Several studies have suggested the gabapentin has the potential to become a routine part of acute postoperative pain treatment. Patients with preoperative pain and poor postoperative pain management are at risk of developing prolonged postoperative pain, in up to 50% in some series [1]. In Mongolia, the demand for total knee arthroplasty (TKA) has increased, and TKA is recognized as causing significant postoperative pain [2]. International centers use multimodal balanced analgesia, including non-steroidal anti-inflammatory drugs, opioids via patient-controlled infusion pumps, local infiltration, and femoral nerve block [3]. In comparison, the medical supply system in Mongolia is underdeveloped, resulting in frequent shortages and inconsistent supplies of medicine. Patient-controlled analgesia (PCA) pumps, ultrasound access, nerve stimulators, and insulated needles for nerve blocks are seldom available. Furthermore, anesthesiologists are unfamiliar with multimodal analgesia and have inadequate practical training in peripheral nerve blockade. Hence, this study explored an option for multimodal analgesia based on a new medication that does not require additional equipment or complex procedures. We assessed the use of oral gabapentin as an adjuvant to multimodal analgesia in our country.

Gabapentin is an anticonvulsant that has antinociceptive and antihyperalgesic properties. It has a well-established role in the treatment of chronic pain. It is effective for neuropathic pain, such as diabetic neuropathy and postherpetic neuralgia [4,5]. Many meta-analyses and clinical trials have shown that perioperative gabapentinoid use has a significant opioid-sparing effect and probably improves postoperative pain scores relative to controls. Several studies have examined whether gabapentin treatment has the potential to become a routine part of acute post-surgical pain management [6-11]. However, a recent study suggested that gabapentin cannot prevent acute postoperative pain in TKA [12].

We recognized that with our current multimodal analgesia regimen, our patients rarely complain of postoperative pain, even on movement of the knee. As a measure of pain relief, we used the amount of fentanyl (background infusion and PCA bolus).

Therefore, this study examined the effect of gabapentin as a component of multimodal analgesia by comparing the pain scores using a visual analogue scale (VAS) and fentanyl use between the two groups. We also explored opioid-related adverse effects following TKA.

This study was approved by the Ethics Committee of Mongolian National University of Medical Sciences (File No.: 13-16/2A 2013-05-10). All patients in the study provided written informed consent.

We calculated the sample size needed to find a difference in fentanyl consumption (μg) when patients are treated with gabapentin compared with standard treatment. We set a statistical power of 80% at the 0.05 significance level and set a clinically acceptable margin for fentanyl consumption at 65 μg. This required 37 subjects in each group. The study size was increased to 50 patients per group to ensure that a sufficient number of patients were included that experienced nausea and vomiting as side effects. The study included TKA patients seen at the First Central Hospital of Mongolia between November 2013 and August 2015 with American Society of Anesthesiologists (ASA) class I-III; age 15-75 years; and body mass index (BMI) < 35 kg/m². Out of 122 eligible patients scheduled for TKA during this period, 22 were excluded for the following reasons: diabetes mellitus, renal or hepatic insufficiency, preoperative opioid usage, peripheral neuropathy, required general anesthesia, were unable to use PCA, or declined participation in this study (Fig. 1). Consequently, 100 patients were enrolled and randomly assigned to control (placebo) and treatment (gabapentin) groups (Fig. 1).

Random assignment was carried out by choosing a sealed envelope from a transparent box that originally contained 50 envelopes for each group. The senior anesthesia nurse picked the envelope 1 day prior to surgery and presented the result of the selection to the pharmacist who provided the tablets to the unit nurse who was blinded to the results. The pharmacist had no access to or interaction with the patients. The surgeons, anesthesiologists, unit nurses, and patients were all blinded during the study.

This study examined the effects of gabapentin on postoperative pain following TKA and any nausea and vomiting in the two groups. The treatment group was given 600 mg of gabapentin (Tebantin 300 mg, Gideon Richter, Budapest, Hungary) 2 h before the surgery and 300 mg of gabapentin at 9:00 p.m. for 3 days postoperatively. Given that all TKA surgeries are planned surgeries, the hospital schedules them during the first half of the day. The control (placebo) group was given identical appearing placebo capsules at the same times as those prescribed for the treatment group.

The two patient groups did not differ significantly in age, gender, BMI, duration of anesthesia, or surgery apart from the ASA class (Table 1).

Pain scores analyzed using the VAS revealed a very low level of pain overall, with the mean VAS score often below 1. As expected, the VAS was marginally higher during movement. In addition, the VAS was consistently higher in the control group at all times starting 6 h postoperatively. After applying Bonferroni’s correction for repeated measures, the VAS score differed significantly at rest at 24-47 h and with movement at all times beginning 6 h postoperatively (Table 2).

On the first postoperative day, the background fentanyl dose was 485.1 ± 13.5 μg for the treatment group and 491.7 ± 17.5 μg for the controls (P = 0.053). On the second day, it was reduced to 349.7 ± 83.2 for the treatment group and 405.2 ± 64.1 for the controls (P = 0.001). The bolus fentanyl dose was 12.3 ± 20.7 for the treatment group and 14.1 ± 17.6 (P = 0.656) for the controls, and did not differ significantly (Table 3).

In terms of side effects, the incidence of PONV was compared between the two groups (Table 4). Incidence of nausea was almost twice as low in the treatment group compared with the control at 6-11 h postoperatively, but the differences were not statistically significant.

This study suggests that perioperative gabapentin reduces postoperative fentanyl use in patients undergoing TKA; however, the difference was not clinically significant. Pain after TKA is due to both surgical stimulation and neurogenic factors. Recent postoperative pain treatment methods include several analgesic drugs with different mechanisms of action [3]. Gabapentin is primarily used as an anticonvulsant, but many studies have demonstrated that it also has antihyperalgesic effects [6-11]. Presurgical treatment with gabapentin may prevent abnormal pain responses such as hyperalgesia and allodynia and it reduced acetic acid-induced visceral nociception in animal studies [13,14]. The mechanism of the antihyperalgesic action may be the result of postsynaptic binding to the alpha2-delta subunits of the voltage-gated calcium channels in the dorsal horn neurons in the spinal cord, causing decreased calcium entry into nerve endings, attenuating postsynaptic excitability, and decreasing the release of neurotransmitters. The decreased calcium influx reduces the release of excitatory amino acids such as glutamate and substance P, leading to a reduction in the hyperexcitability of dorsal horn neurons induced by tissue and nerve damage [15,16].

There is evidence that gabapentin safely reduces the VAS pain score, increases patient satisfaction and decreases postoperative nausea, vomiting and pruritus [6-11,17]. Gabapentin has been used to treat postoperative acute and chronic pain following major lower limb surgery [7,18-21]. However, a recent well-designed study found that the use of gabapentin cannot prevent acute postoperative pain following TKA, and it resulted in increased adverse reactions [12].

Pre-procedural gabapentin treatment is also effective in treating pain during spinal, otolaryngological, gynecological, and endoscopic procedures, and burn wound debridement [9,15,16,22-25]. Some studies suggest that it reduces the stress response that may occur during laryngoscopy and tracheal intubation [26].

In our study, diclofenac sodium, metamizole, and a single- shot femoral block were administered preoperatively. Gabapentin was used as an additional agent in the treatment group. Postoperatively, all patients were given a background infusion of PCA fentanyl. On the first day, the fentanyl consumption was the same in both groups. On the second day, however, the fentanyl consumption was significantly lower in the treatment group. Clinically, however, 50 μg may not provide a significant difference. This difference may be attributed to the use of multimodal analgesia. Using the VAS, the overall level of pain was low compared with other studies [6-11], although the scores were higher in the control group. This overall low level of pain reported in our Mongolian patients may be an area for further study. In animals, gabapentin increases the effect of diclofenac sodium when these are used together in the subarachnoid space [27]. In our patients, diclofenac sodium 75 mg IM was given 1 h preoperatively and three times a day postoperatively to both groups. This treatment will affect postoperative pain relief. One study reported that gabapentin and morphine have synergistic effects [28].

Studies have used different doses of gabapentin for pre- and postoperative pain management. Some studies suggest starting with a 300-mg dose for acute pain, although a preoperative dose of more than 600 mg was not effective at reducing postoperative pain [29]. We gave gabapentin 600 mg 2 h preoperatively and 300 mg for 3 nights postoperatively. Some studies reported a higher incidence of sedation and somnolence with higher doses, so we opted for 300 mg of gabapentin in the evenings because our patients were not closely monitored at night.

Gabapentinoid drugs have relatively mild side effects, but high doses can cause dizziness, sedation, nausea, loss of balance, lower limb edema, urinary retention, constipation, and pruritus [11,12,30]. Several studies using gabapentinoids for acute postsurgical pain have reported PONV. In a study using gabapentin for hysterectomy pain, PONV was more common in the control group than in the treatment group. Studies have revealed that gabapentin reduces PONV [8,30]. In our study, there was no significant difference in the incidence of vomiting between the two groups, while nausea was 50% less frequent in the treatment group 6-11 h postoperatively, which is consistent with other studies [8,21]. One of our patients experienced higher sedation on the 2^nd and 3^rd postoperative days; however, no serious problem was identified on brain computed tomography. The PCA fentanyl and gabapentin were discontinued in this patient, who was removed from the analysis. We did not observe any other side effects of gabapentin, such as loss of balance, lower limb edema, and pruritus. In our hospital setting, all TKA patients had lower limb edema for 3-4 days, which was mainly due to fluid infusion to manage hypotension, the tourniquet, and the major surgery leading to disruption of the lymphatics.

There are several limitations to our study. The distribution by ASA class in the two groups was relatively uneven. There is also increasing debate in the arthroplasty literature on the value of a physiotherapy measure of functional outcome. Therefore, future research should incorporate functional outcome measures, both self-reported and rehabilitation-based, to monitor recovery following TKA. One reason that we wished to explore the value of gabapentin in our country (with its irregular supply chain, limited access to PCA machines, and limited skills in peripheral nerve blocks) was to see if the medication would be valuable under our conditions. We now plan to study the use of gabapentin without the use of nerve blocks or PCA fentanyl. While this might be seen as providing a less satisfactory level of multimodal analgesia, it is standard practice in some areas; also, the simple addition of oral gabapentin may improve outcomes in these settings.

In conclusion, perioperative gabapentin for TKA does not reduce postoperative pain or lead to a clinically significant reduction in fentanyl use in the context of multimodal analgesia.