The Impact of Pre-emptive Large Dose of Methylprednisolone Combined With Gabapentin on Pain Treatment and Convalescence After Total Knee Arthroplasty in Elderly. A Randomized Control Study

Background The aim of the study was to assess whether administration of gabapentin and methylprednisolone as “pre-emptive analgesia” in a group of patients above 65 years of age would be effective in complex pain management therapy following total knee arthroplasty (TKA). Material and Methods One hundred seventy, above 65 years old patients were qualied for the study, and 10 patients were excluded due to clinical situation. One hundred sixty patients were double-blind randomized into two groups: the study (eighty patients) and controls (eighty patients). The study group received as “pre-emptive” analgesia a single dose of 300 mg oral gabapentin and 125 mg intravenous methylprednisolone, while the others placebo. Perioperatively, all the patients received opioid and nonopioid analgesic agents calculated for 1 kg of body weight. We measured the levels of inammatory markers (leukocytosis, C-reactive protein - CRP), pain intensity level at rest (numerical rating scale - NRS), the life parameters and all complications. Results Following administration of gabapentin and methylprednisolone as “pre-emptive” analgesia CRP values being lower on all postoperative days ( 1, 2 days - p<0,00001, 3 day – p=000538), leukocytosis on day 2 (p<0,0086) and 3 (p<0,00042), the NRS score at rest 6, 12 (p<0,000001), 18 (p<0,00004) and 24 (p=0,005569) hours postoperatively . Methylprednisolone with gabapentin signicantly decreased the dose of parenteral opioid preparations (p=0,000006). The duration time of analgesia was signicantly longer in study group (p<0,000001). No infectious complications were observed; in the control group, one patient manifested transient ischaemic attack (TIA). pain on the day of surgery, the dose of opioid analgesic preparations, the level of inammatory parameters without infectious


Introduction
Total knee arthroplasty (TKA) is performed in older patients due to degenerative lesions for improvement the quality of life. The postoperative period is associated with inconveniences, including pain of maximal intensity on day 1 1 . Surgery, as a mechanical factor, initiates the pain process, incites nociceptors, evokes hyperalgesia, releases in ammatory mediators at the site of surgery and through damaging the vessels along with the anticoagulative and antiadhesive lining covering the vascular endothelial cells, initiates local as well as generalized the in ammatory process [2][3][4] .
Prolonged administration of glucocorticoids in patients with osteoarthritis limits the in ammatory process, reduces chronic pain, through inhibition factors evoking hyperalgesia, synthesis of proin ammatory factors and blocking elements of the inborn immune system. The use of methylprednisolone at the dose of 125 mg as "pre-emptive" analgesia  has been also initiated since 2013, the Lundbeck Foundation of Denmark has been recommending using the medication as an element of the Enhanced Recovery After Surgery (ERAS) protocol in TKA [5][6][7][8][9]11 .
Gabapentin is employed in managing chronic pain due to its effect exerted on cerebral modulation and perception of pain, somnolence as adverse effect, postoperatively, is bene cial 12,13 .

Objective
The objective of the study was assessment of employing methylprednisolone and gabapentin in complex pain management in the perioperative period in patients above 65 years of age subjected to TKA. The authors attempted to answer whether administration of a single dose of methylprednisolone and gabapentin as "pre-emptive" analgesia would reduce: (1) the level of postoperative pain, the numerical rating scale (NRS) at rest every 6 hours on day 0, (2) the dose of parenteral analgesics agents, mainly opioids, (3) the occurrence of adverse effects that would delay early rehabilitation, (4) the in ammatory process parameters, (5) maintain stable glycemia levels.

Study design and patients enrollment
This study was a single-center, prospective, double-blind randomized controlled trial conducted in a tertiary care hospital. Ethical approval for this study was provided by the Bioethics Committee of the Jagiellonian University, Krakow, Poland (nr 1072.6120.11.2020, 23/01/2020) and registered with ClinicalTrials.gov (ID: NCT04653415, 28/11/2020). All research was performed in accordance with relevant guidelines and the Declaration of Helsinki. After obtaining oral and written consent to participate in the study, consecutive patients above 65 years of age, operated on due to unilateral TKA in the period June 1 to December 31, 2019, with the procedures following the ERAS protocols were recruited. We excluded patients due to clinical situation that 1/ restricted glucocorticoid administration: diabetes type 1 and 2, CRP levels above normal values (≥ 5 mg/l), chronic steroid treatment, peptic ulcers treated in the past 30 days and 2/and the chronic pain in the course of gonarthrosis, high intensity requiring use opioids.

Randomization
Before surgery all the included patients were randomized into two groups -the study (pre-emptive large dose of methylprednisolone and gabapentin) and controls (placebo).The allocation was performed in the preanesthetic clinic. Individual not involved in the study prepared block randomization (block sizes 4 and 6) and used sealed envelope technique for allocation concealment. Clinical trial was coded by the topic manager without affecting the experimenters.

Procedure
First and foremost, prior to anesthesia induction, each patient received prophylactic anti-infection intravenous cephazolin 2.0 g, tranexamic acid 1.0 g for hemostasis control, and an anti-emetic agentondansetron 8 mg. Patients were then subjected to the standardized procedure of subarachnoid anesthesia with subsequent unilateral femoral nerve block on the operated side, followed by the surgical procedure -unilateral TKA. Fluid crystalloids administration was standardized to 12 ml/kg in the rst hour of surgery, followed by 6 ml/kg for the remainder of surgery. Packed red blood cells were prepared in case if blood loss exceeded 600 ml and a hemoglobin concentration < 10 g/l during the time of operation. Pain management was carried out based on the results of the NRS scale at rest. Patient NRS scores were checked every 6 hours. Intravenous PCA (patient-controlled analgesia) with oxycodone hydrochloride was administered for NRS scores ≥ 4 points, and intravenous paracetamol with metamizole for NRS scores of 2-4 points. All pain medications were calculated for 1 kg of body weight. In keeping with the ERAS protocol, on the day of surgery, the patients received oral uids and meals, were mobilized and rehabilitated.
The study Group M received as "pre-emptive" analgesia oral gabapentin − 300 mg, intravenous methylprednisolone − 125 mg, while the control Group K received an oral placebo -a tablet without any pharmacological properties, and 0.9% saline solution intravenously. The statistical analysis of the groups addressed the demographic dates, life parameters, general condition in keeping with the ASA (American Society of Anesthesiology), POSSUM (Physiologic and Operative Severity Score for the enUmeration of Mortality and Morbidity) score, total dose of analgesic medications administered parenterally calculated for 1 kg of body mass in response to value of NRS at rest on day 0, time of administration of the rst dose, and duration of peripheral nerve block. On the day of surgery and on subsequent days, indicators were made based on glycaemia levels and in ammatory markers: C-reactive protein (CRP) and leukocytosis (WBC) levels.

Statistical analysis
The statistical analysis was performed using the T-Student test for independent groups employing the Cochran-Cox modi cation; the resultant statistical signi cance was p < 0.05 (PQStat v 1.6.8 software). A statistical power analysis was also conducted to validate the adequacy of the sample size (> 80%).

Results
The analysis included a group of elective 170 patients above 65 years of age, operated on due to unilateral TKA in the period June 1 to December 31, 2019, with the procedures following the ERAS protocols in our department. From the study were excluded 10 patients due to clinical situation that 1/ restricted glucocorticoid administration: diabetes type 1 and 2, CRP levels above normal values (≥ 5 mg/l), chronic steroid treatment, peptic ulcers treated in the past 30 days and 2/and the chronic pain in the course of gonarthrosis, high intensity requiring use opioids.The schematic owchart as per the CONSORT is given in Fig. 1.
The two groups of patients were numerically comparable: Group M consisted of 80, Group K of 80 patients. No differences were seen between the groups in mean age, duration of surgery, initial and postoperative life parameters (excluding the pulse rate on day 0 in the control group), perioperative risk according to the ASA scale, postoperative e ciency, possible complication development, perioperative mortality to the POSSUM scale, comorbidities. Signi cantly longer time of postoperative hospitalization values were seen in the controls group (Table 1, 2).  In the postoperative period the analysis focused on in ammatory parameters in the two groups: leukocytosis levels, CRP values on day 0, 1, 2, 3 postoperatively in blood and in surgical wound drainage on day 0, glycemia levels in consecutive postoperative days, pain sensation on day 0 based on the NRS scale at rest every 6 hours, dosage of analgesic agents administered on the day of surgery (Table 3, Fig. 2, Fig. 3),

Discussion
The large joint arthroplasty, in agreement ERAS protocol requires analgesic management for initiation of rehabilitation as early as on the day of surgery 14,15 . This proceeding limits the time of hospitalization, the risk of infectious and other complications 1,2,14−16 .
The mean postoperative hospitalization in the present material did not differ from data currently reported in publications and meta-analyses 7,11,14,16−19 equaling 3.01 days in the study group. In the control group this time was signi cantly longer -by two days (p = 0.0113); due to: -prolonged, more severe pain on day 0, is illustrated by the level of pain at the NRS scale, this necessitated employing higher doses of analgesics, including opioids (Fig. 2, Fig. 3 The analysis of 1246 patients by Osinski et al (2019) evaluated the effect of the type of anesthesia with analgesic peripheral block employed in the course of unilateral TKA, the mean postoperative hospitalization time was shorter by 0,9 day in patients who received regional anesthesia as compared to general anesthesia, up to day 4 postoperatively achieved better exion movement in the implanted knee joint, by the mean value of 10 17,21 . In our material, all patients received regional anesthesia with analgesic peripheral block, we observed 2 patients in the study and control groups with di culties in achieving satisfactory exion of the operated joint. In study group that time for two patients were shorter than almost double than it was in control group -by 5 days v.s. 8 and 9 days, the difference in time resulted from one variable: administration of methylprednisolone and gabapentine in "pre-emptive" analgesia.
The authors analyzed patients above 65 years of age. In some populations this is still the age that opens the "older patients" group. More frequently the literature on the subject de nes the elderly group as including patients above 85 years of age since this is the age at which a progressive decrease of the functional reserve occurs, leading to increased morbidity and mortality. At present it is di cult, to follow the standpoint of biologists, related to progress in life and in medical sciences, to include patients whose age starts at 65 or even 75 years of life in the group of the "elderly" patients 22 . Our material showed no intergroup differences in initial state, severity of comorbidities with respect to their state as measured by the ASA and POSSUM scales ( Table 2). A complication -TIA, occurred in the controls in a patient in whom no abnormalities, including blood ow to central nervous system (CNS) (echocardiography, electrocardiography, cervical and spinal vessels). Searching for various causes of the complication development since it occurred in the control group which received no methylprednisolone, an agent that stabilizes circulatory parameters in the postoperative period, stabilizes the vascular endothelial lining that shows antiadhesive and anticoagulatory parameters in the postoperative period 4,9 . With exception of the above, the present authors did not observe any systemic complications or deaths. The staff of the Orthopedic Center, University Hospital of Copenhagen did not observe signi cant difference of circulatory system parameters on the day of surgery in the course of mobilization, rehabilitation in patients after TKA into two groups, one with "pre-emptive" analgesia with methylprednisolone and the controls where no methylprednisolone was administered 23 . "Methylprednisolone" patients did not demonstrate any signs of subjective intolerance of verticalization as opposed to the control group where 40% of the individuals interrupted verticalization 23 .
In the group of the patients analyzed in the present material, methylprednisolone with gabapentin as "preemptive" analgesia signi cantly decreased the employed dose of all parenteral analgesics -opioidsoxycodone hydrochloride, paracetamol, metamizol in mg/kg body weight per day. The time of the rst opioid dose administration after surgery completion measured in hours was also different in the two groups (Fig. 3). It was the consequence of pain experienced at rest as measured by the NRS scale at every 6 hours postoperatively (Fig. 2); this is the explanation of the signi cantly higher pulse in the postoperative period in the controls as compared to the study group (Table 1). Starting in 2007, publications have been presenting the effect of preoperative administration of rst dexamethasone, subsequently methylprednisolone [15,[22][23][24][25] on the postoperative period: postoperative hospitalization time, infectious complications, stability of the circulatory system following the initial mobilization, pain at rest and during activity 6,7,14,16,[18][19][20]23,[25][26][27][28][29][30] .
Gabapentin as the analgesic medication due to its inhibitory effect exerted on the nociceptors is employed alone or in combination with celecoxib as "pre-emptive" analgesia 16 . A signi cant decrease of the dose of analgesic preparations, including opioid agents, as employed in pain management on the day of TKA followed by their use in consecutive three days 1 hour before mobilization allowed for effective rehabilitation and achieving proper degree of knee joint exion what was presented by 8 .
The literature on the subject evaluated parameters as CRP level, but also endogenous anti-in ammatory protein pentraxin-3, markers of vascular endothelial dysfunction that initiate in ammatory processes: syndecan-1, thrombomodulin, sE-Selectin, or vascular endothelial growth factor (VEGF) 4,8,9,26−29 . In 2017, Lindberg-Larsen with coworkers demonstrated signi cantly higher levels of pentraxin-3 in the groups of patients who were administered a single dose of methylprednisolone, in the rst 24 hours postoperatively and documented the absence of topical and generalized in ammatory processes 24 . Numerous authors demonstrated the CRP level lacking signi cance when the two groups were compared 26 . In the present material, the analysis included the following in ammatory parameters: leukocytosis was signi cantly higher on day 1 in the study group as opposed to the controls, yet on subsequent days (day 2 and 3 postoperatively), it was signi cantly lower in the study subjects (Table 3). In turn, CRP values were signi cantly lower in all time sequences in the group of methylprednisolone-administered patients as compared to the controls. Drainage uid CRP levels did not differ in the two groups. The two groups were initially statistically comparable with respect to leukocytosis and blood CRP values ( Table 3).
As it was demonstrated in the present material, a single dose of methylprednisolone did not signi cantly affect uctuations of glycemia levels in the analyzed patients, it should be emphasized, that patients with glucose intolerance were excluded from the study (Table 3). Similar observations are re ected in data reported in the literature on the subject: among others, by 22 .
Degenerative lesions involving the peripheral neurons occurring in the process of aging lead to prolonged conduction within all peripheral nerves, the excitability threshold of sensory receptors is elevated -this is true for pain receptors too 22 . The peripheral block time as the time of subarachnoid anesthesia are prolonged. In the presented material, the time of subarachnoid neuraxial anesthesia with supplementary peripheral blockade of the femoral nerve was signi cantly different in the two groups, being almost threefold longer in the study group as compared to the controls. As the material encompassed patients above 65 years of age whose reactions to topical anesthesia medications were similar, the difference in time resulted from one variable: administration of methylprednisolone in "pre-emptive" analgesia (Fig. 3).

Conclusion
In summary, the use of a single dose of gabapentin and methylprednisolone as "pre-emptive analgesia" in the group of patients above 65 years old: (1) measurably decreases postoperative pain levels assessed in keeping with the NRS scale at rest in all time intervals on the day of surgery unilateral TKA and decreases the dose of analgesic agents, including opioid preparations (oxycodone hydrochloride), (2) signi cantly lower levels of in ammatory parameters: CRP values have been demonstrated on all postoperative days, leukocytosis levels on day 2 and 3 postoperatively, (3) supports circulatory system stability, (4) no statistical difference has been demonstrated in glycemia levels, (5) no occurrence of adverse effects that would delay early rehabilitation of the patient in accordance with the ERAS protocol. Declarations