By Palanisamy Vijayanand
I’ve learned that even when I have pains, I don’t have to be one - Maya Angelou (1928 – 2014). It is likely that the celebrated African American author and civil activist, and famous resident of Winston-Salem, alluded to emotional pains when she made the popular statement. How about persistent physical pains? Studies have shown that emotional disruption and cognitive deficits are an integral part of the pain experience – a fundamental challenge when it comes to managing it. The cognitive deficits induced by persistent pain are in the domains of sustained selective attention, learning and memory, processing speed and executive function. An ideal analgesic, therefore, would be one that relieves pain as well as restores the cognitive deficits. The reality, however, is far from satisfactory, with analgesics only being partly effective in relieving pain, and in the bargain worsening the cognitive deficits. A recent study from Wake Forest School of Medicine, a more famous institution of Winston-Salem, throws light on the mechanisms which drives these changes. But first, the clinical observations.
a) If cognitive deficits are in entirety due to a chronic stressor such as pain, then relieving or reducing the pain should reverse the cognitive deficits. Treatment with anti-neuropathic pain medications such as gabapentin reduces the pain to an extent, but does not reverse the cognitive deficits in humans.
b) The cognitive impairments are more pronounced in persistent pain compared with noxious stimuli in an unstressed state (acute pain).
c) When used in acute pain or as pre-emptive analgesia, one of the major adverse effects of gabapentin is cognitive deficits. These deficits are observed to a much lesser extent when used in persistent neuropathic pain states.
Put together, these observations suggest an independent, and yet to be discovered, neurobiological mechanism, which could explain the cognitive deficits in persistent pain. And as therapy in its current form would be intolerable, a yet to be discovered mechanism that provides protection against the gabapentin induced cognitive effects in persistent pain. Could it be the same mechanism? Is it possible that the mechanism which might be responsible for the cognitive deficits could also protect against it?
There exists a proven link between a person’s personality and the functions of the prefrontal cortex; destruction of the anterior two-thirds of which results in deficits in concentration, orientation, abstracting ability, judgment, and problem solving ability. In an animal model of neuropathic pain, Suto and colleagues focused on the role of noradrenergic tone arising from the locus coeruleus (LC) and influencing the prefrontal cortex (PFC) in contributing to cognition. They have shown that these cognitively impaired neuropathic animals have higher levels of noradrenaline in the PFC, and the cognitive deficits could be reversed by the systemic administration of alpha-1 adrenoceptor antagonist, prazosin. Berrocoso, in her commentary, observes that, ‘as the only source of noradrenaline in the PFC is the LC, these two experiments suggest noradrenergic mediation in the LC-PFC loop during attention processes’.
The neurobiology of persistent pain, as a result of neuroplasticity, is different to that of acute pain. Is there also a difference between acute and persistent pain with respect to the neurobiology of cognition? In theory it does. It has been theorized that the LC-PFC which chugs along with a phasic discharge and moderate release of noradrenaline in acute pain, shifts its mode of discharge to tonic and excessive release in persistent neuropathic pain. The resultant surplus noradrenaline thereby explains the increased prevalence of attentional deficits in persistent pain.
In the second part of their study, Suto and colleagues tested the effects of gabapentin in normal and neuropathic animals. Systemic administration of gabapentin in normal animals resulted in impaired object recognition test, which was reversed with prazosin. In addition, systemic and local LC administration of gabapentin resulted in increased concentration of noradrenaline in PFC, and increased c-fos expression in PFC projecting LC neurons. These findings could potentially explain the altered mental state and dizziness when gabapentin is administered perioperatively. Notably, such negative effects were not found in neuropathic animals. The c-fos expression, which reflects the total number of LC neurons activated, was the same in normal and neuropathic animals. However, the number of PFC projecting LC neurons was not modified in neuropathic animals receiving gabapentin. This fascinating difference explains the lack of effect on cognition by gabapentin in neuropathic animals, and potentially in humans too. In other words, the functional reorganization and neuroplasticity caused by and responsible for the maintenance of persistent pain states; interestingly affords protection against the cognitive effects of gabapentin which is used in its treatment.
Suto T et al. Peripheral nerve injury and gabapentin, but not their combination, impair attentional behavior via direct effects on noradrenergic signaling in the brain. PAIN (2014), doi: http://dx.doi.org/10.1016/j.pain.2014.05.014
E. Berrocoso, Gabapentin, a double-agent acting on cognition in pain?, PAIN (2014), doi:http://dx.doi.org/10.1016/j.pain.2014.06.012
Sara SJ et al. The locus coeruleus and noradrenergic modulation of cognition. Nat Rev Neurosci. 2009 Mar;10(3):211-23. doi: 10.1038/nrn2573. Epub 2009 Feb 4.