Editor's note: This is Part 2 of PRF’s coverage of selected talks from a pre-conference workshop on pain and aging, held July 23 in San Francisco, US, at the 2017 International Association of Gerontology and Geriatrics (IAGG) World Congress. See Part 1 here.
Sleep and pain
Michael Smith, Johns Hopkins University, Baltimore, US, considered the relationship between sleep disturbance and pain in older adults, two highly comorbid conditions. Other conditions, such as sleep apnea, circadian rhythm disorders, and restless leg syndrome are also comorbid with pain, he noted.
What does sleep look like in chronic pain patients? Smith referred to a 2016 meta-analysis that found that people with chronic pain show increased disruption of sleep continuity, compared to healthy controls (Bjurstrom and Irwin, 2016). In terms of sleep architecture, a reduction in slow wave sleep emerged as the most consistent finding. However, many of the 29 studies included in the meta-analysis had methodological flaws, so more objective descriptive work is needed with large sample sizes to understand the precise sleep abnormalities that these patients experience.
What is the relationship between pain and sleep? Traditionally, Smith said, it has been thought that pain increases arousal, which then disrupts sleep, leading to a further increase in pain. But there is also a reciprocal view according to which sleep deprivation leads to hyperalgesia and spontaneous pain.
Longitudinal studies, which have been performed primarily in healthy adults, show a bidirectional relationship, with sleep leading to pain, and pain to sleep. Meanwhile, prospective epidemiological studies have shown a strong relationship between sleep and pain, including, in those with poor sleep, a doubling or tripling of risk of new-onset chronic pain, and the persistence and worsening of emergent musculoskeletal pain. Poor sleep is also a predictor of the progression of regional pain to widespread pain, whose remission occurs upon restoration of sleep. Finally, insomnia has been shown to increase the risk of acute injury-induced chronic pain.
Smith then looked to studies of conditioned pain modulation (CPM), which declines with age, to better understand the relationship between sleep and pain, since impaired CPM has been associated with many chronic pain disorders, including fibromyalgia, temporomandibular disorder, irritable bowel syndrome, low back pain, and tension headache. He pointed to an early study he and his colleagues performed in 32 young, healthy women that assessed the effects of forced awakening and restricted sleep on pain (Smith et al., 2007). Findings indicated that disturbing the continuity of sleep resulted in impaired CPM and an increase in spontaneous pain, while sleep restriction did not, compared to controls who slept undisturbed. A recent study published last year in the Journal of Pain, which also looked at healthy young women, replicated these findings (Iacovides et al., 2017). In this case, sleep fragmentation resulted in hyperalgesia in response to superficial and deep experimental muscle pain. Several other studies have documented impairments in CPM due to poor sleep, both in chronic pain disorders, including chronic jaw pain, fibromyalgia, rheumatoid arthritis, and osteoarthritis, and in primary insomnia, Smith said.
Interestingly, one mechanism to explain the effects of sleep disruption on CPM and pain could be inflammation. Smith explained that blood cells from sleep-deprived individuals produce more inflammatory mediators such as interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha; Irwin et al., 2006; Irwin et al., 2008). Meanwhile, basic science studies have shown that inflammation can increase nociceptor sensitivity. Clinical studies have also linked inflammation to pain and to sleep.
Along these lines, in 2015, Smith and colleagues conducted a case-control study in older adults examining the effects of insomnia and knee osteoarthritis (KOA) on inflammation (Quartana et al., 2015). This research examined four groups: those with KOA and good sleep; those with KOA and insomnia; those with insomnia alone; and healthy controls with good sleep and no KOA. The investigators examined IL-6 levels in these subjects, who were challenged with heat or cold pressor pain. Results showed that an increase of IL-6 in response to pain was higher in subjects with insomnia alone, compared to the three other groups.
Smith then discussed the clinical implications of all the findings, focusing on treatment of insomnia. In terms of drug treatments, of most note, opioids compromise sleep, and also increase the risk of sleep apnea. On the other hand, anticonvulsants have been shown to improve sleep. Nevertheless, first-line treatment for insomnia is cognitive behavioral therapy (CBT), according to recent clinical practice guidelines (e.g., see Qaseem et al., 2016). A 2002 meta-analysis from Smith and colleagues found that CBT was just as effective as drugs for those with insomnia in middle-aged subjects, (Smith et al., 2002). And, a 2006 meta-analysis found CBT effective for middle-aged adults, and for older adults over age 55 (Irwin et al., 2006).
Finally, clinical trials in chronic pain patients also show the effectiveness of CBT for sleep problems in those individuals. For instance, a double-blind study from Smith and colleagues showed the effectiveness of CBT for both insomnia and pain in knee osteoarthritis patients (Smith et al., 2015). However, study results are mixed with regard to the effects of CBT on pain, though effect sizes can be large.
Treating pain with drugs in older adults
In a session on pain treatment in older adults, Benny Katz, a clinician at St Vincent’s Hospital Melbourne, Australia, provided his perspective based on his experience in a pain clinic for older people, where he sees patients who have not responded to standard therapies. The focus of his talk was on the efficacy and tolerability of commonly used analgesics.
Most drug treatments for older people in pain—back and knee pain are the most common types of bothersome pain in these individuals—have limited evidence to support their use, he said. For instance, according to a meta-analysis of 13 randomized controlled trials, paracetamol (acetaminophen) had no benefit for low back pain, and only a very small benefit for osteoarthritis pain that was likely not clinically meaningful for the patient (Machado et al., 2015).
Paracetamol is generally considered a safe drug, but the evidence shows this is not the case for non-steroidal anti-inflammatory drugs (NSAIDs), which clouds the picture for their use. Katz pointed to a 2017 network meta-analysis including 76 randomized trials with a total of nearly 60,000 patients that found that the NSAID diclofenac was the most effective NSAID for use in hip and knee osteoarthritis pain; this drug was able to produce a minimum clinically important difference both for pain and function (da Costa et al., 2017). This is encouraging, though Katz noted that the average age of subjects in the trials was in the 60s, so the generalizability of the results for those older than that is unclear.
However, much evidence has accumulated that NSAIDs are unsafe to use. Take, for instance, another 2017 meta-analysis that looked at individual patient data from nearly 450,000 older individuals, including more than 60,000 who had experienced acute myocardial infarction (Bally et al., 2017). All of the NSAIDs considered in the analysis, including diclofenac, celecoxib, ibuprofen, naproxen, and rofecoxib, increased the risk of acute myocardial infarction; this risk was highest in the first month of NSAID use and with higher doses. Odds ratios ranged from 1.24 for celecoxib to 1.58 for rofecoxib; diclofenac had an odds ratio of 1.53.
What about opioids? Do they work for pain in older adults? The question is pressing, considering the explosion of opioid consumption not only in the United States but in other countries such as Australia as well. Katz noted that the greatest increase in opioid use in Australia has been seen in those over 80 years of age. Short-term studies show efficacy in both neuropathic and musculoskeletal pain, but there are no controlled studies lasting longer than four months, and there is no evidence at all beyond six months.
Against this backdrop is the well-documented increase in abuse of these drugs, along with opioid-induced hyperalgesia. Opioids also have additional safety concerns. For instance, opioids increase the risk of falls and fractures―outcomes that are already common in older age groups. Indeed, a 2013 electronic medical records study of more than 13,000 subjects aged 65-89 years who had been diagnosed with osteoarthritis found that the increased risk of falls and fractures was higher for opioids than for NSAIDs and COX-2 inhibitors (Rolita et al., 2013). Another study (Li et al., 2013) of nearly 22,000 fracture cases and more than 85,000 matched controls in adults aged 18-80 years found that, for opioids used for non-cancer pain, current use of one opioid prescription was associated with a highly increased fracture risk (adjusted odds ratio of 2.70). This risk did decrease as the number of prescriptions increased, and there were no differences among age groups, with those over 70 showing a similar risk profile as those over 60 and under 60.
Opioids also increase the risk of death. Katz pointed to data over approximately the past 15 years, both from the US and from Australia, showing a direct correlation between the number of opioid prescriptions and opioid-related mortality. He said that in Australia, since 2012, more people died from prescription medicines than from traffic accidents, and that deaths from illicit drugs are catching up with those from incidents on the road.
Based on the evidence, then, Katz concluded that, in comparison to acute pain, drug approaches to manage chronic pain are not as effective. However, it is important to individualize therapy to each patient, he stressed, since an individual patient may respond differently than the average patient in a drug clinical trial. Finally, if a drug does work well in a patient, that individual may be prepared to accept the risk of adverse events, but if the drug is ineffective, it should be discontinued.
Non-pharmacological therapies for pain in older adults
Turning to non-drug therapies was Cary Reid, Weill Cornell Medical College, New York, US, including psychological, physical, and complementary medicine approaches.
Why focus on non-drug strategies to alleviate chronic pain in older adults? Reid answered that the risk of adverse drug events (ADEs) increases with age, including ADEs that result in hospitalization (Salvi et al., 2012). Older adults also tend to take many different medications, and suffer from co-occurring diseases as well, both of which increase the likelihood of ADEs (Davies and O'Mahony, 2015).
At the same time, doctors do not wish to cause harm to their patients, while patients often are afraid of both pain medications and the ADEs that may ensue. Considering the billions of dollars spent on pain relievers each year, non-drug approaches could help drive those costs down, and also move people away from opioids and all of their attendant problems. Reid noted that non-drug approaches are already being pursued by many older adults, who report that these interventions, including exercise, massage, yoga, and acupuncture, are helpful to them.
The case is fairly strong, then, to consider use of non-pharmacological therapies to manage chronic pain in older people. But do they actually work? With regard to psychological therapies, including CBT, self-management programs, mindfulness meditation, and acceptance and commitment therapy, Reid presented the results of a meta-analysis he and his colleagues performed looking at the impact of these interventions on chronic non-cancer pain, primarily musculoskeletal pain, in older adults. The meta-analysis included 23 studies of approximately 2,700 subjects who underwent an intervention or served as controls; the average age of participants was just over 70.
The latest analysis from this study, Reid told PRF after the meeting, shows statistically significant improvements in pain, catastrophizing beliefs, and pain self-efficacy. Of these, only pain was reduced both at the time when treatment was completed and after six months; effects on catastrophizing beliefs and pain self-efficacy were significant only at the time of treatment. The effects were relatively small, and diminished over time. When looking at whether treatment effects varied depending upon how the intervention was delivered, the study found that results were statistically significant only when the interventions were given to a group, rather than with individual therapy. And, in comparison to a previous systematic review of middle-aged adults (average age of 48; de Williams et al., 2012), treatment effects on pain for CBT in Reid’s study were similar, but other effects were smaller.
The picture may not seem encouraging—small effects that dwindle with time and are weaker in older adults; however, the average treatment effects seen in Reid’s study may mask variations at the level of the individual patient. Some older patients with chronic pain may, in fact, benefit substantially from a psychological therapy, while others may receive no benefit.
And there is an additional reason to be optimistic. In 2013, researchers examined an outpatient, CBT-based pain self-management program, delivered jointly by a psychologist and a physical therapist, consisting of exercise, pain education, and pain coping strategies. These subjects were compared to an exercise-attention control group that would have to decide on their own to do exercise and did not receive any attention, encouragement, or directives from the treatment team throughout the study (Nicholas et al., 2013). This randomized controlled trial included 141 subjects age 65 and older.
Results indicated that, immediately after treatment, there were statistically significant improvements on many measures, including pain-related distress and disability, depression, fear avoidance, catastrophizing, pain self-efficacy, and functional reach (to test balance). Many, though not all, of the benefits persisted after one month. Significant improvement was also seen at one month on several measures compared to a waitlist control group. But what about the long term? In a follow-up study published last year, the same researchers found that the pain self-management group maintained many of the gains at one year, compared to the exercise-attention control group, though the effects had somewhat diminished over time (Nicholas et al., 2017).
As far as physical treatments go, several meta-analyses of exercise in osteoarthritis patients show medium effect sizes for reductions in pain and function, with few adverse events. A 2015 meta-analysis of studies examining chronic musculoskeletal pain, in patients with a mean age of 57 who engaged in walking exercise, found small to moderate reductions in pain and function post-treatment. However, the improvement in pain did not persist beyond one year, though the improvement in function did (O'Connor et al., 2015).
Meanwhile, meta-analyses of tai chi studies show moderate effects that do not persist over time. And for yoga, meta-analyses in non-elderly patients also show moderate effects on pain and pain-related disability. But there are few studies of this intervention in elderly populations, though a pilot study did reveal positive effects on pain and physical function after an eight-week chair yoga intervention (Park et al., 2017). Here, though, only the effect on function persisted at three months after the intervention. No meaningful safety issues have been reported either with tai chi or with yoga.
Reid concluded that there is enough evidence to recommend all of the non-pharmacological treatment approaches he discussed in his talk for older adults with chronic pain. But there is still much to learn. For instance, the mechanisms by which psychological therapies may help chronic pain remain unclear, and it is still uncertain how to boost the beneficial effects of these therapies. In addition, while Reid’s work shows that the treatments had superior outcomes when delivered to a group, compared to delivery to individuals, which components of psychological therapies work the best, and in which particular subgroups of older adults, awaits further study. Finally, it is also unclear how other factors, such as a person’s degree of cognitive impairment, demographic factors like race/ethnicity, and a patient’s level of social support (which affects the adoption and use of psychological therapies) may affect treatment outcomes.
Read Part 1 of our meeting coverage here.
Neil Andrews is a science journalist and executive editor of PRF.
Image credit: simondannhauer/123RF Stock Photo.
