), as well as mood at the immediately preceding assessment point, prospectively predicted outcomes over 3 years in multivariate repeated-measures analyses. In most analyses, symptoms of depression and anxiety, both at baseline and at the preceding time point, were significant independent predictors of worse pain and function after controlling for relevant covariates. Collectively, elevated distress appears to be a significant risk factor for reduced treatment benefit (i.e., less improvement in pain and disability) over short and medium-term follow-up periods in patients with sciatica. Future research should determine whether the prospective identification and treatment of patients with high levels of distress (a "yellow flag") is associated with improved treatment outcomes.

The impact of disability compensation on long-term treatment outcomes of patients with sciatica due to a lumbar disc herniation.

STUDY DESIGN: Prospective, observational study. OBJECTIVE: To compare long-term disability and health-related quality of life outcomes of individuals receiving or not receiving workers' compensation at baseline evaluation. SUMMARY OF BACKGROUND DATA: Disability compensation has long been associated with poor clinical outcomes. However, most studies have assessed outcomes over short time periods using unvalidated measures without controlling for potential confounders. METHOD: Patients with sciatica due to a herniated lumbar disc were treated by physicians in community based orthopedic, neurosurgical, and occupational medicine practices throughout Maine. Outcomes assessed included disability compensation and work status, and health-related quality of life, controlling for initial treatment received and factors predicting initial workers' compensation status. RESULTS: Among 440 eligible patients, 172 (86%) receiving workers' compensation and 222 (92%) not receiving workers' compensation at baseline evaluation completed at least one follow-up between 5 and 10 years (80% completed 10-year). Baseline demographics, past back history, imaging findings, symptoms, functional status, and expectations significantly differed according to the patient's baseline workers' compensation status. After 5-10 years, most patients, regardless of baseline workers' compensation status (yes or no), were not receiving disability compensation (83% vs. 96%, respectively) and were employed (78% for both groups). However, workers' compensation patients were significantly more likely to be receiving disability compensation and had worse symptoms, functional status, and satisfaction outcomes. Outcome differences diminished in magnitude after controlling for baseline differences among patients receiving workers' compensation or not but continued to favor those not initially receiving workers' compensation. Initial treatment received, either surgical or nonsurgical, did not influence these findings. CONCLUSIONS: Long-term employment and disability outcomes were favorable for most patients with a disc herniation, regardless of initial workers' compensation status. However, individuals initially receiving workers' compensation had worse disability and quality of life outcomes compared to individuals not receiving workers' compensation. Despite these differences, long-term work outcomes were similarly favorable.

Long-term outcomes of surgical and nonsurgical management of lumbar spinal stenosis: 8 to 10 year results from the maine lumbar spine study.

STUDY DESIGN: A prospective observational cohort study. OBJECTIVE: To assess long-term outcomes of patients with lumbar spinal stenosis treated surgically or nonsurgically. SUMMARY OF BACKGROUND DATA: The relative benefit of various treatments for lumbar spinal stenosis is uncertain. Surgical treatment has been associated with short-term improvement, but recurrence of symptoms has been documented. Few studies have compared long-term outcomes of surgical and nonsurgical treatments. METHODS: Patients recruited from the practices of orthopaedic surgeons, neurosurgeons, and occupational medicine physicians throughout Maine had baseline interviews with follow-up questionnaires mailed at regular intervals over 10 years. Clinical data were obtained at baseline from a physician questionnaire. Most patients initially undergoing surgery had a laminectomy without fusion performed. Outcomes including patient-reported symptoms of leg and back pain, functional status, and satisfaction were assessed at 8- to 10-year follow-up. Primary analyses were based on initial treatment received with secondary analyses examining actual treatment received by 10 years. RESULTS: Of 148 eligible consenting patients initially enrolled, 105 were alive after 10 years (67.7% survival rate). Among surviving patients, long-term follow-up between 8 and 10 years was available for 97 of 123 (79%) patients (including 11 patients who died before the 10-year follow-up but completed a 8 or 9 year survey); 56 of 63 (89%) initially treated surgically and 41 of 60 (68%) initially treated nonsurgically. Patients undergoing surgery had worse baseline symptoms and functional status than those initially treated nonsurgically. Outcomes at 1 and 4 years favored initial surgical treatment. After 8 to 10 years, a similar percentage of surgical and nonsurgical patients reported that their low back pain was improved(53% vs. 50%, P = 0.8), their predominant symptom (either back or leg pain) was improved (54% vs. 42%, P = 0.3), and they were satisfied with their current status (55% vs. 49%, P = 0.5). These treatment group findings persisted after adjustment for other determinants of outcome in multivariate models. However, patients initially treated surgically reported less severe leg pain symptoms and greater improvement in back-specific functional status after 8 to 10 years than nonsurgically treated patients. By 10 years, 23% of surgical patients had undergone at least one additional lumbar spine operation, and 39% of nonsurgical patients had at least one lumbar spine operation. Patients undergoing subsequent surgical procedures had worse outcomes than those continuing with their initial treatment. Outcomes according to actual treatment received at 10 years did not differ because individuals undergoing additional surgical procedures had worse outcomes than those continuing with their initial treatment. CONCLUSIONS: Among patients with lumbar spinal stenosis completing 8- to 10-year follow-up, low back pain relief, predominant symptom improvement, and satisfaction with the current state were similar in patients initially treated surgically or nonsurgically. However, leg pain relief and greater back-related functional status continued to favor those initially receiving surgical treatment. These results support a shared decision-making approach among physicians and patients when considering treatment options for lumbar spinal stenosis.

Long-term outcomes of surgical and nonsurgical management of sciatica secondary to a lumbar disc herniation: 10 year results from the maine lumbar spine study.

STUDY DESIGN: A prospective cohort study. OBJECTIVE: To assess 10-year outcomes of patients with sciatica resulting from a lumbar disc herniation treated surgically or nonsurgically. SUMMARY OF BACKGROUND DATA: There is little information comparing long-term outcomes of surgical and conservative therapy of lumbar disc herniation in contemporary clinical practice. Prior studies suggest that these outcomes are similar. METHODS: Patients recruited from the practices of orthopedic surgeons, neurosurgeons, and occupational medicine physicians throughout Maine had baseline interviews with follow-up questionnaires mailed at regular intervals over 10 years. Clinical data were obtained at baseline from a physician questionnaire. Primary analyses were based on initial treatment received, either surgical or nonsurgical. Secondary analyses examined actual treatments received by 10 years. Outcomes included patient-reported symptoms of leg and back pain, functional status, satisfaction, and work and disability compensation status. RESULTS: Of 507 eligible consenting patients initially enrolled, 10-year outcomes were available for 400 of 477 (84%) surviving patients; 217 of 255 (85%) treated surgically, and 183 of 222 (82%) treated nonsurgically. Patients undergoing surgery had worse baseline symptoms and functional status than those initially treated nonsurgically. By 10 years, 25% of surgical patients had undergone at least one additional lumbar spine operation, and 25% of nonsurgical patients had at least one lumbar spine operation. At 10-year follow-up, 69% of patients initially treated surgically reported improvement in their predominant symptom (back or leg pain) versus 61% of those initially treated nonsurgically (P = 0.2). A larger proportion of surgical patients reported that their low back and leg pain were much better or completely gone (56% vs. 40%, P = 0.006) and were more satisfied with their current status (71% vs. 56%, P = 0.002). Treatment group differences persisted after adjustment for other determinants of outcome in multivariate models. Change in the modified Roland back-specific functional status scale favored surgical treatment, and the relative benefit persisted over the follow-up period. Despite these differences, work and disability status at 10 years were comparable among those treated surgically or nonsurgically. CONCLUSIONS: Surgically treated patients with a herniated lumbar disc had more complete relief of leg pain and improved function and satisfaction compared with nonsurgically treated patients over 10 years. Nevertheless, improvement in the patient's predominant symptom and work and disability outcomes were similar regardless of treatment received. For patients in whom elective discectomy is a treatment option, an individualized treatment plan requires patients and their physicians to integrate clinical findings with patient preferences based on their symptoms and goals.

The Maine-Seattle back questionnaire: a 12-item disability questionnaire for evaluating patients with lumbar sciatica or stenosis: results of a derivation and validation cohort analysis.

STUDY DESIGN: Analysis of health-related quality of life data obtained from a prospective cohort study of patients with sciatica due to an intervertebral disc herniation or lumbar spinal stenosis. OBJECTIVE: To derive and validate a shortened version of a previously validated 23-item modification of the Roland-Morris Disability Questionnaire. SUMMARY OF BACKGROUND DATA: For patients with low back pain, improving health-related quality of life is often the main goal of therapy. The Roland-Morris Disability Questionnaire is one of the best validated and most frequently used back-specific functional status measures. A shortened version may permit more widespread use in clinical and research settings. METHODS: Data from 507 patients with sciatica enrolled in the Maine Lumbar Spine Study were used to derive a shortened version of a 23-item modification of the original Roland-Morris Disability Questionnaire using qualitative and cluster analysis techniques. The internal consistency, construct validity, reproducibility, and responsiveness in detecting change over a 3-month period for a new 12-item scale was compared to the original 23-item scale. The 12-item scale was then validated in an independent cohort of 148 patients with lumbar spinal stenosis. RESULTS: Internal consistency was very good but modestly lower for the 12-item instrument compared to the 23-item original scale. Reproducibility over a 3-month interval was good and did not differ between the 12-item and original scale. Findings from the validation cohort were similar or better than the derivation cohort. A high degree of construct validity with patient-reported symptoms was demonstrated for the 12-item and original scales. The responsiveness and interpretability of the 12-item scale over 3 months was excellent and comparable to the original scale. Responsiveness assessed in patients with lumbar spinal stenosis in the independent validation cohort showed consistent findings compared to patients with a disc herniation in the derivation cohort. CONCLUSIONS: This short, simple, self-administered 12-item back-specific functional status questionnaire performed extremely well in comparison with the original 23-item scale. If validated in additional study populations, this new questionnaire may be useful in the clinical setting as a way for providers to prospectively compare their outcomes of care to other patient populations, and to study treatment effectiveness.