Abstract
BackgroundMany Osteoarthritis (OA) patients report with clinical features to their pain that cannot be explained by purely peripheral mechanisms. Yet, the analgesic agents available that tackle centrally driven chronic pain often provide only partial pain relief, or have dose‐limiting side effects. We explored a combination therapy of the centrally acting analgesic agents tapentadol and pregabalin, to investigate if they could be used in combination to provide superior analgesia.MethodsUsing electrophysiological single‐unit recordings taken from spinal wide dynamic range neurons, Diffuse Noxious Inhibitory Controls (DNIC) were assessed as a marker of potential changes in descending controls in a monoiodoacetate (MIA) model of OA. We investigated if a subcutaneous injection of tapentadol or pregabalin, both alone and in combination, inhibited neuronal responses and restored the expression of DNIC, quantified as a reduction in neuronal firing in the presence of a conditioning noxious stimulus.ResultsTapentadol restored DNIC‐induced neuronal inhibition in MIA animals, while pregabalin inhibited pre‐conditioned mechanically evoked neuronal responses but did not restore DNIC. Given in combination, tapentadol and pregabalin restored DNIC expression and also inhibited spinal neuronal responses.ConclusionsWe propose that there is both central sensitization and an imbalance in inhibitory and facilitatory descending controls in MIA animals. The combination therapy of tapentadol and pregabalin restored descending noradrenergic inhibitory tone and also inhibited nociceptive transmission at the level of the spinal cord.SignificanceThis study shows that pregabalin and tapentadol target different mechanisms of centrally driven chronic pain associated with osteoarthritis, and that when administered together can restore descending inhibitory tone whilst also tackling spinal neuronal hyperexcitability and may therefore provide superior analgesia.
Highlights
Most analgesics used to treat Osteoarthritis (OA) aim to tackle pain at the level of the joint, yet the continuous barrage of afferent nociceptive signals and the high level of plasticity in the central nervous system (CNS) means hypersensitivity of second‐order neurons in the dorsal horn often develops (Schaible, 2012; Wieland, Michaelis, Kirschbaum, & Rudolphi, 2005)
Patients with a less efficient Conditioned Pain Modulation (CPM) before surgery were more susceptible to developing post‐operative chronic pain following surgery, indicating that assessing CPM responses can provide crucial information on a patient's physiology (Yarnitsky et al, 2008)
We have demonstrated that Diffuse Noxious Inhibitory Controls (DNIC) are absent in MIA animals, and a study found patients with severe knee OA pain had significantly less DNIC than healthy controls, indicating relevance of our study to the clinic (Arendt‐Nielsen et al, 2010)
Summary
Most analgesics used to treat Osteoarthritis (OA) aim to tackle pain at the level of the joint, yet the continuous barrage of afferent nociceptive signals and the high level of plasticity in the central nervous system (CNS) means hypersensitivity of second‐order neurons in the dorsal horn often develops (Schaible, 2012; Wieland, Michaelis, Kirschbaum, & Rudolphi, 2005). Many OA patients develop referred pain at sites distant to initial joint damage and suffer from chronic pain following total knee replacement surgery, which suggests discordance between nociceptor activation and the resulting pain (Malfait & Schnitzer, 2014). These features indicate that the pain associated with OA cannot always be considered purely peripheral; it is important to consider spinal hypersensitivity and dysfunctional descending controls when tackling these clinical manifestations (Wylde, Hewlett, Learmonth, & Dieppe, 2011). We investigated how tapentadol and pregabalin affected spinal neuronal activity and the functionality of descending controls through measuring DNIC responses in MIA animals
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