Reckziegel, Diane
(2017)
Neuroimaging studies to understand neural mechanisms of pain in osteoarthritis.
PhD thesis, University of Nottingham.
Abstract
Osteoarthritis pain is a major cause of long-term disability and chronic pain in the adult population, which can lead to reduced quality of life and serious comorbidities such as depression. Together with the substantial burden chronic osteoarthritis pain (COAP) causes at the individual level, associated economical costs are alarming and set to rise given the ageing population. Yet there are very few effective treatments available, which include both pharmacological and non-pharmacological options. Around one in five COAP patients do not receive satisfactory pain relief, even after undergoing joint replacement surgery. This strongly supports the notion that chronic osteoarthritis pain has a central component, and reflects the need for improved understanding of neural mechanisms of chronic pain and chronic pain relief.
Substantial advances have been achieved over the past two decades towards unravelling the role of the central nervous system in predisposition, development and maintenance of chronic pain. Despite these efforts, there is still a major gap in integrating these advances and translating them into more meaningful treatments.
The studies presented here endeavour to shed light on these aspects by capturing multidimensional contributions from brain mechanisms, negative mood and pain characteristics to COAP and to the effect of treatment, with the overall aim of improving current understanding of central components of this condition and mechanisms of centrally acting analgesic treatment.
More specifically, the principal objectives consist of: 1. Identifying markers indexing neuroplasticity changes linked with COAP, and molecular mechanisms in COAP; 2. Studying neural correlates of the analgesic effects of opioids, the strongest pain killers available, in individuals with COAP and explore whether pain phenotyping may predict the extent of treatment response; 3. Assessing the neural effects of the antidepressant duloxetine and investigating potential predictors of treatment outcome.
In order to achieve these objectives four studies are undertaken. First, the microstructure of the brain in chronic osteoarthritis pain is investigated in a cross-sectional manner in 46 individuals (23 COAP), in an attempt to identify potential signs of structural neuroplasticity. Analysis of cerebral microstructure with diffusion imaging techniques is sensitive to minor changes in myelination and axonal loss, thus being a plausible marker of neuroplasticity. Second, in a similar study design, the brain of 39 participants (20 COAP) is examined on the molecular level, focusing on neurotransmitter levels within one key region involved in pain, namely the anterior cingulate cortex (ACC). Using the setting of randomised controlled trials (RCT), the third and fourth projects are planned and developed, with novel investigational protocols being established before recruitment takes place. Previously established multi-modal structural, blood oxygen level dependent (BOLD), and blood flow imaging of the brain are included, in addition to novel task-related functional paradigm and quantitative sensory testing. Study three consists of a mechanistic, saline controlled, acute intervention study of remifentanil involving 28 individuals with COAP, while a sub-chronic placebo controlled investigation of duloxetine (77 COAP) constitutes study four. Remifentanil is a μ−opioid agonist, a strong analgesic, while duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI), novel class of antidepressants. All four studies are performed at 3T.
No abnormalities in brain structure were found in association with COAP, but an inverse correlation between ACC -aminobutyric acid levels and pain severity was seen, which was not dependent on negative affect or age, explaining nearly 60% of the variance. Pinprick-related BOLD activity in COAP was characterised and partially modulated by the opioid remifentanil, preferentially in patients with more impaired conditioned pain modulation (CPM). 77 participants consented into study four. Fifty-six participants completed the study, from which 34 received duloxetine treatment for 6 weeks, while 22 received placebo equivalent. Around half (53%) of duloxetine intakers reported clinically meaningful pain relief, against 36% of placebo intakers. Interim analysis of the effects of duloxetine on pinprick-related activity did not detect activity changes, albeit lower baseline anterior insula activity showed association with better treatment outcomes after duloxetine, but not placebo. Additionally, responders to either duloxetine or placebo had a tendency for lower ACC activity prior to treatment.
These results suggest that, differently from other chronic pain conditions, such as back pain and fibromyalgia, COAP is not accompanied by major apparent structural reorganisation nor abnormal ACC neurotransmitter levels. However they also indicate some shared mechanisms between COAP and fibromyalgia, given cingulate GABA encoding of perceived pain severity, which supports use of GABA levels as a marker for mechanistic evaluation of GABAergic modulation for pain relief in COAP. The observed absence of structural abnormalities in COAP, suggests that this condition may be simpler to treat than other types of chronic pain. The GABA association seen in COAP, and previously shown in fibromyalgia, indicates that certain mechanism-based drugs may be useful for both COAP and other conditions.
Results from the opioid study, in conjunction with the published literature suggest shared neural mechanisms of opioidergic analgesia between chronic pain states and the healthy state. Additionally, they point out that CPM might allow prediction of the need for centrally acting drugs. In the duloxetine study however, CPM was not related with differential treatment outcomes. Instead the anterior insula seem to play a role in determining the likelihood of clinically meaningful treatment response to duloxetine. However, results from both these analgesic studies must be interpreted with caution as they were based on a sub-sample of the full dataset acquired, as recruitment was still ongoing. Both RCTs have now been completed, and analyses of the full dataset is ongoing. Collectively, findings in this dissertation provide new evidence to the field of chronic pain research, suggesting that the structural and neurochemical brain reorganisation seen in other chronic pain conditions are likely pain-type specific, besides some partially overlapping mechanisms which are characterised here. The analyses of the RCTs of opioid and SNRI treatments, albeit preliminary, elucidate some putative mechanisms and predictors of centrally-mediated analgesia in COAP. Nevertheless, the full dataset, based on the rich methodology and protocols developed as part of the PhD, which is now available and undergoing investigation, should allow firmer conclusions regarding these two major classes of drugs and placebo in chronic pain.
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