Drug Effects and Altered Perioperative Pain Processing

FIGURE 1 The three pain-lab tests upon which the suggested construct of pain modulation profile is based.

The advent of dynamic psychophysical protocols took us ahead in the ability to describe pain modulation of individuals. This line includes tests that try to evoke an experimental process of pain modulation in the examined subject, thus, bringing us closer to the ‘real’ pain experience pain patients go through. The most commonly used test protocol to examine pain facilitation is temporal summation. In this protocol subjects receive a series of identical painful stimuli, and report the intensity along the series, or at least at its start and end. Typically, given that the first stimulus is painful, subjects will report an increase in pain intensity along the series. Spatial summation is another protocol representing pain facilitation. Though less explored, it represents an increase in pain perceived intensity as the area of stimulation increases.

Test protocols that examine pain inhibition consist of conditioned pain modulation (CPM)[54] based on DNIC [29], and offset analgesia (OA)[18]. In the first, two remote painful stimuli are given, a test-stimulus and a conditioning-stimulus. The pain intensity rating given for the test-stimulus when given alone (practically a suprathreshold) usually decreases when it is reapplied concomitantly or immediately after administration of the conditioning stimulus, which should be painful as well [see 11, 40 for methodology]. Not all healthy individuals express this inhibition, about one quarter to one third, pending on the protocol used for the stimulation, express an increase of the pain rating to the test-stimulus due to conditioning stimulation. These individuals express facilitation of the test stimulus pain as a result of the conditioning stimulus pain and are said to have less efficient CPM response than those who are able to inhibit pain. The OA protocol consists of a single noxious stimulus, whose intensity is slightly increased for a very short time, and immediately returned to the initial intensity. Individuals typically report lesser pain intensity at the immediate post-offset epoch, compared to the report given in the beginning for the same stimulus intensity.

The profile of pain modulation, as reflected by the above mentioned tests, thus, can consist of results of three kinds of tests: (i) Suprathreshold estimation of pain intensity, where individuals reporting higher pain will be termed pro-nociceptive, and those with lower pain will be anti-nociceptive. (ii) Mainly facilitatory tests, where individuals reporting enhanced summation will qualify as pro-nociceptive, while those with lower summation (or even adaptation or habituation) are anti-nociceptive. (iii) Mainly inhibitory tests, where individuals with less-efficient CPM, for example, are pro-nociceptive, while those with efficient CPM are anti-nociceptive. It is not yet clear what are the interrelations between the various factors of pro-nociceptivity – is presence of one factor different in its clinical expression than presence of two or three, and whether the factors contribute equally, or have different weights.

Clinical implications of pro-nociceptivity are under current research, and understanding is cumulating. The part of the puzzle which is best known, is the presence of pro-nociceptive lab tests in patients with chronic pain. This has been shown repeatedly for both the inhibitory and the facilitatory tests, in many pain syndromes; for CPM, less-efficient inhibitory pain modulation was reported for fibromyalgia [2,20,25], irritable bowel syndrome [12, 24, 45], migraine [42], tension-headache [8, 37], temporo-mandibular disorder (32), osteoarthritis and muscle pain [4, 26] and whiplash [14]. For TS, enhanced pain facilitation was documented for fibromyalgia [28,39,46,47], osteoarthritis [4], migraine [50], temporo-mandibular disorder [17, 33, 43, 44] and whiplash [30,48]. Other parts, for example, the clinical expression of anti-nociceptive pain modulation profile are much less explored.

In the context of pain in the perioperative period, one needs to distinguish between (i) pain modulation at pain free pre-operative time, and its effect on upcoming pain on one hand, and (ii) the changes in pain modulation acutely and chronically after surgery, and their association with clinical pain –acute or chronic – on the other. For the first, there is a good number of papers exploring the predictive value of suprathreshold magnitude estimation of pain on the acute post-operative pain, as briefly mentioned previously. Data was reviewed by Abrishami [1], showing suprathreshold heat pain magnitude estimation to the factor most likely to correlate with post-operative pain in the acute phase. Though not all studies supported the concept, the data does concur with the notion of lab based pro-nociception expressed later as higher acute pain phenotype. A few works examined the predictive value of dynamic psychophysical parameters on post-operative pain. Our group had shown that CPM affects chronic post-operative pain. In a cohort of patients scheduled for thoracotomy, an efficient CPM was found to predict lower rates of chronic post-thoracotomy pain [55]. Similar data was also obtained by Wilder-Smith et al, for abdominal surgery [52]. Landau et al reported prediction of acute post cesarean section pain by preoperative CPM [27]. For TS, Weismann-Fogel et al [49] found higher acute post thoracotomy pain for subjects with enhanced summation. These studies, again, concur with the basic understanding that individuals who exhibit pro-nociception are at higher risk for acquisition of pain – acute or chronic – in the context of surgery.

Changes in pain modulation after surgery were reported in a few papers. Wilder-Smith et al [51, 53] reported an anti-nociceptive state during the first 24 hours after back surgery, shifting later to pro-nociceptivity. In many studies the experimental pain parameters in the acute post-operative period are under influence of analgesic agents, and it is difficult to deduct on the ‘natural history’ of pain modulation at that period [51]. The overall conclusion seems to be that the CNS exposure to peripheral nociceptive activity drives a shift of pain modulation towards pro-nociceptivity. Being in this profile probably causes patients to be more susceptible to pain by various stimuli, and maybe also less responsive to pain treatment. The very interesting question on how does this pro-nociceptivity affect the chances of acute post-operative pain to become chronic is still open.

The influence of drugs on pain modulation depends on the drug mode of action. This text, will concentrate on drugs which act centrally, and can be considered as modulating central pain processing. Drugs can be used: (i) before surgery, to potentially render the system more anti-nociceptive, and therefore more resistant to the nociceptive neuronal barrages, resulting in lower clinical pain. The term pre-emptive, or better: preventive analgesia had been used for this concept [see 22 for elaborate discussion], and (ii) after surgery, when drugs are expected to lower the pro-nociceptive modulation derived from the nociceptive exposure during surgery. Before going into more details on these two lines, I would like to elaborate on the interaction of drugs and pain modulation, where data is available mostly from non-surgical medical disorders. The leading concept here is that for analgesic drugs that have a CNS effect, efficacious use of the drug will be obtained if administration is based on coupling of drug’s mode of action with patient’s dysfunction of pain modulation. This way, if for a specific patient a certain mechanism is dysfunctional, for example, CPM is less efficient, a drug that augments pain inhibition, and therefore improves CPM, would be the likely drug to cause pain amelioration for this individual. For another individual, whose CPM is efficient, one would expect a little effect of such drug – if any. For the latter patient, drugs which exert their analgesic effect via other modes of action should be used. Our group has recently shown that painful diabetic neuropathy patients responded to duloxetine along this line of thinking [56]. Duloxetine is an SNRI, whose main action is to inhibit reuptake of noradrenalin and serotonin, the two neurotransmitters that exert the descending pain inhibition effect at the spinal dorsal horn level. We found that patients with less efficient CPM were the ones to respond to the drug, while those with efficient CPM to begin with, did not respond to the drug. Further, for the former, CPM improved in parallel to the decrease in pain, while for the latter, it did not change.

A parallel line can be drawn for the facilitatory tests. Patients with enhanced summation should be the ones to best respond to drugs of the gabapentinoid family, which are Ca⁺⁺ channel ligands, whose main mode of action is reduction of neuronal sensitization. Reduction of TS by PGB has been demonstrated in healthy volunteers [3

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