From pain and depression, the NIH Pain Consortium Symposium agenda moved to pain and sleep disorders. Michael Vitiello, University of Washington School of Medicine, Seattle, US, described results of a randomized clinical trial of cognitive-behavioral therapy (CBT) for comorbid insomnia and pain. Vitiello, a sleep researcher, said his move to study pain has been inspired by accumulating evidence that one way to improve chronic pain may be to treat the comorbid sleep disturbances that frequently come along with it.
The relationship between sleep and pain, like the pain-depression relationship, is complex. Previously, most assumed that pain caused sleep disturbance, but new thinking holds that insomnia might actually contribute to pain. As far back as 1924, researchers knew that sleeplessness enhanced pain sensitivity, and a growing body of data suggests that experimental disruptions of sleep can lead to increased pain (Roehrs, 2009). Now, Vitiello and colleagues are producing data suggesting that improving sleep can improve pain.
For people with insomnia, cognitive-behavioral therapy can help. Vitiello said that CBT is “robust for sleep and can improve sleep even in the presence of ongoing pain.” But results of the treatment on pain have been mixed. In a previous study of CBT for insomnia, Vitiello found that people with osteoarthritis experienced improvements in both insomnia and pain (Vitiello et al., 2009). That result led him to devise a study to compare the effect of CBT for pain with a combination of CBT for pain plus insomnia. The study involved 367 older adults, mostly women, who received weekly 90-minute training sessions for six weeks.
The results of that study showed that the intervention reduced insomnia but not pain after nine months. At 18 months, there was no effect on either endpoint, suggesting that the combined therapy not only did not improve pain, but might have actually diluted the effectiveness for insomnia (McCurry et al., 2014).
But a post-hoc analysis reveals more reason for hope. When the researchers broke the subjects into groups based on severity of pain and insomnia, they found that the treatment actually worked for the most severe cases, with significant decreases in pain achieved at 18 months in the 98 most affected subjects.
Next, in additional analysis, the results of which have just been published (Vitiello et al., 2014), the researchers looked at people whose sleep improved at two months (regardless of which study arm they were assigned to) versus non-improvers and found that short-term sleep improvers showed continued improvement in sleep as well as decreases in pain severity and arthritis symptoms at 18 months. From this, Vitiello concluded that successful treatment of sleep disturbances in the short term may reduce pain in the long term. He is now proposing to conduct a larger randomized trial in severely affected people, with delivery of therapy by phone.
Monika Haack, Harvard Medical School, Boston, US, reported on her studies of the effects of sleep deprivation and insomnia on inflammation, pain sensitivity, and pain modulation. Haack has found that people with primary insomnia (sleeplessness with no apparent medical cause) report pain on twice as many days as controls, and report increased pain sensitivity. Many studies on evoked pain show sleep deprivation decreases pain thresholds, and Haack showed the same in the insomnia subjects, along with a reduced ability to modulate pain (Haack et al., 2012).
To study sleep deprivation in the lab, Haack brings subjects into a clinical research center, where for 14 days she can rigorously control sleep times, food and drink, and physical and social activity. In healthy volunteers, she has demonstrated that experimental sleep deprivation causes an increase in spontaneous reporting of pain, and decreases in conditioned pain modulation.
To look for physiological changes that accompany sleep deficits, Haack focused on changes in inflammatory markers in people subjected to sleep restriction and recovery in a pattern that mimicked the common experience of sleep restriction on work or school days and catch-up sleep over the weekend. When subjects were put through repeated cycles of restriction and recovery, she saw increases in the cytokine interleukin 6 (IL6) that became progressively worse with each cycle. Even though subjects felt refreshed after the recovery sleep phase, IL6 levels did not return to normal. This suggests that the subjective feeling of recovery from sleep deprivation may not be reflected by resetting of biological systems, Haack said. In addition, an increase in spontaneous pain with sleep deprivation correlated with IL6 levels and with an increase in urine prostaglandins. Together, the results suggest that inflammation induced by sleep deprivation may contribute to the excess pain reported by sleep-deprived people.
A clean sweep with sleep
What is sleep for, anyway? That question has long puzzled neurobiologists. In her talk, Maiken Nedergaard, University of Rochester, US, outlined recent findings pointing to sleep as a crucial interlude that allows the brain to clean house metabolically by flushing out toxic metabolites through the cerebrospinal fluid (CSF). Nedergaard recently discovered that the flushing process occurs mainly during sleep: In her talk, she presented some new data about how pain can have a significant impact on the brain’s hygiene.
The brain makes up just a fraction of total body weight, but it uses almost 25 percent of the body’s glucose, which means it must produce a lot of waste. The brain lacks a lymphatic system like the one that drains interstitial fluid, and waste, from other tissues, so just how it keeps clean has been unclear. It has been known for some time that CSF flows through the brain in channels alongside the vasculature, its movement driven by the pulsing of the large arteries (Rennels et al., 1985). Nedergaard developed a method to directly visualize that flow in living animals using florescent tracers and in-vivo two-photon video microscopy. In mice, the tracer can be seen moving first along the vasculature and then into the brain tissue spaces before being cleared with the exiting CSF, which drains alongside large veins. Astrocytes facilitate the exchange of substances between CSF and brain interstitial fluid, so Nedergaard coined the term glymphatic system (a combination of glia and lymphatic) to describe this brain-cleaning mechanism.
In a high-profile study published last year, Nedergaard and colleagues showed that glymphatic flow is most active during sleep. When they compared tracer flow in mice anesthetized with ketamine, or naturally asleep, or just waking up, they saw an active transfer of tracer in anesthetized or sleeping mice, but not in awake mice (Xie et al., 2013).
Nedergaard wanted to know how pain might affect glymphatic function. She did a spinal nerve ligation in mice and looked at tracer distribution after three days. In normal, awake mice, little or no tracer enters the brain. After spinal nerve ligation, when the mice were in pain, there was even less tracer than in normal awake mice. In anesthetized, injured mice, there was a slight increase in tracer in CSF, but Nedergaard said she was not yet sure if this was real because the results with ketamine are always more variable.
Because glymphatic function runs opposite to excitation and alertness, Nedergaard speculated that pain might reflect a state of high alert, and thus low waste clearance. The study, while preliminary, raises several interesting questions: Do people in pain need more sleep? Does glymphatic flow contribute to the clearance of inflammatory cytokines, and if so, could increasing clearance reduce pain? And finally, could imaging of clearance provide a novel diagnostic measure of pain?
Crowd sourcing for better treatments
The symposium was also a chance to unveil a new resource for pain treatment and research. Sean Mackey, Stanford University, Palo Alto, US, introduced a new registry designed for gathering clinical data, now in use at his Stanford pain clinic. The goal, he said, is to capture outcome and other data on patients who visit the pain clinic, and to then take advantage of that mass of data to improve patient care and research.
To do that, Mackey and colleagues at Stanford collaborated with the NIH to develop the Stanford-NIH Health Electronic Registry of Outcomes (HERO), an open-source, open-standard, highly flexible and free health and treatment registry. The system allows the collection of, and easy access to, outcome and other data on large numbers of pain patients. Having the data on hand will enable physicians to make better decisions for individual patients based on the patient’s own history and the accumulated data of all patients. The data will also allow comparative effectiveness research as well as “pragmatic” or “practice-based evidence” trials, which analyze outcomes of different treatments in clinical populations (see PRF related news story).
Mackey said he has been collecting these kinds of data at the Stanford pain management center for the last 15 years, starting with a pen and paper, and then using software programs, but he needed more. HERO incorporates easy data import from electronic medical records and collection of patient outcomes based on the NIH Patient Reported Outcomes Measurement Information System (PROMIS).
In HERO, patients enter data using electronic questionnaires. Because of the electronic format, the questionnaires are adaptive, which means that, depending on the answers to initial questions, subsequent questions are tailored mid-test. Mackey said this allows for questionnaires that cover a wide range of situations with many fewer questions, so patients take less time and provide more useful information than older pen-and-paper instruments. PROMIS data are also normative—scores are compared to population norms, allowing pooling and data comparison. Patients enter data at home or in the office on phones and other mobile devices.
The system was rolled out in August 2012, Mackey said, and currently has roughly 10,000 data points on 3,500 patients. The adoption has occurred with minimal complaints from staff or patients. Mackey said the system “has changed the culture of how we practice pain management. Providers use this all the time for teaching and for providing care.”
Mackey showed one example of a woman with chronic regional pain syndrome (CRPS). She had scored above normal on measures of depression and anxiety, and was in the lowest 10 percent of the population on measures of physical function. After initial pharmacological treatment, questionnaire data revealed evidence of improvement in mood and less pain interference, but no change in her physical function. So Mackey gave her a health educator, and by the next visit the patient did show an improvement in physical function. “We can watch what happens over time on multiple measures and adjust treatment accordingly,” Mackey explained. “For some patients, there seems to be some kind of barrier to improvement that shows up early. If they can get over that, they continue to improve,” he said. “We can use this system to ask what that barrier is and how to get people over it. “
Another useful output of the system is the generation of population-based information on the clinical population of pain patients. Comparing the Stanford clinic population to US norms, Mackey showed that his patients skew to the top percentiles for measures of pain, anxiety, fatigue, pain interference, depression, and physical function. But some patients are different—they appear happy and calm, and the system allows Mackey and colleagues to easily identity these interesting outliers with severe pain and dysfunction, but no anxiety, depression, and anger. “What can we learn from them?” he asked.
HERO started as a pain registry, but has morphed into a general health registry, and the group is now working on other versions including Headache HERO, Orthopedic HERO, and GI HERO. Built on industry-standard, non-proprietary tools, the system can accommodate any kind of survey. Mackey has plans for future enhancement and is looking for partners who want to add in features.
Junior investigators highlighted
Each year at the symposium, a junior investigator is recognized with the Mitchell Max Award, given for the best poster presentation. The award honors the late Max, a visionary pain researcher at the NIH and the University of Pittsburgh, US. The 2014 prize went to Fadel Zeidan, a postdoctoral fellow at Wake Forest School of Medicine, North Carolina, US, for work investigating the analgesic mechanisms of mindfulness meditation. Zeidan compared the effect of mindfulness meditation, sham mindfulness meditation, a placebo-conditioning regimen, or a neutral intervention on thermal pain sensitivity and brain activity (measured by arterial spin labeling MRI) in a total of 75 healthy volunteers (17-20 per intervention). In the study, the mindfulness intervention was most effective, reducing pain intensity by 26 percent and unpleasantness by 44 percent. Placebo and sham meditation also reduced pain intensity and unpleasantness significantly (by 19 and 24 percent), but to a lesser extent. In the imaging arm of the study, meditation was found to significantly deactivate the thalamus and the periaqueductal grey matter more than placebo, sham meditation, or control conditions. These results, together with Zeidan’s previous work, suggest that mindfulness meditation probably attenuates pain through multiple mechanisms, while placebo and sham meditation likely engage the expected descending control processes. In his presentation, Zeidan stated that mindfulness-based studies employing robust comparison conditions may better help attract insurers to pay for mindfulness and other psychological interventions that are known to work for pain.
Other young investigators who were runners up for the Max prize were Eric Bair, University of North Carolina, Chapel Hill, US, who described his work identifying patient subtypes in the OPPERA study, and Lisa Kilpatrick, University of California, Los Angeles, US, who described the first study looking at changes in resting-state brain connectivity in 82 women with interstitial cystitis/painful bladder syndrome compared to 85 healthy controls. Overall, her results so far suggest that women with this disease may have altered attention to visceral input and changes in sensorimotor functional connectivity to areas normally linked to pelvic floor function that are different from healthy women.
In addition to these talks there was a comprehensive overview of the TRPV1 channel structure from keynote speaker David Julius, University of California, San Francisco, US, and additional presentations from Linda Watkins, University of Colorado at Boulder, US, and Clifford Woolf, Boston Children’s Hospital, US. 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.
See Part 1.
Image credit: NIDA
