**5. Pregabalin**

The pregabalin is an antiepileptic drug whose effectiveness to treat neuropathic pain was discovered in 1965 [37]. It was originally used in the 1990s as an anticonvulsant drug [20] and in 2004 it was approved by FDA for neuropathic pain, then fibromyalgia in 2007 and spinal cord injury neuropathic pain in 2012 [30]. Over the last decade, pregabalin has acquired a new use, for preventing postoperative acute pain and as an opioid spare strategy, and its use became widespread and routine in some countries [20].

Pregabalin has no activity at GABA receptors, but it acts on binding to the α-2δ subunit of voltage-gated P/Q-type calcium channels [21]. The α-2δ receptor has 4 isoforms. The α-2δ-1 isoform mediates the effects of gabapentinoids, and it is found in the brain, skeletal, cardiac, and smooth muscle. The α-2δ-2 and α-2δ-3 isoforms are present in non-neuronal tissues as well, and the α-2δ-4 subunit is expressed in retinal neurons and other non-neuronal tissues [23].

The binding to the α-2δ may inhibit or modulate the process of calcium influx through these channels, on the synaptic bulb of presynaptic neurons, thus inhibiting the release of glutamate and substance P. Additionally, the analgesic effect may occur due to activation on the descending inhibitory noradrenergic pathways [21, 37] and due to inhibition of ascending pain transmission [21, 30].

The bioavailability of pregabalin is approximately 90% and its half-life is about 6–7 hours which allows its use twice a day. Its binding to proteins is minimal and the drug is renally excreted [21, 38].

#### *Topics in Regional Anesthesia*

In comparison to gabapentin, pregabalin has an affinity for the type N voltage dependent calcium-channel six times higher [38]. Because of the expression of α-2δ in cerebellum and hippocampus, pregabalin can cause dizziness, balance disorders, ataxia, visual disturbances, sedation, somnolence, and cognitive impairment [30]. Pregabalin has an antiemetic potential, and it showed significant results for postoperative nausea and vomiting (PONV) reduction, but the primary outcome was never the PONV occurrence [39].

Currently, pregabalin is part of the multimodal anesthetic approach as well as opioid-spare strategy [9, 30]. In addition, although FDA has not approved, pregabalin is used to prevent acute postoperative pain [30].

A 2017 meta-analysis evaluating the use of gabapentinoids for the treatment of acute postoperative pain following spinal surgery showed reduced pain scores compared with placebo. However, the heterogeneity caused by different dosing protocols reduced the level of evidence [24]. In addition, pregabalin seems to be more effective in conditions associated with chronic pain [24]. On the other hand, in an editorial of Anesthesiology published in 2020, the evidence of risk of perioperative gabapentinoids was described to increase, while the benefit has diminished [30].

A 2019 review article showed the limited analgesic benefit of gabapentinoids. In addition, they were shown to increase sedation and dizziness. These drugs increase the potential of opioid-induced respiratory depression and sedation, and they are not part of strategy in enhanced recovery [39].

Finally, in a recent meta-analysis it was reported that the perioperative use of gabapentinoids failed to demonstrate differences in postoperative acute, subacute and chronic pain and the adverse effects caused are underreported [20].

Regarding pregabalin use in the context of regional anesthesia, there are few studies published. The use of pregabalin could not reduce the pain scores at rest or with movement with regional anesthesia. The only positive results were the pooled results of both general and regional anesthesia that showed a 24 h opioid consumption reduction. However, there are several limitations of this study, such as heterogeneity and the risk of bias in individual studies [40].

As the use of pregabalin for the management of postoperative pain is *off label*, there are no dosing guidelines for this indication, neither the ideal dose [40] nor the treatment duration are established [21]. Additionally, it is very unlikely that the use of gabapentinoids could provide additional analgesia benefits in the context of regional anesthesia. Only in selected groups there might be some benefits, and these groups are not known. Therefore, this drug, if recommended, should be used cautiously. Further studies are needed to evaluate the real cost-effectiveness of this approach.

The use may initiate preoperatively, intra-operatively, or postoperatively. Despite scarce evidence, some studies recommend: Pregabalin 75–300 mg 1-2 h before incision, Pregabalin 150–300 mg twice a day, with use for 5 days and Pregabalin 150 mg twice a day for 14 days [21].

Patients in hemodialysis demand extra care, because of its renal excretion [39]. Therefore, the maximum daily dose of pregabalin (in mg) and its correlation with creatinine clearance (in ml/min) is: 600 mg if the clearance is higher than 60 ml/ min; 300 mg if the clearance range is from 30 to 60 ml/min; 150 mg if the clearance range is from 15 to 30 ml/min; and 75 mg if the creatinine clearance is lower than 15 ml/min [21].

#### **6. Conclusion**

Despite the inconsistencies between the reported results, gabapentinoids may be a strategy for preventive and multimodal analgesia in major surgeries, particularly

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

pregabalin, considering its pharmacokinetics profile. Situations where there are limitations of regional anesthesia techniques or in cases where there is an intention to reduce the use of opioids or anti-inflammatory drugs at the trans-operatory period are good opportunities for their use. However, further studies are needed to evaluate the real cost-effectiveness of this approach. Additionally, specific attention should be paid to minor and ambulatory surgeries as well as for the elderly patients to which gabapentinoids are clearly not beneficial and potentially harmful.
