A clinical genetic method to identify mechanisms by which pain causes depression and anxiety
- Mitchell B Max1Email author,
- Tianxia Wu2,
- Steven J Atlas3,
- Robert R Edwards4,
- Jennifer A Haythornthwaite4,
- Antonella F Bollettino1, 6,
- Heather S Hipp1, 6,
- Colin D McKnight1, 6,
- Inge A Osman1, 6,
- Erin N Crawford1, 6,
- Maryland Pao5,
- Jemiel Nejim1, 6, 7,
- Albert Kingman2,
- Daniel C Aisen1, 6,
- Michele A Scully1, 6,
- Robert B Keller8,
- David Goldman6 and
- Inna Belfer1, 6
© Max et al; licensee BioMed Central Ltd. 2006
Received: 06 March 2006
Accepted: 19 April 2006
Published: 19 April 2006
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.
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.
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.
Decades of cross-sectional surveys have shown that chronic pain, depression, and anxiety often coexist. However, data derived from a single time point is consistent with diverse causal links  e.g., that (1) pain causes mood or anxiety disorders; (2) these affective disorders increase pain; (3) a common biological predisposition underlies both pain and affective disorders; or (4) pain or affective disorder do not directly cause the other but frequently associate with a "true" causal variable such as somatization, occupational or social stress, or ineffective coping style.
Recent reports have more directly examined the direction of causation by assessing pain and mood over time in thousands of individuals. In primary care practices and diverse occupational settings, mood or anxiety disorder at baseline predicts the subsequent onset of any chronic pain syndrome ; chronic widespread pain ; or chronic low back , neck , abdominal  or shoulder, arm, or knee pain . Chronic pain at baseline predicts later anxiety or depressive symptoms . Treatment of depression in patients with osteoarthritis reduces pain one year later .
Although these studies have strengthened the evidence for bidirectional causal links between pain and mood, the designs are not suited for inferring physiological mechanisms. A crucial limitation is that idiopathic "central pain amplification" or "multisomatoform" conditions  were mixed with conditions in which a measurable structural injury dominates the pain phenotype. To optimize mechanistically-oriented clinical studies one should collect relatively homogeneous patient samples and assess putative physiological mediators. Predominantly structurally determined pains may have a different causal relationship to mood than multisomatoform pains. Cohorts with pain caused by common and measurable structural lesions like acute surgical wounds or degenerative joint disease would be expected to resemble the general population in prevalence of previous affective disorder. In patients with multisomatoform pains, however, lifetime prevalence of depressive and anxiety disorders is triple that of the general population . In these patients, some feature of brain physiology may predispose to both pain and mood disorders, and it may be more challenging to tease out causal relations between pain and affect.
An economical approach to searching for these molecular mediators is to piggyback on existing longitudinal studies of painful diseases caused by definite structural lesions that include serial pain measurements and standard quality of life questionnaires. Most such questionnaires assess depression and anxiety. Perturbations of affect on these measures, although not diagnostic of clinical disorder, provide a convenient assessment of these negative emotions. To pursue this approach, we collected DNA from former participants in a large study of surgical and non-operative treatment of sciatica caused by intervertebral disc herniation [14, 15]. Discectomy variably relieves patient's pain with effects occurring soon after a uniform time point, creating a quasi-experimental design for testing the effects of pain on later mood. In this sciatica study and others ( and RR Edwards et al., in preparation), baseline mood accounts for only a small component of the pain relief afforded by discectomy, so one can get a clearer look at the effect of pain on later mood.
In this paper we present a descriptive analysis of mood during the year following surgery, and illustrate a method for detecting genetic polymorphisms that predispose to pain-influenced mood and or anxiety disorders. This approach adapts a gene-environment interaction model that has been proposed to facilitate the detection of genes that predispose to psychiatric disorders in the presence of specific quantified stressors, such as the interaction of serotonin transporter polymorphisms and life stress to influence depression , and of monoamine oxidase polymorphism and parental abuse to influence conduct disorder . In the current paper, we are defining the lumbar spine, nerve root, and its pain input to the central nervous system as part of the "environment" in which the brain generates an affective state.
Participants were members of the sciatica group of the Maine Lumbar Spine Study (MLSS ), a prospective cohort study conducted by approximately half of Maine's orthopedists and neurosurgeons who actively treat spine disease . Patients were enrolled between 1990 and 1992, and surgical or nonsurgical treatment was determined by clinician judgment and patient preference. Patients completed questionnaires at study entry, after 3, 6, and 12 months, and then annually through year 10. Individuals who initially embarked on nonsurgical treatment but elected surgery at or before month 6 were included in the surgical group because recent data was available to serve as a baseline. Patients who crossed over to surgery after month 6 were not included in this study because the "baseline" may have occurred 6–12 months preoperatively. After completion of the 10-year study, the NIDCR and MLSS investigators developed a collaboration to collect DNA from consenting patients, under a protocol approved by the NIDCR Institutional Review Board. Of the 277 patients treated surgically, 162 contributed DNA. We also collected DNA from 118 patients treated nonsurgically and included them in our analysis of pain and mood scores at baseline. We did not include nonsurgical patients in genetic analyses of late mood change because this group was smaller, often lacked confirmatory spine imaging studies, and was probably more heterogeneous with regard to underlying pathology and treatment. Moreover, their changes in pain during the early months of the study were much smaller and more gradual than the surgical group . This temporal course does not offer as clear an experimental model as the abrupt one-time surgical perturbation of pain.
The primary measure of pain for this pain-mood study was the Bodily Pain intensity item on the Short-Form-36 (SF-36) quality of life instrument  at baseline, 3, and 6 months. Patients responded to the question "How much bodily pain have you had during the past 4 weeks?" by choosing from "very severe," "severe," "moderate," "mild," "very mild," and "none." This has been a standard scale used in analgesic clinical trials for more than 50 years. As part of the SF-36, the scale has been shown to be reliable and to be sensitive to changes in pain produced by joint replacement .
Depression and anxiety measures
The mood measure was the Mental Health (MH) subscale of the SF-36 health survey. This subscale includes three Likert scale items about the frequency in the previous month of depressed vs. happy moods, and two items about the frequency of anxious vs. peaceful moods, each with 6 possible responses ranging from "all of the time" to "none of the time." Because depressive and anxious symptoms usually coexist in medically ill patients, the developers of the scale combined the items into a single score, which correlates closely with DSM-IV psychiatric diagnoses .
Choice of mood candidate genes
The met allele at the val158met polymorphism in the catechol-O-methyltransferase gene (COMT) reduces the ability of the enzyme to metabolize catecholamines, and has been associated with variability in an experimentally evoked pain threshold and unpleasant pain-related affect  and with anxiety disorders .
The short allele in the intron 2 tandem repeat polymorphism of the serotonin transporter gene (SLC6A4) lowers the level of expression of the transporter protein  and alters cerebral processing of fear stimuli . This allele has been associated with neuroticism and the risk of lifetime major depression ; and with depression related to stressful life events .
The met allele of the val66met polymorphism in the brain-derived neurotrophic factor gene (BDNF) lowers activity-induced secretion of this trophic factor. The met allele has been associated with geriatric depression  and anxious temperament .
In addition to the a priori selection of three putative mood genes, we carried out exploratory analyses of polymorphisms in 25 additional genes that we had previously genotyped for pain genetics studies. We recognized that correction for multiple testing a cohort of several hundred patients  might render these analyses suitable only for generating hypotheses for future study. The genes were: galanin; galanin receptors 1, 2, and 3; interleukin (IL)-1α and β; IL-1 receptor antagonist; IL-6; IL-10; IL-13; tumor necrosis factor α; adrenergic receptors 2A, 2B, and 2C; mu opioid receptor; glial cell derived neurotrophic factor (GDNF); tyrosine hydroxylase; kainate-3 glutamate receptor; downstream regulatory element antagonistic modulator (DREAM); bradykinin receptors B1 and B2; chemokine receptor 5; purinergic receptor ligand-gated ion channel P2X4; calcium channel, voltage-dependent, α2/δ subunit 2; and chemokine (C-X-C motif) ligand 5 (ENA-CXCL5).
The physical position and frequency of minor alleles (>0.05) from a commercial database (Celera Discovery System, CDS) were used to select SNPs spaced at 2–5 kb intervals throughout each gene region plus 4–6 kb upstream and 4–6 kb downstream of each gene. Allele frequencies of markers and their locations in the genes described in the Results appear in Additional file 1.
Genomic DNA was extracted from lymphoblastoid cell lines and diluted to a concentration of 5 ng/μl. Two-μl aliquots were dried in 384-well plates.
Polymerase Chain Reaction (PCR) amplification
Genotyping was performed by the 5' nuclease method  using fluorogenic allele-specific probes. Oligonucleotide primer and probe sets were designed based on gene sequences from the CDS. Reactions were performed in a 5 μl volume containing 2.25 μl TE (ABI Assays On Demand) or 2.375 μl TE (ABI Assays By Design), 2.5 μl PCR Master Mix (ABI, Foster City, CA), 10 ng genomic DNA, 900 nM of each forward and reverse primer, and 100 nM of each reporter and quencher probe. DNA was incubated at 50°C for 2 min and at 95°C for 10 min, and amplified on an ABI 9700 device for 40 cycles at 92°C (ABI Assays on Demand) or 95°C (ABI Assays By Design) for 15 s and 60°C for1 min. Allele-specific signals were distinguished by measuring endpoint 6-FAM or VIC fluorescence intensities at 508 nm and 560 nm, respectively, and genotypes were generated using Sequence Detection System V.1.7 (ABI). Genotyping error rate was directly determined by re-genotyping 25% of the samples, randomly chosen, for each locus. The overall error rate was <0.005. Genotype completion rate was 0.96.
Inference of haplotypes
Haplotype phases – i.e., how the directly measured SNP alleles were distributed into two chromosomes in each patient – were inferred by the expectation-maximization (EM) algorithm (SAS/Genetics, Cary, North Carolina, USA).
We specified as our primary analysis the test of the interaction between a (1) particular genetic polymorphism and (2) the mean bodily pain at the 3 and 6 month postoperative time points in predicting the SF-36 MH at 12 months. The secondary analysis was the same analysis carried out on the baseline SF-36 MH score, examining the effect of genotype, baseline pain score, and their interaction. This latter analysis included patients who elected non-surgical treatment as well. If there is no interaction, the functions describing bodily pain as a contributor to mood (i.e., regression of mood on bodily pain) are the same across the different SNP genotypes. The initial selection of covariates from the MLSS dataset was based upon the chronic pain literature and winnowed by modeling of the data prior to analyzing for genotypes. We pre-specified the additive model as most plausible for the effects of 0, 1, or 2 copies of a polymorphism on mood but also carried out analyses of dominant and recessive models.
Relation between pain and mood
Baseline pain and mood
Contributions of the variables to baseline SF-36 Mental Health scores
Correlation (r) with
Baseline bodily pain
Length of episode
R2 from the model including all above variables
Time course of mood after successful or unsuccessful discectomy
surgical patients provided baseline and 3 month questionnaires and DNA. We divided these patients into four groups according to the percent reduction they reported on the 0–5 point SF-36 bodily pain intensity from pre-surgical baseline to the first postoperative observation at 3 months: 75–100%, 50–75%, 25–50%, and ≤ 25%. Fig 3a (top left) shows the time course of bodily pain intensity over 3 years for the four quartiles. Fig 3b (top right) shows the time course of SF-36 MH; and Figs 3c and 3d (bottom) break this down into the items of the SF-36 MH relating to depression and anxiety, considered separately.
The baseline points in Figs 3b–d show little difference in mood between the groups at baseline, suggesting that factors other than baseline mood account for most of the large inter-individual differences in surgical relief of pain. At the three-month time point, the three groups of patients with the greatest reduction of pain from baseline reported an immediate improvement in mood. Surprisingly, the quartile of patients with the least improvement in pain reported, on average, a small improvement in mood from 6 to 24 months.
Contributions of the variables to 1-year SF-36 Mental Health scores
Correlation (r) with
1 year SF36-MH
Mean bodily pain at 3 and 6 month
Baseline bodily pain
1 year SF36-MH
3 or 6 month
R2 from the model including all above variables
Genetic analysis of relation between pain and mood
Baseline mood scores
These data illustrate an approach to investigating causal relationships among pain, mood, and genetic polymorphisms patients who undergo a surgical procedure that produces variable degrees of pain relief. The degree of surgical relief of pain at the first two postoperative time points explains 20% of the variance in mood at 1 year (p <0.0001), but there is also additional inter-individual variation in mood (Fig. 4), some of which may result from inherited genetic variation. Because surgical relief of pain is a large abrupt change occurring at a fixed time point, this experimental design is well-suited for studying physiological events over time.
Although the galanin-2 receptor and mu opioid receptor are plausible candidates to mediate effects of pain on mood, and showed graphical patterns consistent with a pain-gene interaction, we cannot prove these specific effects because of our modest sample size. Although this was the largest prospective study of pain from a uniform lesion that we could identify at the outset of the project, a several hundred patient cohort does not provide sufficient power to correct for the tests of dozens of genes and multiple analytical models unless the relative risk conferred by the polymorphism is more than 2.5, larger than most common polymorphisms for which a link to medical diseases have been established . However, major medical centers perform thousands of many types of pain-relieving operations each year, making possible more powerful searches of this type. The number of simultaneous statistical tests supported by candidate studies increases steeply with sample size. For example, just an eight-fold increase in N permits a million-fold increase in independent tests, sufficient to examine the genome in detail .
Another limitation of this study is the lack of clinical diagnosis of anxiety or depressive disorder. Across cohorts of patients, the SF-36 MH subscale correlates strongly with research psychiatric diagnoses and changes with successful treatment, but cannot provide individual diagnoses . The SF-36 pain measure does not have optimal precision either, for estimating the actual pain level over many months. Bellamy et al.  found that a 0–10 point numerical scale and 100 mm VAS were more sensitive than a 5-category pain intensity scale, while Jensen and McFarland  reported that the average of 7 pain measurements at different times gives a better estimate of actual pain than 1–2 measurements. Quality of life researchers are currently seeking to improve diagnostic precision with computerized adaptive algorithms that choose items to hone in on each subject's response range.
It is possible that some of patients with the most severe mood disorder may have refused to return questionnaires or contribute DNA, lessening the study's power to examine this link. Another possible gap is that in the 16 years since this study was begun, pain psychologists learned that styles of coping with pain and environmental stressors are as important determinants of many pain outcomes as mood. This study did not include detailed measurements of pain catastrophizing , pain self-efficacy, and stressors in the work and personal environment , which one might consider for a new prospective study of pain and mood.
While we cannot exclude a false positive in this study, the possible mood mediating effects of the galanin-2 and mu opioid receptor polymorphisms should be studied in additional cohorts of patients with pain. The neuropeptide galanin is widely expressed in the central nervous system, including areas regulating emotionality . It has been implicated in a wide range of physiological functions including pain control and cognition and in behaviors such as anxiety and depression . We recently reported that haplotypes in the galanin gene were associated with anxiety-associated alcoholic phenotypes in humans . The three galanin receptor subtypes, GALR1, GALR2, and GALR3 , are widely distributed in mood-related brain areas such as hypothalamus, central amygdaloid nucleus, and thalamus  and may mediate anxiety-associated behavior . No common functional polymorphism has yet been identified in the human GALR2 gene. There is strong linkage disequilibrium (LD) between all SNP pairs we genotyped, and on the related chromosome region (HapMap; http://www.hapmap.org). Although the SNPs used in our study are not located within GALR2, they are within 5 kb of the start and end sites of the gene (Fig 4), and are within a haplotype block encompassing GALR2, its regulatory elements, and neighboring genes. The nominally significant pain-gene interaction on mood of three out of four SNPs in this region and the haplotype may reflect the contribution of a functional allele in GALR2 or the genes located nearby.
The mu opioid receptor is also a plausible candidate to mediate between pain and mood. The endogenous opioid system and μ-opioid receptors modulate affective behaviors  as well as affective components of acute pain . Opioid treatment of chronic pain is often accompanied by striking improvements in mood . Although the human mu opioid receptor gene (OPRM1) has polymorphisms that affect receptor function and are associated with some behavioral phenotypes , no associations with depression and anxiety disorders have yet been reported . The three OPRM1 SNPs most closely associated with pain-related mood scores in our study are in high linkage disequilibrium and in the same haploblock, which also includes the previously reported functional non-synonymous SNP Asn40Asp (rs1799971). However, the latter SNP was not associated with mood scores. Therefore we assume that the association signal, if replicated, could be attributable to another functional allele that is still unknown.
In this study, we have tested mood effects of genes that we had already genotyped based on their involvement in chronic pain processing. For future studies on pain-mood interaction, one might select additional candidate genes reportedly associated with anxiety and depression; e.g., the genes for corticotropin-releasing hormone (CRH) , the adenosine A(2A) receptor , the dopamine D4 receptor , and tryptophan hydroxylase .
It is interesting that among patients in the quartile with the least surgical pain relief, mood did not deteriorate, and actually improved from 6 months on. Within this quartile of patients (Fig. 4), for example, pain levels at 24 months after surgery were equivalent to the presurgery levels, but mood at 24 months was considerably improved from baseline. It would be interesting to examine individual differences in resilience factors, including genetic resilience factors, that are associated with improvements in mood in the face of the surgical failure to relieve pain.
The preceding analysis of gene effects mediating mood responses to unrelieved pain in surgical patients is a gene × environment (G × E) interaction study. Thus far, the most widely cited examples of G × E interactions on behavioral endpoints [17, 18] involve an environmental stress. Although our most suggestive results for the genes we examined pertained to unique pain-gene interactions on mood, the same analytic method might help to identify other genes that have a general effect on mood, demonstrated by a main effect in the regression. A potential advantage of this study design is that patients are all subject to a similar stress – several months of a painful condition followed by major surgery – and then experience variable levels of residual pain, a stressor that can be well-quantified and corrected for in the analysis. Without detailed measurements of environmental stress, it may be difficult to identify genes for depression or anxiety. For example, although twin studies suggest that the heritability of unipolar major depression disorder is 40–50%  it has been difficult to replicate candidate gene associations, possibly because the environmental circumstances triggering depression are so varied . A major surgical procedure may provide a somewhat uniform stressful situation. Within this setting, the two factor analysis shown above may remove a large amount of variance in late mood due to pain, increasing sensitivity to a main effect of a genetic polymorphism involved in general mood-regulating mechanisms not specific to patients with pain.
It is possible that alternative statistical methods may better detect "mood" or "pain-mood" genes in the types of surgical cohort studies illustrated above. For example, patients without any pain might be excluded from the pain-mood analyses, or different time-points might be chosen for the pain and mood variables. The relative merits of alternative methods can be compared more persuasively once a robust gene effect is identified to use as a gold standard.
A better understanding of the specific mechanisms linking pain and mood may open up a set of new interventions to decrease the morbidity of chronic pain conditions. Basic science studies in animals [13, 50] including microarray search methods are likely to yield a long list of candidates. We have demonstrated a simple method to search for genetic polymorphisms that contribute to interindividual variation in the manner in which pain produces depression or anxiety, using cohorts of patients who have undergone a surgical procedure that variably relieves pain. Cross-correlation with the results of the types of human genetic approaches outlined here may help researchers to prioritize targets and develop treatments or prophylactic interventions for pain-specific depression and anxiety.
Supported by NIDCR Intramural Grant DE00366 (MBM) and NIAAA Intramural Grant Z01AA000301 (DG). The Maine Lumbar Spine Study was supported by grants from the Agency for Healthcare Research and Quality (HS-06344, HS-08194, and HS-09804). SJA (P60 AR048094) and RRE (K23 AR051315) is supported in part by funding from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. JAH is supported in part by funding from the National Institute of Neurological Disorders and Stroke (K24 NS02225). We thank Yen A. Wu, MPH for preparing the clinical dataset, Ann Scher for suggestions on data presentation, and Suzan Khoromi and Beata Buzas for reviewing the manuscript. The funding bodies had no input into the design or publication of the current study.
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