**3. Gabapentinoids**

Gabapentinoids, a class of drugs including gabapentin and pregabalin, were originally marketed in the 1990s for use as antiepileptics but they have anxiolytic effects and subsequently they were approved to treat neuropathic pain conditions [19, 20]. In Anaesthesiology, these drugs have received increased attention in recent years particularly for preventive analgesia while, on the other hand, the prescription of opioids tended to decrease once they were related to adverse events and suboptimal patient outcomes.

Gabapentinoids were designed as GABA analogues although they do not have any effect on GABA receptors directly [21]. These drugs bind to voltage-gated calcium channels, reducing calcium influx inside the presynaptic terminals [21].

The voltage-gated calcium channels are composed of multiple subunits, but the α-2-δ component has a great association with pain processing. Some studies suggest that increased levels of these subunits may lead to neuropathic pain, even without nerve damage [22]. When the nociceptors are sensitized and activated by a minimal stimulation, the action potential transmitted to the dorsal horn allows the activation of voltage-gated calcium channels and a calcium influx and glutamate release, evoking primary hyperalgesia. In other words, at the site of inflammation and in the dorsal horn, an excitatory signal is produced, increasing postsynaptic nociceptive activation [6, 22]. On the other hand, gabapentinoids can soften the release of excitatory neurotransmitters and reduce the hyperexcitability of dorsal horn neurons induced by tissue injury, explaining their effectiveness on neuropathic pain [22].

Other sites of action involved in the gabapentinoids' analgesic effect have been described with limited evidence, such as sodium channels, NMDA receptors and others. Briefly, a more accurate description of their mechanism is the depression of presynaptic excitatory input onto dorsal horn neurons through interactions with α-2-δ subunit of the voltage-gated calcium channels that are upregulated after injury. Moreover, they inhibit forward trafficking from the dorsal root ganglion, their recycling from endosomal compartments and stimulate glutamate uptake. Additional mechanisms not directly related to neurotransmitter release at dorsal horn include inhibition of descending serotoninergic facilitation, stimulation of descending inhibition, anti-inflammatory actions and influence on the affective component of pain [23]. Indeed, a meta-analysis concluded that gabapentinoids can reduce pain scores in the first 24 hours as well as they may decrease the cumulative consumption of morphine and side-effects, such as nausea, vomiting and itching after spinal surgery [24].

In pharmacological aspects, gabapentinoids have only oral presentations and are easily tolerable by the patients. The most common side effects reported are sedation, dizziness or headache, peripheral edema, and visual disturbances [25].

Although gabapentin and pregabalin have similar structure and mood of action, pregabalin presents higher affinity to the calcium channels subunit site which may evoke not just an increased efficacy but also a risk for side effects in situations that require higher doses [23].

The main differences between these two drugs arise not from different modes of action but rather from different bioavailability. Although both drugs are absorbed by amino acid carriers, gabapentin absorption is limited to a relatively small part of the duodenum, whereas pregabalin is absorbed throughout the small intestine [26]. Therefore, gabapentin presents a plasmatic peak concentration in three hours, in opposition with pregabalin which is rapidly absorbed and demonstrates a peak of plasmatic levels in just one hour associated with a more linear pharmacokinetic profile and less variable bioavailability [21].

Gabapentinoids have a low rate of binding with plasma proteins, their metabolism is not dependent on the liver, and they are excreted unchanged in the urine. Also, the elimination half-life ranges of gabapentin and pregabalin are 4.8–8.7 h and 5.5–6.3 h, respectively [22]. On these terms, patients with kidney failure must have a medication dose adjustment [27, 28]. Similarly, these agents should be used with caution, or the dose should be decreased in elderly [29].

#### **4. Gabapentin**

Gabapentin was first approved by the Food and Drug Administration in 1993 and it was initially meant to treat seizures, but as time goes by, it started to be used for chronic pain [30]. Gabapentin consists of a GABA molecule covalently bound to a lipophilic cyclohexane ring. Considering its lipophilic profile, it can cross the blood–brain barrier and it can become an active GABA agonist. As an anticonvulsant drug, it can inhibit tonic hindlimb extension in the electroshock seizure model, as well as clonic seizures [30].

Although gabapentin is approved to treat chronic pain with regular doses ranging from 900 to 1200 mg per day, it is also used as antiepileptic medication (900 to

#### *Gabapentinoids in Preventive Analgesia: Pharmacological and Clinical Aspects DOI: http://dx.doi.org/10.5772/intechopen.98900*

1800 mg daily) usually requiring a second anticonvulsant drug. However, it is not approved by the FDA for treating or preventing surgical pain, despite its off-label use increase worldwide as well as its recommendation for larger doses and longer treatment duration [31–33].

Gabapentin began to be used as a co-analgesic in the preoperative, as the studies showed no risk of intake, besides the fact that it substantially reduces pain during movement and decreases morphine consumption, making it a very promising medication in the opioid sparing or multimodal strategy. Even though the FDA has not approved it for this use, preoperative gabapentinoids have been widely used. The most common side effects associated with gabapentin use were: sedation, dizziness and peripheral edema [34].

Several clinical studies and meta-analyses reveal that perioperative gabapentin helps to evoke a markedly opioid-sparing effect and a decrease in postoperative pain score [35, 36]. In contrast, Verret et al. reported no clinically significant analgesic effect for the perioperative use of gabapentinoids and a greater risk of adverse events [20].

The use of 150 to 1200 mg of gabapentin prior to the surgery, and in the day after is the most common strategy for decreasing narcotics consumption in a multimodal strategy [21]. The use may initiate preoperatively, intra-operatively, or postoperatively. Despite little evidence, some studies recommend: Gabapentin 1200 mg 1-2 h before incision, Gabapentin 600 mg three times a day for 5 days and Gabapentin 600 mg for up to 14 days [21].

However, patients may show some level of sedation and, therefore, it is recommended to avoid its use in ambulatorial patients as well as caution use in elderly and in patients with cognitive impairment. On the other hand, there are almost no studies using gabapentin and regional anesthesia, so more data should be gathered in order to develop a safe protocol for larger and more routine use, considering risk and benefits.
