Fibromyalgia is common, affecting around 2% of people in the general population.1,2 The 2017 EULAR recommendations state that tramadol – a weak opioid – may be considered for pain management in fibromyalgia, but advise against use of strong opioids due to lack of evidence of efficacy, and the high risk of side effects and addiction.3 However, with limited therapeutic options available to tackle this condition, opioids are frequently used in clinical practice.
The impact of the opioid epidemic in North America has caused concern around the world. Long-term opioid use is associated with potential harm and adverse outcomes. In their abstract presented at the 2023 annual congress, in a session on Pain in RMDs, Ramirez Medina and colleagues argue that understanding the factors associated with long-term opioid use in such patients is the first step in helping to develop targeted interventions for de-prescribing.
The team conducted a retrospective cohort study using data from the Clinical Practice Research Datalink (CPRD) – a UK database of electronic health records from primary care. Overall, 28,554 fibromyalgia patients without prior cancer who were new opioid users between 2006 and 2021 were included. Long-term opioid use was defined as having at least three opioid prescriptions within a 90-day period, or at least one prescription lasting 90 days or more in the first year of follow-up.
Findings show that 26% of new opioid users became long-term users in the first year. Several factors were associated with higher risk of long-term opioid use. These included mean daily morphine milligram equivalents (MME) at initiation, history of suicide and self-harm, substance use disorder, deprivation, and obesity. Modelling showed that, of these, the three most important variables were mean MME/day at initiation, history of suicide and self-harm, and deprivation.
The team surrounding Professor Martin Diers and Benjamin Mosch analysed the magnetic resonance imaging data of 23 female patients with fibromyalgia and 21 healthy control subjects. They wanted to examine the volume of the grey matter, i.e. the nerve cells, in various pain-processing areas of the brain, and the so-called white matter, which mainly consists of the fibre connections between the nerve cells through which signals are transmitted. “One of our goals was to find out whether the directionality of the diffusion of water molecules differs in certain areas of the brain, in other words: whether we can identify any regional differences in signal transmission,“ explains Benjamin Mosch.
The researchers found changes of the grey matter volume mainly in the pain network of the brain, i.e. in the regions responsible for processing and evaluating pain. “In certain regions responsible for the inhibition of pain, we found a decrease in grey matter in the patients compared to the healthy individuals,” explains Benjamin Mosch. “In patients, the volume of these regions was significantly reduced.”
Regarding the transmission of signals, changes were found in the thalamus. The thalamus is considered as an important node in neuronal pain processing. The deviations of the white matter in patients with fibromyalgia compared to healthy controls indicate an altered conduction of pain signals in patients with fibromyalgia.
Relationships between brain structure, perception and behaviour
The team finally related the results of the structural brain changes to perceptional and behavioural characteristics of the study participants. The amount of decreased volume in a number of relevant brain regions is inversely related with the amount of perceived pain the patients report. The researchers made an interesting observation when analysing the correlation between depressiveness or activity levels with the change in the volume of certain brain areas. The volume of the so-called putamen correlated negatively with the expression of depressive symptoms and positively with the activity level of the participants. “This indicates that changes in the brain may not be permanent, but that they can be influenced; in other words they might be reversible, for example through an active everyday life,” concludes Benjamin Mosch.
Up to 1 in 3 with rheumatoid arthritis or fibromyalgia may be at risk, warn researchers
Patients with rheumatic and musculoskeletal conditions are vulnerable to long term opioid use, with up to 1 in 3 of those with rheumatoid arthritis or fibromyalgia, who take these drugs for the first time, potentially at risk, suggest the findings of a research letter, published online in the Annals of the Rheumatic Diseases.
People with rheumatic and musculoskeletal conditions are often prescribed opioids to manage their pain, and a proportion of them will become long term users with the attendant risks of dependence and harmful side effects, point out the authors.
Most research defines long term opioid use as 90 or more days, although definitions vary, and there are no contemporary estimates of the scale of long term opioid use, they add.
To assess the proportion of patients transitioning to long term use among those newly started on an opioid, they drew on the anonymised medical records of 841,047 adults whose details had been entered into the Clinical Practice Research Datalink (CPRD), a nationally representative UK-wide primary care research database.
Some 12,260 of them had been diagnosed with rheumatoid arthritis, 5195 with psoriatic arthritis, 3046 with axial spondyloarthritis, 3081 with systemic lupus erythematosus (SLE), 796,276 with osteoarthritis, and 21,189 with fibromyalgia.
Each patient had been newly prescribed an opioid up to 6 months before, or any time after, their diagnosis between January 2006 and end of October 2021 and had been monitored for at least a year.
Long term use was defined as either standard (3 or more opioid prescriptions issued within a 90 day period, or 90+ days’ opioid supply in the first year); or stringent (10 or more opioid prescriptions filled over more than 90 days, or 120+ days’ opioid supply in the first year); or broad (more than 3 opioid prescriptions at monthly intervals in the first 12 months).
In all, 1,081,216 new episodes of opioid use were identified among all the patients, just under 17% of whom transitioned to long term use under the standard, 11% under the stringent, and 22% under the broad definitions.
Most (97%+) of new prescribing episodes meeting any of the definitions were captured by the broad definition. Just under half fulfilled all three.
The highest proportion of long term opioid users were patients with fibromyalgia—27.5% 21%, and 34% for each of the respective definitions—followed by those with rheumatoid arthritis—26%, 18.5%, and 32%—and those with axial spondyloarthritis—24%, 17%, and 30%.
The lowest proportion of transitioners were among those with osteoarthritis:16.5%, 11%, and 21.5%, for each of the respective definitions.
The proportion of patients with SLE and fibromyalgia who became long term opioid users noticeably increased between 2006 and 2019, rising from 22% to 33%, and reaching 29% in 2020.
A statistically significant decreasing trend was observed for patients with rheumatoid arthritis, although the overall proportion remained high at 24.5% in 2020.
Under the stringent definition, 1 in 5 patients with fibromyalgia and 1 in 6 of those with rheumatoid arthritis or axial spondyloarthritis fulfilled definitions for long term opioid use within 12 months of starting an opioid.
But this proportion could be as high as 1 in 3 for those with fibromyalgia or rheumatoid arthritis, and 1 in 3.5 for those with axial spondyloarthritis, using the broad definition, say the researchers.
“The findings warrant vigilance in practice of opioid prescribing for [rheumatoid and musculoskeletal conditions] since long term opioid therapy is associated with poor outcomes (eg, opioid dependence and opioid-related adverse events),” they warn.
And they advise clinicians to instigate medication reviews or deprescribing and to consider non-drug treatments for pain relief to minimise the risks of “avoidable harms” in this group of patients.
Fibromyalgia is a mysterious chronic pain disorder that is difficult to treat. Its causes are also still largely in the dark. A study conducted by the team at the Clinic for Psychosomatic Medicine and Psychotherapy at Ruhr University Bochum, Germany, provides evidence that certain brain areas involved in processing pain don’t function normally in fibromyalgia patients. In healthy people, they ensure that pain that we can control is easier to bear. The study found that these brain areas showed altered activity in patients with fibromyalgia.
Controlling the off switch for heat pain
The degree to which we experience pain and the restriction caused by it depend largely on how we perceive it. If we have the feeling that we can control the pain and shut it down ourselves, for example, we will tolerate it better than if we feel at its mercy. “For people with chronic pain, the inability to control repeated attacks of pain is one of the most significant causes of impaired quality of life,” explains Benjamin Mosch, lead author of the study. “And yet, the underlying neural mechanisms have so far mainly been studied in healthy controls.”
The team compared two female cohorts in the current study: 21 healthy participants and 23 fibromyalgia patients. Both groups were exposed to heat pain while their brain activities were monitored by functional magnetic resonance imaging. In one experimental run, the participants were able to stop the pain stimulus themselves. In another run, a computer controlled the start and end of the stimulus. “We kept the duration of the stimuli terminated by the computer the same on average as the stimuli terminated by the test subjects,” says Martin Diers.
Cognitive resources are impaired
When women in the healthy control group were able to terminate the pain stimulus themselves, a number of mainly frontal brain areas were activated that seem to play an important role in modulating pain. This observation is consistent with previous studies involving healthy subjects. “Interestingly, however, we didn’t detect any such activations in our patient group,” points out Martin Diers. “This can serve as evidence for impaired pain processing among patients with fibromyalgia. It indicates that the cognitive resources for dealing with acute pain are impaired in these patients.”
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