Pharmacology Notes

Central sensitisation is a process of amplifying and maintaining nociceptive input. It can be either helpful (ensuring protection of an injured body part) or harmful (as part of self-sustaining chronic neuropathic pain). Sustained activity from the C fibres, either from severe tissue injury, ongoing inflammation or peripheral nerve injury, results in changes in receptor responsiveness and excitability of the dorsal horn neurone. As a result, the threshold for excitation of the second-order neurone is lower, and sensory fibres entering the nervous system from areas adjacent to the injured area are able to trigger a nociceptive response even though the tissue they supply is not injured. This explains how the cutaneous zone of secondary hyperalgesia is found to be wider than that for the primary response—that is, noninflamed areas adjacent to the wound become sensitive. In essence, secondary hyperalgesia involves a widening and amplification of the central nervous system response to stimuli from and around the injured or inflamed area.

Central sensitisation also involves temporal summation or ‘wind-up’ if the input from C-fibre activity is sufficiently intense and prolonged. With sustained release of substance P at the first central synapse, intracellular kinases (especially protein kinase C) are activated in the second-order neurones, causing phosphorylation of the N-methyl-D-aspartate (NMDA) receptor. Phosphorylation enables glutamate to open this channel, thus significantly amplifying the influx of calcium and increasing the likelihood of impulse propagation. The dorsal horn neurone is now likely to respond to what would previously have been subthreshold inputs. The pain pathways are now ‘wound up’, and small stimuli result in large responses. Prevention of NMDA-receptor activation using drugs such as ketamine has been shown experimentally to stop wind-up from occurring and to decrease central sensitisation (see Pre-emptive analgesia).

The mechanisms for widening of the receptive field near the injury may also involve wide dynamic range neurones, which are located deeper in the dorsal horn, typically in the region of lamina V. They receive inputs from a variety of noxious (eg A-delta, C) and non-noxious (eg A-beta) sources. Referred pain, the dermatomal projection of visceral pain, results from the convergence of inputs on neurones such as wide dynamic range neurones in these deeper laminae. Wide dynamic range neurones also demonstrate ‘wind-up’ by increasing their discharge rate until it becomes almost continuous.

Wide dynamic range neurones may provide the basis of the important ‘gate control’ theory of pain. This theory proposed, in part, that afferent input from non-noxious sensory receptors could decrease the passage of noxious input entering the same neural pathway by activating inhibitory presynaptic interneurones in the substantia gelatinosa. This may be the mechanism of the pain relief obtained by rubbing an area near to an injury, or using transcutaneous electrical stimulation (TENS), or acupuncture.

Central sensitisation is initiated during the initial intense afferent neurological barrage (eg following trauma or during surgery under general anaesthesia). ‘Pre-emptive analgesia’ is a therapeutic strategy that has arisen following the discovery in laboratory experiments that a reduction in central hypersensitivity and plasticity (‘wind-up’) occurred when analgesic drugs were administered before the nociceptive event. In practice, it is not feasible to markedly reduce all nociceptive input associated with surgery and, not surprisingly, the results of clinical studies over the last 10 to 15 years have been inconsistent.

Pre-emptive analgesia is frequently misunderstood to mean that starting an analgesic strategy before surgery will automatically result in profoundly decreased pain and analgesic requirements following the procedure. Although this is to some extent true, pre-emptive analgesia actually refers to a process initiated before an acute nociceptive stimulus (the surgery) that prevents central nervous system sensitisation (central hypersensitivity). Therefore, to be most effective, pre-emptive analgesia strategies must interact with all sites of nociceptive input into the spinal cord—wound infiltration with local anaesthetics will not block inputs from deeper structures, and epidural analgesics may not block all relevant dermatomes or autonomic nociceptive pathways. Importantly, the period of intense nociceptive input may continue well into the postprocedural period, and be heightened by peripheral sensitisation (including inflammatory processes). Thus the treatment used should extend in time to cover this stimulus as well. To achieve this level of control of central sensitisation is very difficult in clinical practice, which explains why the treatment effect seen in many studies is small or absent despite encouraging laboratory work.

Fortunately, blocking nociception or giving analgesics early is effective in decreasing subsequent analgesic requirements, even if sensitisation is not fully prevented. This is called ‘preventive analgesia’, and is characterised by drug effects working beyond their expected intensity or duration. Preventive analgesia has been shown to occur with local anaesthetic techniques (given before surgery), and in some studies with ketamine and dextromethorphan. The effectiveness of opioids and NSAIDs in this role has been less consistently shown.