Interest in pain is on the rise at the US National Institutes of Health (NIH), said Nora Volkow, chief of the National Institute on Drug Abuse, welcoming participants to the 9th Annual NIH Pain Consortium Symposium, held May 28-29, 2014, in Bethesda, US. Volkow noted a significant increase in research funding at the NIH for chronic pain conditions, which amounted to $400 million in 2014, up from $279 million in 2008. That is still just about 1 percent of the entire NIH pie, but in an era of shrinking budgets overall, that is no small progress.
The increase follows the 2010 Affordable Care Act (aka Obamacare), which mandated a hard look at the state of pain education, care, and research. That legislation led to the 2011 report from the Institutes of Medicine on the public health impact of pain (see PRF related story and commentary).
For those who want to know where that money and other federal funds are going, the NIH recently announced the launch of a database of all the federal grants related to pain (see press release and news coverage). The Interagency Pain Research Portfolio is a publicly accessible, searchable resource that for the first time collects information on all federal research, including efforts by the NIH, the Centers for Disease Control, the Department of Defense, the Food and Drug Administration, and others in one place.The database reflects the Pain Consortium’s mission to enhance pain research and promote collaboration across government agencies.
Volkow also announced that on September 29-30, 2014, the NIH Office of Disease Prevention will sponsor a workshop on the role of opioids in treating chronic pain. Prescription opioid misuse, addiction, and overdose deaths have grabbed the attention of physicians, patients, the media, and policy makers, but data that would support the proper use of these drugs for chronic pain are severely limited. The workshop will tackle the scientific issues around opioid use for chronic pain. Registration will open in June. For more information, see 2014 NIH Pathways to Prevention workshop on The Role of Opioids in the Treatment of Chronic Pain.
The theme of this year’s symposium was biological and psychological factors that contribute to chronic pain. Over one and a half days, speakers discussed comorbid factors including depression, sleep disturbances, and inflammation. Summaries of selected talks on pain and depression are presented here; Part 2 deals with pain and sleep. In addition, an archived webcast of the entire meeting is available on the NIH website (view Day 1 and Day 2). The complete meeting agenda is here.
Pain and depression—what is the relationship?
Pain can certainly be depressing, and some data suggest that depression increases the risk of pain. But in his overview talk on the topic, Dan Clauw, University of Michigan, Ann Arbor, US, said that getting to a precise understanding of how often the two conditions co-occur is actually not easy. One problem is that the clinical instruments designed to identify depression are often “contaminated” by measures, such as sleep disturbances and headaches, that are also present in chronic pain conditions. Clauw said that going forward, studies seeking to measure comorbidity will need to isolate the cognitive and affective aspects of depression from somatic symptoms that are shared with chronic pain.
In people who do have pain and depression, which comes first? Nearly all studies suggest that chronic pain increases the risk of depression, but a fair number of data also suggests the opposite: that people with a history of depression are at a higher risk for chronic pain. Clauw noted that the magnitude of the increased risk for pain is modest (less than a twofold increase), and when measured in similar studies, other factors seem more important: Early life stressors, other psychiatric conditions, prior pain, prior somatic symptoms, and poor sleep are all stronger predictors of subsequent chronic pain. “Depression, although a risk, is not one of the stronger risks for development of subsequent pain,” Clauw said. Nonetheless, depression could be an important absolute risk factor for pain because it is so common.
In considering future directions, Clauw raised what he called “the 800-pound gorilla in the room”—what central nervous system factor or factors should researchers focus on when thinking about chronic pain? “It’s not depression, or catastrophizing. It’s something I don’t have a name for, but I see it over and over,” he said. The “something” manifests in a quartet of symptoms that cut across many diseases and include widespread pain, fatigue, memory and mood problems (including depression), and sleep disturbances.
Clauw, a rheumatologist, said he saw this in people who had consumed contaminated tryptophan in the 1980s. They first developed eosinophilia myalgia syndrome, but when the acute inflammatory phase resolved, these individuals looked like they had a severe form of fibromyalgia. He also saw an epidemic of this in veterans of the first Gulf War, and in a very high proportion of veterans from the Iraq and Afghanistan conflicts who suffer from the “polytrauma triad” of centralized pain, post-traumatic stress disorder, and mild traumatic brain injury.
This disorder goes by several names: fibromyalgia; somatization, or somatoform disorder (which involves pain in multiple areas early in life); and central sensitization, or regional idiopathic pain. This same symptom complex is very common in diseases such as interstitial cystitis, tension headache, irritable bowel, temporomandibular joint disease, vulvodynia, and dry eye. Clauw said that in his tertiary clinic, he sees patients who have had untreated disease for 30 years. These are people who have had pain in many regions over their lives and have been seen by many specialists who have a tendency to focus on where the pain is at that point in the patients' lives rather than on a lifelong history of pain in multiple areas of the body. “These are the people that all subspecialists dislike: They are a huge clinical problem,” Clauw said. “In aggregate, this may be one of the most common clinical diseases known to man, and may be the most disabling.”
This group of symptoms seems to represent some type of centralized pain state. Clauw believes that different chronic pain conditions differ in the proportion of individuals who “centralize” their pain. On the low end of a continuum are primarily nociceptive conditions such as osteoarthritis, where only 15-20 percent of people will clearly exhibit centralization, to the other end of the continuum, where nearly all patients exhibit this (e.g., fibromyalgia). It’s important to tease this out in each patient, he said, because different drugs are effective for each type of pain.
Currently, the best way to approximate this centralized state, Clauw thinks, is the concept of “FM-ness.” The current FM diagnostic criteria involve assessment of pain location and severity, as well as fatigue, depression, and other symptoms, generating an aggregate score that can range from 0 to 31 (Wolfe et al., 2011). The cut-off score for probable fibromyalgia is 13, but Clauw said the scale can also be viewed as a continuous measure of the centralization of pain, with low scores reflecting mainly nociceptive conditions, and higher scores indicating a larger degree of central nervous system involvement.
To support this idea, Clauw showed data from his ongoing study looking at the relationship between FM score and postoperative outcomes of osteoarthritis patients after knee or hip replacement surgery (Brummett et al., 2013). In the study, the researchers assessed patients before surgery for a battery of known risk factors for postoperative pain, but added a new factor—the FM score based on the 2011 revised diagnostic criteria (Wolfe et al., 2011). Only 9 percent of the 519 subjects studied met FM criteria—most subjects had scores between 5 and 10, and when Clauw analyzed outcomes for the patients with scores below 13, he found that the FM score predicted everything bad: post-operative pain, anxiety, and depression. The FM score highly predicted post-operative opioid use—for each one-point increase, patients needed an additional 9 mg opioids per day, and many still had ongoing pain. In terms of predicting six-month pain and global outcomes, the FM score subsumes all other variables they measured, Clauw said.
The FM score is not an ideal measure, Clauw said. “We hate this measure and are trying to move away from this. We think there are relative weightings of the items on this questionnaire or other questions that could be added that would improve the measure, and that it will be particularly important to validate this against biological measures such as brain imaging. He thinks that they are looking at some kind of central nervous system condition that starts in childhood, persists into adulthood, and "severely challenges the historical notion that most chronic pain is due to a problem in the region of the body where the individual hurts."
Mechanistic clues from animal work
A. Courtney DeVries, Ohio State University, Columbus, US, presented new animal work exploring the physiological mechanisms by which stress and social factors influence the risk of pain and depression after nerve injury. Previously, she had shown that stress (induced by two hours of daily restraint for two weeks) exacerbated allodynia and depressive-like behavior in the forced swim test after spared nerve injury in male mice. Stress alone did not induce allodynia or depressive-like behavior, but it made both worse via a mechanism involving induction of IL1beta expression in the brain (Norman et al., 2010). DeVries noted that while all of this work was done in male mice, she and her colleagues have since looked at females and do not see sex differences.
In more recent work, DeVries looked at the effects of social interaction on pain and depression in the same model. She found a reduction in allodynia and depressive behaviors in animals housed in pairs before injury compared to animals reared alone. In addition, if animals were paired after injury, she could see a significant decrease in allodynia.
Looking at the combined effects of pairing and stress on pain, DeVries showed that pairing in stressed animals improved allodynia, but did not completely eliminate it. Animals reared in isolation and exposed to stress fared worst of all. She has not yet looked at effect of pairing on the depressive behaviors, but predicts that those behaviors will be more amenable than allodynia to improvement with social interaction.
How might pairing improve pain? DeVries thinks that, like stress, the effect of pairing may be mediated by changes in IL1beta, because giving IL1beta to paired animals increased allodynia to the level seen in socially isolated mice. In contrast, treating socially isolated mice with IL1 receptor antagonist reduced allodynia to levels comparable to paired mice. The results may apply to other forms of pain—DeVries said she can demonstrate the effect of social interaction and stress on ischemia-induced allodynia, too.
For treatment, accentuate the positive
In her talk, Mary Davis, Arizona State University, Tempe, US, turned around the question of pain and depression. She asked why the pain field focuses so much on negative mood and emotions when data from other fields suggest that the presence of a positive affect predicts good outcomes better than negative affect predicts bad outcomes (e.g., see Southwick and Charney, 2012). Davis, who works on pain and mood regulation in women with chronic pain, asked whether, rather than focus mainly on diminishing negative moods, clinicians should pay more attention to actively promoting positive mood and emotions to build resilience in the face of chronic pain?
That idea is supported by her recent data (Davis et al., 2014) showing that in depressed women with pain, inducing a positive mood improved the response to stress in terms of pain. In the study, Davis looked at 110 women with fibromyalgia and/or osteoarthritis, of whom 29 percent were depressed. The subjects were subjected to a stress-inducing interview and then randomly shown either a humorous film clip or a neutral film clip. Afterwards, they were queried about their mood and pain.
The stress interview caused both depressed and non-depressed subjects to become more despondent and report more pain. After viewing the film clip, the non-depressed subjects showed a spontaneous rebound to better mood, regardless of whether they saw a positive or neutral clip. However, the depressed women rebounded only if they viewed the funny clip. The changes in mood tracked with clinical pain: The depressed subjects reported that their pain was reduced only in the positive mood induction group. The results suggest that interventions that serve to boost positive mood post-stress in depressed chronic pain patients could help lessen pain.
In a test of the clinical efficacy of mood improvement, Davis and colleagues had previously showed that mindfulness-based therapy, which enhances positive affect, pain coping, and resilience, was more effective than cognitive-behavioral therapy (which focuses on restructuring negative thoughts) or education at reducing joint tenderness in depressed people with rheumatoid arthritis (Zautra et al., 2008). When looking at daily diaries in patients from that study, Davis detected an increase in daily resilience with mindfulness training—on high-pain days, the patients showed less catastrophizing and less emotional reactivity to stress. This was not true for CBT or education.
More recently, the group demonstrated the possibility of delivering mindfulness-based therapies online aimed at boosting positive affect and social engagement. In a randomized trial, Davis and her group compared the effects of mindfulness training to general health tips, delivered online to 79 fibromyalgia patients. The groups showed no changes in pain after completing the short (four-hour total) intervention, but everyone improved on negative affect. Mindfulness was better than health tips at boosting positive affect, enjoyment of family, and pain coping efficacy (Davis and Zautra, 2013). Although the effects were small, the results are promising and highlight the potential of Internet-based delivery of low-cost and widely accessible psychological interventions for improving pain coping skills.
For more, see Part 2.
Image credit: NIDA