Gérard Mick and Virginie Guastella (eds.)Chronic Postsurgical Pain201410.1007/978-3-319-04322-7_10
© Springer International Publishing Switzerland 2014
10. Antiepileptics and Perioperative Anti-hyperalgesia: A Survey
(1)
Anaesthesiology and Intensive Care Clinic, Pain Unit, Claude Huriez Hospital, CHRU Lille, 59037 Lille Cedex, France
Abstract
The gabapentinoids, which are a new generation of antiepileptics (AEs), have pharmacological properties that allow perioperative hyperalgesia to be reduced. They have little analgesic effect of their own, but they limit the intensity of pain and the use of analgesia postoperatively. Gabapentinoids thus reduce the incidence of chronic postsurgical pain.
Key Points
The gabapentinoids, which are a new generation of antiepileptics, have pharmacological properties that allow perioperative hyperalgesia to be reduced.
They have little analgesic effect of their own, but they limit the intensity of pain and the use of analgesia postoperatively.
Gabapentinoids reduce the incidence of chronic postsurgical pain.
Introduction
The rationale for using antiepileptics (AEs) in a multimodal perioperative analgesia strategy is based on both an empirical observation and a theoretical conclusion. The surgical approach causes tissue and nerve injuries which result in signs of primary hyperalgesia at the site of the injury and secondary hyperalgesia in adjoining areas. These injuries thus cause neuronal hyperexcitability, particularly in the dorsal horn of the spinal cord, a phenomenon which is commonly referred to as sensitisation. Two hypotheses have been put forward: (1) the spinal cord neuronal hyperexcitability involved in the development of hyperalgesia is partly linked to the transmission of the nociceptive information through synapses whose activity depends on the opening of voltage-dependent calcium channels and could consequently be reduced by AEs which are capable of blocking these channels; (2) since nerve injuries are caused by surgery and some AEs are used to treat neuropathic pain, their use could prevent the occurrence of chronic postsurgical pain. As of today, not all AEs have been used in multimodal analgesia strategies. First gabapentin and then pregabalin, which are referred to collectively as gabapentinoids, have been the subject of special interest because of their pharmacological profile and the results obtained in animals in the area of preventing the central sensitisation associated with tissue or nerve injury.
Pharmaceutical Properties of Gabapentinoids
Gabapentin was initially developed to treat spasticity [1]. From 1993 onwards, the clear anticonvulsant properties of this molecule [2, 3] meant that it could be marketed for preventive treatment of epilepsy, and less than 10 years ago the same was done in the case of pregabalin. More recently the indications for gabapentinoids have been extended to included chronic neuropathic pain [4], particularly diabetic neuropathy [5, 6] and post-zoster pain [7] as well as pain due to other causes [8–11]. Gabapentinoids are structural analogues to gamma aminobutyric acid (GABA) but they actually have no effect on the gabaergic system.
Pharmacokinetics
Absorption
After giving different amounts of gabapentin in a single dose by the oral route, in studies carried out in healthy volunteers, the mean time taken to reach the maximum plasma concentration (Tmax) is approximately 2–3 h, regardless of the dose taken and the formulation [12, 13]. Absorption of gabapentin is linked to an active, saturable transport mechanism (the L-amino acid transfer system) [14, 15] which is present in the intestines and at the blood–brain barrier. This small intestinal transport system partly accounts for the dose-dependent bioavailability by the oral route of approximately 73.8 ± 18.3 % in the case of 100 mg, which gradually falls as the dose administered is increased (35.7 ± 18.3 % for 1,600 mg) [15]. A maximum dose of 5 g per day in three divided doses has been proposed [2], and the usual dose indicated for treatment of neuropathic pain is between 900 and 3,600 mg per day.
Pregabalin has good bioavailability and is absorbed rapidly by the oral route, with a peak plasma concentration reached in 30 min–2 h and an equilibrium level in 24–48 h. Unlike gabapentin, there is a linear relationship between the increase in the dose administered and the plasma concentration. The usual dose indicated in epilepsy and neuropathic pain ranges from 150 to 600 mg per 24 h in adults [16, 17].
Distribution, Metabolism and Excretion
Gabapentinoids do not bind significantly to plasma proteins [18]. They do seem to cross the placental barrier [19] to a large extent and are similarly secreted in breast milk [19]. These molecules are not metabolised in man and cause no enzyme induction or inhibition [20, 21]. After oral administration, the excretion half-life of gabapentin ranges from 5 to 7 h, which means that it has to be taken three times daily. The excretion parameters are not changed following repeated dosing [22]. Oral gabapentin is 80 % excreted unchanged by the kidneys, while the remaining 20 % is excreted in the faeces. Renal excretion of gabapentin reduces with age and dose adjustments are needed in people with renal impairment based on creatinine clearance. In haemodialysis, the maintenance dose of gabapentin is 200–300 mg after each 4 h haemodialysis session. Pregabalin has an excretion half-life of 6.3 h and is 98 % excreted unchanged by the kidneys. Dose adjustment is therefore required in renal impairment.
Drug Interactions
Antacids containing magnesium and aluminium reduce the bioavailability of gabapentin by about 20 %. Cimetidine reduces the apparent oral clearance of gabapentin by modifying the renal excretion of the drug [14]. A study of drug interactions showed no interactions with gabapentin or pregabalin [23], but in clinical practice it has been found that there is a risk of peripheral oedema when it is used in combination with angiotensin converting enzyme inhibitors (ACEi).
Significant Side-Effects in the Context of Perioperative Use
The gastrointestinal side-effects that commonly occur with gabapentinoids may limit their usefulness, but nausea and vomiting have not been reported in studies involving a single high dose of gabapentin. Rorarius et al. found no significant difference in the incidence of side-effects between oxazepam or gabapentin, which appear in one in three cases and include dizziness, dry mouth or sleepiness [24], while Ho et al., found that the incidence of dizziness and sedation was higher in the patients receiving gabapentin [25]. Concomitant administration with other medications, however, only slightly increases the risk of these side-effects occurring [26].
Pharmacodynamics
The mechanism of action of gabapentin and consequently of pregabalin, which binds to the same receptors, was unknown for a long time, but a number of recent studies have made it possible to understand the activity of these molecules better, particularly in relation to neuropathic pain. Some outstanding questions still exist today on the various sites and mechanisms of action of this family of drugs.
Site of Action
Carlton et al. showed that gabapentin has a peripheral action, in a test using intraplantar formalin as a model of acute inflammatory pain in the rat, and obtained a reduction in pain behaviour after using gabapentin without the occurrence of a local anaesthetic effect [27]. Pregabalin also has a peripheral action in a model of neuropathic pain in the rat [28]. The posterior ganglion, in a model of nerve ligation in the rat, is the site of a gene regulation which gradually increases the expression of voltage-dependent calcium channel alpha2-delta units, which are ligands for gabapentinoids, correlated with the tactile allodynia caused by the nerve lesion [29]. It is at this site that gabapentin inhibits calcium flows, preferentially those from type N calcium channels [30], which play an important part in the pathophysiology of neuropathic pain [31, 32]. In the superficial layers of the dorsal horn of the spinal cord, gabapentin reduces the amplitude of post-synaptic currents evoked by nociceptive stimulation, so it can be suspected that there is inhibition of glutamatergic transmission in the central synapse of C fibres. In the deep layers, a more contrasting effect has been demonstrated, with an increase in post-synaptic flows at the level of NMDA receptors [33]. Finally, behavioural studies have shown that gabapentin administered intracerebroventricularly acts supraspinally by activating the alpha2 receptors of the noradrenergic system [34], while this result is only obtained in cases where there is a peripheral nerve lesion [35].
Conditions for Activity
Mechanisms of Action
A number of systems have been studied which are potential targets of gabapentinoids and it is important to avoid any conception that their mechanisms of action are limited.
The Gabaergic System
Gabapentinoids do not act on GABA A receptors [40]. Pregabalin does not act on GABAB receptors, while gabapentin may cause super-selective activation of these receptors [41]. Incubation of gabapentin on dishes of human neocortex obtained from epilepsy surgery increases the concentrations of GABA, but these results were not found in dishes of rat cortex [42]. It is very improbable, however, that the antinociceptive action of gabapentin is even partly associated with an increase in the intracerebral concentration of GABA.
Glutamatergic System
NMDA receptors are involved in the thermal and mechanical allodynia that occurs after nerve injury [43]. Due to the effectiveness of gabapentin in neuropathic pain, the hypothesis has been put forward that it has an anti-NMDA action by increasing the affinity of glycine for its site on the receptor [44] or by reducing the sodium flux across presynaptic receptors [45]. Gabapentin in fact increases the activity of NMDA on gabaergic neurons in the dorsal horn in the rat [46]. It has been noted, however, that in models of postoperative pain insensitive to anti-NMDA molecules administered intrathecally [47], gabapentin was found to have a marked anti-allodynic effect [48, 49]. Finally, gabapentinoids cause a reduction in the intracerebral concentration of glutamate [50], but no link has been established between this and any clinical action [41].
Voltage-Dependent Sodium Channels
Unlike most antiepileptics, gabapentinoids do not affect voltage-dependent sodium channels [41].
Voltage-Dependent Potassium Channels
Voltage-Dependent Calcium Channels
Since neuroplasticity after peripheral nerve lesions contributes to neuropathic pain, Luo et al. suggested that expression of the alpha2-delta subunit in the posterior ganglion may be involved in the development of allodynia after peripheral nerve injury [29]. Over-expression of alpha2-delta subunits has been found in the posterior ganglion in a model of partial nerve ligation in the rat, but not in a rhizotomy model, which suggests that the expression of the alpha2-delta subunit is peripheral in origin [30]. The specific link between gabapentin and the alpha2-delta subunit of voltage-dependent calcium channels [53, 54] causes inhibition of synaptic reuptake of excitatory neurotransmitters, which is the best known mechanism of action of gabapentinoids. There are four isoforms of the alpha2-delta subunit, but only alpha2-delta-1 and 2 are involved in the action of gabapentin. The alpha2-delta-1 subunit is found in all mouse tissues, while alpha2-delta-2 is only found in the brain and the heart. The alpha2-delta subunit and the β subunit are auxiliary subunits for all types of calcium channels and they are associated with the α1 pore in the calcium channel, where they increase transmembrane calcium flows [55] and promote incorporation of calcium channels into the membrane [56]. Gabapentin interacts with all types of voltage-dependent calcium channels (N-L-TP/Q) [57], but its action on type N channels, which are closely involved in all models of nerve injuries, is dominant [58–60]. This blockage of alpha2-delta activity is known to be a fundamental mechanism of action of gabapentinoids [41, 61]. While allodynia and hyperalgesia begin to occur soon after a neurological injury [43], the expression of alpha-2-delta-1 subunits only becomes evident after 7 days [29]. Furthermore, the ubiquitous distribution of alpha-2-delta subunits and the fact that they are blocked by gabapentin or pregabalin may give rise to a large number of major side-effects which are not found in clinical practice [62], which confirms that the effect depends on plasticity processes occurring after nerve injury.
Alpha2-Adrenergic System
The very rapid anti-hyperalgesic effect of gabapentin in animal models of postoperative pain, at a time when the alpha2-delta subunits have not yet been overexpressed, suggests the existence of other mechanisms of action. In the mouse, gabapentin has a supraspinal action, where it activates the noradrenergic bulbospinal tract [34]. Noradrenergic inhibitory neurons originating in the brainstem form a noradrenergic descending tract which activates spinal cord alpha2 receptors with noradrenaline reuptake, causing suppression of the activation of nociceptive neurons [63]. Since peripheral inflammation enhances the activation of inhibitory descending tracts and enhances the sensitivity of neurons in the dorsal horn to inhibitory noradrenergic descending influences [64], Hayashida et al. tested the hypothesis that inhibitory noradrenergic descending tracts are activated in a model of postoperative pain in the rat and found that intracerebroventricular administration of gabapentin causes a rapid effect consistent with a supraspinal action, while this anti-hyperalgesic effect of gabapentin is blocked by systemic or intracerebroventricular administration of an alpha2 receptor antagonist [65]. It has been shown in man that oral administration of 1,200 mg of gabapentin 90 min before surgery with spinal anaesthesia caused an increase in the concentration of noradrenaline in cerebrospinal fluid, while this increase was not observed in the placebo group [65].
Serotonergic System
A population of 45 % of nociceptive neurons in the superficial layers of the dorsal horn of the spinal cord express the substance P receptor called NK1. These neurons have an ascending projection to the thalamus but also to the parabrachial area in the rat [66], which is involved in cognitive functions, fear and anxiety [67]. The destruction of neurons expressing NK1 inhibits hyperalgesia behaviours and reduces the hyperexcitability of neurons in the deep layers of the dorsal horn. This process is largely reproduced by blocking 5-HT3 receptors in the spinal cord [68], which seems to corroborate the existence of a spino-bulbo-spinal loop with a serotonergic excitatory descending pathway. 5-HT3 receptors are colocalised with alpha2-delta receptors in presynaptic calcium channels. It therefore seems that activation of 5-HT3 receptors causes opening of voltage-dependent calcium channels, permitting gabapentin to inhibit the release of excitatory neurotransmitters [69, 70]. The action of intrathecal gabapentin is also blocked by the destruction of neurons that express NK1 or by the use of a 5-HT3 antagonist such as ondansetron [71]. Activation of 5-HT3 receptors, however, allows gabapentin to have an inhibitory activity on dorsal horn neurons, which normally does not exist in the rat in the absence of neurological injury. The activation of this spino-bulbo-spinal loop is therefore essential to the action of gabapentin, which may partly explain why gabapentin has no analgesic effect but does have an anti-hyperalgesic effect [72].
Efficacy Data in Preclinical and Clinical Models of Induced Pain
In Animals
Gabapentin has an anti-hyperalgesic action both peripherally [27] and centrally, by reducing the activation of C fibres, which are free afferent endings, in response to nociceptive inflammatory stimuli in the arthritic rat [73, 74]. In the paw incision model in the rat, gabapentinoids have been shown to have an anti-hyperalgesic action [75] and they reduce the allodynia caused by certain nerve injuries including diabetes, but not the neuropathies caused by vincristine. It seems that in the latter case, the allodynia that is seen is not linked to over-expression of alpha2-delta subunits as it is in all the other models [76]. Unlike ketamine, rising doses of pregabalin have not been shown to have any action affecting the sensitisation of converging neurons in rats undergoing repeated electrical stimulation.
In Man
In a comparative, combined double-blinded placebo-controlled study, Eckhardt et al. compared gabapentin with morphine in healthy volunteers in terms of its effect on the tolerance threshold for application of a cold stimulus. Gabapentin plus placebo had no more effect than placebo alone, and only morphine was effective, but much less so than when it was given concomitantly with gabapentin [77]. Dirks et al. observed that oral administration of 1,200 mg of gabapentin in a single oral dose reduced the area of secondary skin hyperalgesia caused by applying capsaicin or heat [78], as well as the primary mechanical allodynia within the area of skin affected by inflammation caused by applying heat. The severity of the pain and the area of hyperalgesia caused by intramuscular injection of hypertonic salt solution, assessed 8 h later in healthy volunteers receiving 1,200 mg of gabapentin, were significantly reduced in the gabapentin group as compared with the placebo group [79].
Finally, although pregabalin at a dose of 900 mg over 2 days caused no change in pain detection thresholds after repeated electrical stimulation [80, 81], Olesen et al. put forward a subcortical mechanism of action and found that visceral pain caused by electrical stimulation of the sigmoid was attenuated [82].
Gabapentinoids and Postoperative Pain
Analgesic Effects
Straube et al. carried out a meta-analysis and assessed the analgesic effect of a single dose of 250 mg of gabapentin on established postoperative pain. Although the intensity of acute postoperative pain for the 177 subjects receiving gabapentin was significantly lower than for the 172 patients in the placebo group, the effect achieved was significantly lower than the effect of using the anti-inflammatories that are generally used [83].
Anti-hyperalgesic and Analgesic-Sparing Effects
The action of gabapentinoids on central nociceptive transmission mechanisms may allow morphine sparing, thereby limiting the various unwanted effects of opioids [84]. Dirks et al. [85] carried out a randomised trial on the effects of a single 1,200 mg dose of gabapentin, administered 1 h before mastectomy, on both the intensity of postoperative pain and postoperative opiate use over 3 days, and found that there was a significant reduction in morphine use and a reduction in the intensity of pain on mobilisation, although pain at rest was not reduced. Fassoulaki et al. compared mexiletine, an anti-arrhythmic used to treat chronic neuropathic pain, gabapentin and placebo in the same type of operation and observed an analgesic-sparing effect in the gabapentin group, as well as a reduction in the intensity of pain at rest and on mobilisation [86]. Since it was necessary to distinguish the effect of gabapentin on the expression of postoperative pain from possible sedative effects likely to reduce the analgesic requirement, Rorarius et al. compared 1,200 mg of gabapentin administered 2.5 h before vaginal hysterectomy with placebo plus 10 mg of oxazepam, a benzodiazepine with anxiolytic properties, and found a reduction in the intensity of pain and analgesic demand in the gabapentin group but not in the group receiving placebo plus the anxiolytic [24]. The reduction in analgesic use resulting from giving gabapentin during the perioperative period has been shown by many studies [87–93] but the reduced intensity of postoperative pain has not systematically been present as well [89, 91, 92]. Dierking et al. confirmed the reduced analgesic requirement after vaginal hysterectomy but did not find a reduction in the intensity of pain at rest, although this remained very moderate and was rated at 20/100 [88], while Fassoulaki et al. [94], in the same type of operation or after thyroidectomy, found that gabapentin was ineffective in treating the pain and also in reducing analgesic use [95]. The use of pregabalin to manage postoperative pain was assessed in a meta-analysis carried out by Zhang et al. comprising 11 randomised controlled studies in a total of 899 patients, of whom 521 received the treatment. In five of the studies, a dose of less than 300 mg administered preoperatively did permit some morphine sparing. At doses higher than or equal to 300 mg the reduction in opioid use was confirmed, while the intensity of postoperative pain at rest or on movement was not always affected. Subsequent meta-analyses found a small reduction in the intensity of postoperative pain, but the side-effects and the cost were judged to be non-negligible [96, 97].
Gabapentinoids in Multimodal Analgesia
Multimodal analgesia may allow a reduction in postoperative opioid use and facilitate early rehabilitation [98]. Studies of the interactions between gabapentin and the other molecules which are generally used in a multimodal strategy may make it possible to identify additive or synergistic effects. Gabapentinoids reduce perioperative anxiety [99–101] but they have much more limited value in terms of reducing the incidence of nausea [102]. They may offer the prospect of making operations more comfortable for patients [103–105].
Gabapentinoids and Morphine
The pharmacokinetics of morphine is not altered by gabapentin, but the area under the gabapentin curve is increased by adding morphine [77]. A single dose of 600 mg of gabapentin improves the analgesic effect of 60 mg of extended-release oral morphine [77]. Since concomitant use of gabapentin and morphine results in an additive analgesic effect in post-zoster or diabetic neuropathic pain [10], the effect of the combined use of these two drugs on the possible neuropathic component of secondary postoperative pain needs to be studied prospectively [106, 107].
Gabapentinoids and Locoregional Analgesia
One possible benefit that may be obtained from the use of gabapentin may be due to the possibility of a double peripheral and central block of painful stimulation, particularly when loco-regional anaesthesia does not make it possible to appropriately cover the area within which hyperalgesia is likely to develop. This combined use has been shown to be more effective than placebo after total hysterectomy with infiltration of local anaesthetics into the abdominal wall [108]. Gynaecological surgery in fact results in much more intense pain with a major hyperalgesic component, due to diffuse peritoneal stimulation, which is usually not adequately alleviated by simple analgesics and NSAIDs. In shoulder surgery carried out under interscalene block [109], and in thyroid surgery with a superficial cervical plexus block [110], the authors did not, however, find that gabapentin had any additive effect on levels of postoperative pain or on analgesic sparing. The injured tissue does not, however, develop secondary hyperalgesia if the loco-regional analgesia blocks the nociceptive stimulus, preventing its transmission to the central nervous system and therefore limiting the effects of gabapentin in terms of reducing opioid use [95, 111].
Gabapentinoids and NSAIDs
NSAIDs are generally included in a multimodal postoperative analgesia strategy. The combination of gabapentin and naproxen or pregabalin and naproxen has been shown to have a synergistic effect on thermal allodynia in a model of chronic inflammatory pain in the rat [112]. Two studies have shown that the concomitant use of 1,200 or 1,800 mg/d of gabapentin and 50 mg/d of rofecoxib for 3 days postoperatively was more effective than each of these drugs administered alone, both in terms of analgesia at rest and on exercise after hysterectomy [93, 113]. The combination of gabapentin and meloxicam was not found to be effective in scapular pain after cholecystectomy, while gabapentin alone reduced the pain intensity [114]. A study in spinal surgery that assessed oral administration 1 h before the operation and during the 12th h postoperatively, in which either placebo, 400 mg of celecoxib, 150 mg of pregabalin or a combination was given, while patient-controlled analgesia was provided postoperatively, showed that the combination of pregabalin and celecoxib made it possible to significantly reduce both the pain intensity and morphine use.
Gabapentinoids and Alpha2 Agonists
Due to the action of gabapentin on descending noradrenergic tracts, an interaction is suspected to exist with clonidine, an alpha2 agonist widely used for the management of perioperative analgesia. Cheng et al. studied a model of postoperative pain resulting from a paw incision in the rat, and were able to show an analgesic effect from 100 μg of intrathecal gabapentin and a synergy between the actions of the two drugs [48], which was confirmed in a model of inflammatory pain [115].
Modalities of Administration
Pandey et al. assessed the optimum dose of gabapentin that should be given perioperatively in order to obtain a significant improvement in pain and in terms of postoperative fentanyl use. A single dose of 600 mg given 2 h before lumbar laminectomy seemed to be optimal, with no significant difference between 600 mg or 1,200 mg when the dose was given preoperatively [116, 117]. Khan et al., however, found no difference in efficacy between 900 and 1,200 mg of gabapentin administered before or after laminectomy, while a dose of 600 mg was insufficient to have a significant effect. It seems that a dose of 100 mg of pregabalin is insufficient to achieve a reduction in pain after minor uterine surgery [118], while 300 mg is effective in acute pain associated with dental extractions [119]. Since gabapentinoids are administered in oral form, using them as a premedication does in any case seem to be easier. Gabapentin is therefore given 1 or 2 h before the operation [90, 111], while 2 h seems to correspond best to the kinetics of gabapentin and pregabalin. Adjustment of the dose of gabapentinoids depending on the type of surgery should be mentioned, as well as continuing to administer it after a single postoperative dose, but at present it is not possible to come up with answers on these points on the basis of the literature.
Related posts:
Psychosocial Factors Involved in the Occurrence of Chronic Postsurgical Pain
The Role of Coxibs in the Management of Postoperative Pain
Risk Factors for Chronic Postsurgical Pain
Perioperative Strategy for Prevention of Chronic Postsurgical Pain: General Foundations
Chronic Post-mastectomy Pain: Clinical Aspects
Scar Neuromas
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
