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Preemptive analgesia with a single low dose of intrathecal morphine in multilevel posterior lumbar interbody fusion surgery: a double-blind, randomized, controlled trial

  • Yujie Wang
    Affiliations
    Department of Anesthesiology, Peking University Third Hospital, 49 North Garden Rd., Haidian District, Beijing, China
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  • Xiangyang Guo
    Affiliations
    Department of Anesthesiology, Peking University Third Hospital, 49 North Garden Rd., Haidian District, Beijing, China
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  • Zhaoqing Guo
    Correspondence
    Corresponding author. Zhaoqing Guo, MD, Department of Orthopedics, Peking University Third Hospital, 49 North Garden Rd., Haidian District, Beijing.
    Affiliations
    Department of Orthopedics, Peking University Third Hospital, 49 North Garden Rd., Haidian District, Beijing, China
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  • Mao Xu
    Correspondence
    Corresponding author. Mao Xu, MD, Department of Anesthesiology, Peking University Third Hospital, 49 North Garden Rd., Haidian District, Beijing, China.
    Affiliations
    Department of Anesthesiology, Peking University Third Hospital, 49 North Garden Rd., Haidian District, Beijing, China
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Open AccessPublished:March 13, 2020DOI:https://doi.org/10.1016/j.spinee.2020.03.001

      ABSTRACT

      BACKGROUND CONTEXT

      Patients undergoing lumbar spinal surgery may experience considerable pain in the early postoperative period, and poor pain control after multilevel lumbar spinal fusion surgery is frequently associated with multiple complications and delayed discharge from hospital.

      PURPOSE

      The current study evaluated the efficacy and safety of preemptive analgesia with intrathecal morphine (ITM) in patients undergoing multilevel posterior lumbar spinal fusion surgery.

      STUDY DESIGN

      Double-blinded, randomized, controlled trial.

      PATIENT SAMPLE

      Ninety-two patients aged between 18 and 80 years who were scheduled to undergo elective lumbar laminectomy (L3–S1) and dual-level fusions.

      OUTCOME MEASURES

      The primary endpoint was the degree of postoperative pain at rest and during movement evaluated using a 10-point visual analogue scale. The secondary outcomes included the consumption of analgesics, the patient-assessed postoperative and satisfaction scores, adverse effects, time to first ambulation, and length of hospital stay.

      METHODS

      Patients were randomly allocated to either the ITM group that received 0.2 mg of ITM or the control (CON) group that received 2 ml of 0.9% saline as a skin infiltration 30 minutes prior to anesthesia induction.

      RESULTS

      The ITM group had a significantly lower visual analogue scale score than the CON group during the first 3 days postoperatively (at rest, P=0.000, during movement, P=0.000). The ITM group used significantly less sufentanil than the CON group in the first 3 days postoperatively (p=.000) in patient-controlled intravenous analgesia, as well as in supplemental analgesic demands. The ITM group reported a greater degree of satisfaction with the whole hospitalization experience than the CON group (2.4±0.6 vs. 1.9±0.6, p=.000). The two groups did not significantly differ regarding adverse effects, length of hospital stay, and time taken to regain the ability to walk without support.

      CONCLUSIONS

      Preemptive analgesia with ITM results in significantly improved early postoperative pain control and decreased postoperative patient-controlled intravenous analgesia consumption, with no increase in adverse effects.

      Keywords

      Introduction

      With the development of the concept of enhanced recovery after surgery, there is an urgent need for more satisfactory postoperative pain control and reduced length of hospital stay postoperatively. Patients undergoing lumbar spinal surgery may experience considerable pain in the early postoperative period. The visual analogue scale (VAS) score for pain on the first day after lumbar surgery is reportedly as high as six to eight points [
      • O'Neill P.
      • Knickenberg C.
      • Bogahalanda S.
      • Booth AE
      Use of intrathecal morphine for postoperative pain relief following lumbar spine surgery.pdf.
      ]. A high degree of postoperative pain after spinal surgery precludes early mobilization, leading to a prolonged hospital stay, increased incidences of cardiovascular and cerebrovascular accidents, effects on the innate immune response, and potential induction of delirium [
      • Samartzis D
      • Bow C
      • Cheung JP
      • et al.
      Efficacy of postoperative pain management using continuous local anesthetic infusion at the iliac crest bone graft site in patients with adolescent idiopathic scoliosis: a parallel, double-blinded, randomized controlled pilot trial.
      ].
      Intrathecal morphine (ITM) was first used to treat severe intractable pain in humans in 1979 [
      • Wang J.K.
      • Nauss L.A.
      • Thomas J.E.
      Pain relief by intrathecally applied morphine in man.
      ]. ITM has definite advantages for perioperative pain control, including improved quality of analgesia and decreased systemic opioid use [
      • Rathmell J.P.
      • Lair T.R.
      • Nauman B.
      The role of intrathecal drugs in the treatment of acute pain.
      ]. ITM has been widely used for the control of postoperative pain due to cesarean section [
      • Carvalho F.A.
      • Tenorio S.B.
      Comparative study between doses of intrathecal morphine for analgesia after caesarean.
      ], cholecystectomy [
      • Motamed C.
      • Bouaziz H.
      • Franco D.
      • Benhamou D.
      Analgesic effect of low-dose intrathecal morphine and bupivacaine in laparoscopic cholecystectomy.
      ], and transurethral resection of the prostate [
      • Duman A.
      • Apiliogullari S.
      • Balasar M.
      • Gurbuz R.
      • Karcioglu M.
      Comparison of 50 microg and 25 microg doses of intrathecal morphine on postoperative analgesic requirements in patients undergoing transurethral resection of the prostate with intrathecal anesthesia.
      ]. A previous study showed that the administration of 9 µg/kg of ITM postoperatively effectively relieves postoperative pain in adolescents with idiopathic scoliosis, and prevents the need for routine ICU entry for further treatment [
      • Li Y
      • Hong RA
      • Robbins CB
      • et al.
      Intrathecal morphine and oral analgesics provide safe and effective pain control after posterior spinal fusion for adolescent idiopathic scoliosis.
      ]. However, large doses of morphine can induce pruritis, nausea/vomiting, urinary retention, and respiratory depression [
      • Chaney M.A.
      Side effects of intrathecal and epidural opioids.
      ].
      Preemptive analgesia is administered before the onset of pain to prevent the plasticity of the central nervous system and the activation of central neurons and their amplified peripheral neurons in response to noxious stimuli, thus providing more effective pain relief than analgesia administered after the onset of pain [
      • Woolf C.J.
      • Chong M.S.
      Preemptive analgesia–treating postoperative pain by preventing the establishment of central sensitization.
      ]. Preemptive analgesic approaches have been well described and adopted for patients undergoing orthopedic surgery of the lower extremities, especially joint arthroplasty [
      • Parvizi J.
      • Miller A.G.
      • Gandhi K
      Multimodal pain management after total joint arthroplasty.
      ]. However, the preemptive analgesic effect of ITM in spine surgery is largely unknown.
      In the present study, we aimed to investigate the efficacy of low dose preoperative ITM (0.2 mg) in patients undergoing multilevel posterior lumbar interbody fusion. The present study will provide useful information for the preemptive use of ITM in spinal surgery, and in other types of surgery that induce severe pain.

      Methods

      This double-blind, randomized, controlled trial was carried out from June 1, 2018 to March 2019.

      Ethics

      Ethical approval for this study was provided by the Ethical Committee NAC of Peking University Third Hospital, Beijing, China [Chairperson Prof. Liu, no. 2018 (203-02)] on May 9, 2018, and the study was registered in the Chinese Clinical Trial Registry on May 28, 2018. Written informed consent was obtained from all participants prior to data collection.

      Participants

      Patients aged 18 to 80 years with an American Society of Anesthesiologists physical status of I to II were eligible if they were scheduled for elective multilevel lumbar laminectomy (L3–S1) with fusion. The exclusion criteria were: patient refusal for study participation, symptoms of L2-3 intervertebral nerve injury (determined by an orthopedic specialist based on physical and imaging examinations), known allergy to one or more medications used in the study protocol, coagulation dysfunction, infection at the puncture site, cognitive disorder (inability to understand the VAS), body mass index (BMI) greater than 35 kg m−2. Patients with a BMI of greater than 35 kg m−2 were excluded because obese subjects are reportedly more likely to have sleep apnea syndrome [
      • Pizzi L.T
      • Toner R
      • Foley K
      • et al.
      Relationship between potential opioid-related adverse effects and hospital length of stay in patients receiving opioids after orthopedic surgery.
      ] and have altered sensory thresholds compared with patients with a normal BMI [
      • Tashani O.A.
      • Astita R.
      • Sharp D.
      • Johnson M.I.
      Body mass index and distribution of body fat can influence sensory detection and pain sensitivity.
      ,
      • Stefanik J.J
      • et al.
      Changes in pain sensitization after bariatric surgery.
      ,
      • Guillemot-Legris O
      • Buisseret B
      • Mutemberezi V
      • et al.
      Post-operative pain in mice is prolonged by diet-induced obesity and rescued by dietary intervention.
      ].

      Randomization and blinding

      The patients were randomly assigned into either the ITM or the control (CON) group with an equal allocation ratio (1:1) according to a computer-generated randomization sequence. Each patient's allocation was concealed in a sequentially numbered, sealed, opaque envelope. The envelope was taken by the attending anesthesiologist when an included patient arrived in the preparation ward. The patient, surgical team, investigator, and nurses in the ward were all blinded to group allocations. Only the attending anesthesiology team and the nurse in the recovery ward were aware of the group allocations in case of emergency.

      Interventions

      When the patients lay down on the surgery table, routine monitoring was commenced (pulse oximetry, noninvasive blood pressure monitoring, and electrocardiography), and intravenous access was established.
      Patients were premedicated with midazolam 2 mg intravenously. Before the ITM injection, the skin overlying the area of the L2-3 intervertebral pace was disinfected, draped, and infiltrated with 2 to 3 ml of 1% lidocaine for local anesthesia in both groups. In the ITM group, the subarachnoid space puncture was performed with a 25-gauge pencil-point spinal needle (BD, Suzhou, China). After confirming the return of clear, free-flowing cerebrospinal fluid, 0.2 mg of morphine in 2 ml of preservative-free 0.9% saline solution (100 µg/ml) was administered intrathecally over 5 to 10 seconds; the spinal needle was then removed. Previous study reported that an ITM dosage of 0.3 mg or more provides satisfactory analgesia for spine surgery, which may increase the risk of adverse effects compared with lower doses [
      • Siribumrungwong K.
      • Cheewakidakarn J.
      • Tangtrakulwanich B.
      • Nimmaanrat S.
      Comparing parecoxib and ketorolac as preemptive analgesia in patients undergoing posterior lumbar spinal fusion: a prospective randomized double-blinded placebo-controlled trial.
      ]. Therefore, in our study, we aimed to investigate the efficacy of low-dose preoperative ITM (0.2 mg), and in our preliminary study, this dose of morphine achieved good analgesia without obvious adverse effects. In the CON group, patients received skin infiltrations with 2 ml of 0.9% saline. Patients were monitored for 15 minutes to check for circulatory instability.
      General anesthesia was then induced using sufentanil, propofol, and atracurium, and was maintained with a continuous infusion of propofol and remifentanil. Bispectral index monitoring was used to assess the depth of anesthesia in both groups. To ensure a sufficient depth of anesthesia, the bispectral index value was maintained between 40 and 50 by adjusting the infusion rate of propofol (4–10 mg kg−1 h−1). The dose of remifentanil (0.01–0.1 µg kg−1 min-1) was adjusted to maintain ideal blood pressure (± 20% of normal blood pressure) and heart rate. If the patient's blood pressure was lower or higher than 20% of the baseline level, the dosage of remifentanil was adjusted; an intravenous injection of 5 mg of ephedrine or 5 mg of urapidil was only given if obvious hypotension or hypertension occurred suddenly. If the heart rate was lower than 45 beats min−1 and did not increase after adjustment of the remifentanil dosage, 0.5 mg of atropine was injected intravenously. Ventilation was controlled with a tidal volume of 7 to 10 ml kg−1, and the ventilator rate (8–12 breaths min−1) was adjusted to maintain an end-tidal CO2 of 35 to 40 mm Hg. At the time of wound closure, all patients received 40 ml of 0.25% ropivacaine in the subcutaneous tissue surrounding the skin incision.
      After extubation of the endotracheal tube, all patients were transferred to the postanesthetic care unit (PACU) and given a patient-controlled intravenous analgesia (PCIA) pump with initial programming consisting of 4 µg kg−1 sufentanil (diluted with 200 ml of normal saline) in 1 ml boluses, with a lockout of 15 minutes, and no background infusion. If these initial procedures did not achieve adequate analgesia, supplemental analgesic agents were used when requested. Patients were first administered a diclofenac sodium suppository (50 mg). If diclofenac sodium gave insufficient pain relief or adverse effects, the patient was then given 50 mg of intravenous parecoxib. The number of patients requesting supplemental analgesics was evaluated for up to 72 hours. The Foley urine tube of all patients was routinely removed on postoperative day 1.

      Primary outcome measure

      The primary outcome was the postoperative pain at rest and during movement evaluated on a 10-point VAS at 1, 3, 6, 12, 24, 48, and 72 hours postoperatively. The VAS scores were collected by a blinded investigator.

      Secondary outcome measures

      • (1)
        Patient hemodynamic indexes, propofol and remifentanil consumption, and the intraoperative use of vasoactive drugs.
      • (2)
        Sufentanil consumption and time to the first bolus of sufentanil after the initiation of PCIA.
      • (3)
        Number of patients needing supplemental analgesics in the first 72 hours postoperatively.
      • (4)
        Time to first ambulation and length of hospital stay.
      • (5)
        Adverse effects.
      • (6)
        Postoperative patient-rated comfort and satisfaction scores (ranging from 0 (fairly dissatisfactory) to 3 (highly satisfactory)) [
        • Zhou L
        • Zhang Y
        • Sun H
        • et al.
        Effect of preemptive dezocine before general anesthesia on postoperative analgesia in patients undergoing laparoscopic cholecystectomy: a prospective observational study.
        ].
      • (7)
        Sedation scores obtained using the Ramsay scale: 1 = anxious and agitated; 2 = cooperative and tranquil; 3 = responds to verbal command only; 4 = asleep, but has a brisk response to light tactile stimulus or a simple verbal command; 5 = asleep, but arousable only by strong physical stimulus; and 6 = asleep, unarousable.

      Sample size

      A previous meta-analysis suggested that ITM was effective for the prevention of lumbar spine surgery pain [
      • Pendi A
      • Acosta FL
      • Tuchman A
      • et al.
      Intrathecal morphine in spine surgery: a meta-analysis of randomized controlled trials.
      ]. Based on this, with a one-sided 5% significance level, power of 80%, mean VAS of the ITM group of 1.6 and mean VAS of the CON group of 2.8 [
      • Yen D.
      • Turner K.
      • Mark D.
      Is a single low dose of intrathecal morphine a useful adjunct to patient-controlled analgesia for postoperative pain control following lumbar spine surgery? A preliminary report.
      ], the estimated minimum sample size was 40 patients per group.

      Statistical methods

      Data were analyzed using the statistical software package SPSS version 25.0 (Chicago, IL). Continuous variables were described as the mean±standard deviation, and differences between groups were analyzed using a series of one-way analysis of variance (ANOVA) with Bonferroni's post-hoc test, while differences between groups over time were analyzed using two-way repeated ANOVA. Categorical variables were described as the number (%), and were analyzed by Fisher's exact test, and repeated measurement of categorical data were analyzed by generalized estimating equations. A p value of <.05 was considered statistically significant.

      Results

      Patient recruitment

      A total of 150 patients were screened for eligibility; 40 patients did not meet the inclusion criteria, 15 patients refused to participate, and three patients were excluded for other reasons. In total, 92 patients were included and received the allocated intervention. Five patients were excluded from the primary analysis for the three following reasons: one patient deferred due to a witnessed onset of atrial fibrillation and four patients needed additional laminectomy of L2-3 after carefully re-examining the patients’ nuclear magnetic images by surgeons (Fig. 1).
      Fig 1
      Fig. 1CONSORT study participant flow diagram.

      Patients’ demographics

      The patients’ demographic characteristics are shown in Table 1. There were no significant differences between the two groups in age, sex, BMI, distributions of the American Society of Anesthesiologists classification, surgery time, and blood loss. The two groups did not significantly differ regarding the numbers of patients with systemic diseases such as arterial hypertension, diabetes, pulmonary disease, and renal disease.
      Table 1Patients’ characteristics and operative data
      CON, n=43ITM, n=44p
      Sex (n, female/male)21/2223/21.83
      Age (years)66.5±7.566.4±5.4.92
      BMI (kg m−2)25.4±3.225.1±3.5.87
      ASA class (I or II)19/2418/26.83
      Surgery time (min)157.4±47.0163.3±50.6.07
      No pre-existing disease (n)3033.64
      Arterial hypertension (n)78>.99
      Diabetes (n)26.27
      Pulmonary disease (n)03.24
      Renal disease (n)20.24
      ASA, American Society of Anesthesiologists; BMI, body mass index.

      Hemodynamic parameters and consumption of vasoactive drugs

      The CON group had a significantly greater decrease in heart rate during the intraoperative period than the ITM group. There we no significant differences in intraoperative and postoperative mean arterial pressure (MBP) between the two groups (Table 2). The two groups did not significantly differ regarding the use of vasoactive drugs such as atropine and ephedrine (Table 3).
      Table 2Intraoperative hemodynamic parameters
      CON, n=43ITM, n=44p
      Heart rate (beats min−1)
       Intraoperative60.7±7.464.2±5.30.003
       Postoperative75.1±6.373.0±6.6.12
      MBP (mmHg)
       Intraoperative83.3±5.381.2±5.10.06
       Postoperative85.4±5.783.8±4.80.17
      Table 3Intraoperative consumption of vasoactive drugs (number of patients)
      Vasoactive drugsCON, n=43ITM, n=44p
      Ephedrine62.16
      Atropine14.36

      Consumption of intraoperative anesthetic medications

      The intraoperative consumptions of anesthetic medications are shown in Table 4. There was no significant difference in propofol consumption between the two groups. The consumption of remifentanil was significantly lesser in the ITM group than in the CON group.
      Table 4Intraoperative consumption of general aesthetic medications
      AnestheticsCON, n=43ITM, n=44p
      Propofol (mg/kg/hr)6.0±0.56.0±0.4.89
      Remifentanil (μg/kg/hr)5.9±0.61.6±0.5.000

      Postoperative pain intensity and sedation levels

      The postoperative pain intensity and sedation scores are shown in Fig. 2. Multi-way ANOVA showed a significant difference in the VAS between the two groups during the first 3 days after surgery (p=.000). The ITM group had a significantly lower VAS score than the CON group at 6, 12, and 24 hours postoperatively at rest [Fig. 2A; F (1, 42)=80.052, P =0.000 at 6h; F (1, 42)=90.711, P =0.000 at 12h; F (1, 42)=271.507, P =0.000 at 24h ], and during movement [Fig. 2B; F (1, 42)=31.967, P =0.000 at 6h; F (1, 42)=279.892, P =0.000 at 12h; F (1, 42)=363.505, P =0.000 at 24h ]. The Ramsay score was significantly lower in the CON group than in the ITM group at 5 minutes after arrival at the PACU [Fig. 2C; F (1, 42)=33.897, P =0.000).
      Fig 2
      Fig. 2Postoperative pain intensity and sedation scores. Visual analogue scale (VAS) scores at rest (A) and during movement (B) were assessed at 1, 3, 6, 12, 24, 48, and 72 hours after surgery in the CON group (grey line) and the ITM group (black line). (C) Sedation levels were assessed using the Ramsay scores at 5, 10, 15, 30, and 60 minutes after arrival at the postanesthetic care unit. CON, control; ITM, intrathecal morphine.

      Time to the first PCIA bolus of sufentanil

      The mean time to the first PCIA sufentanil bolus is shown in Fig. 3. There was a significantly delay in the ITM group compared with the CON group.
      Fig 3
      Fig. 3The time to the first patient-controlled intravenous analgesia (PCIA) sufentanil bolus. There was a significantly delay in the ITM group compared with the control group (313.8±22.9 minutes vs. 223.2±36.4 minutes; p=.000). CON, control; ITM, intrathecal morphine.

      Postoperative PCIA administration of sufentanil

      Multi-way ANOVA showed a significant difference between the two groups in the sufentanil consumption during the first 3 days after surgery (p=.000). The daily and total consumptions of sufentanil via PCIA are shown in Fig. 4A. The respective daily amounts of sufentanil used on postoperative days 1, 2, and 3 in the CON and ITM groups were 55.1±8.1 µg and 25.8±6.4 µg (p=.000), 44.5±11.1 µg and 41.8±10.4 µg (p=.24), 34.0±7.6 µg and 34.5±7.0 µg (p=.75); the total amounts of sufentanil used in the CON and ITM groups were 133.6±15.3 µg and 102.1±13.0 µg (p=.000). Thus, the ITM group used significantly less sufentanil than the CON group on postoperative day 1 and in total.
      Fig 4
      Fig. 4Sufentanil consumption during the first 3 days postoperatively, and in various time periods during postoperative day 1. (A) Respective sufentanil consumptions in the CON and ITM groups on postoperative day 1, postoperative day 2, postoperative day 3, three days in total. (B) Respective sufentanil consumptions on postoperative day 1 in the CON and ITM groups during 0 to 6 hours, 6 to 12 hours, 12 to 18 hours, and 18 to 24 hours. CON, control; ITM, intrathecal morphine.
      Multi-way ANOVA showed a significant difference between the two groups in the sufentanil consumption during the first 24 hours after surgery (p=.000). The sufentanil consumption via PCIA in different time periods on postoperative day 1 are shown in Fig. 4B. The respective amounts of sufentanil used in the CON and ITM groups during 0 to 6, 6 to 12, 12 to 18, and 18 to 24 hours postoperatively and in total were 16.1±5.0 µg and 15.8±5.3 µg (p=.77), 24.9±5.3 µg and 5.8±2.8 µg (p=.000), 13.0±4.1 µg and 2.2±1.7 µg (p=.000), 11.6±3.4 µg and 2.5±1.1 µg (p=.000), and 55.1±8.1 µg and 25.8±6.4 µg (p=.000). Thus, the ITM group used significantly less sufentanil than the CON group during the periods of 6 to 12, 12 to 18, and 18 to 24 hours postoperatively, and in total.

      Supplemental analgesic demands

      In the ITM group, the number of patients needing supplemental analgesics was less than that in the CON group during the first postoperative day, but not during the second and third postoperative days (Table 5).
      Table 5Supplemental analgesic demand (number of patients)
      Supplemental analgesic demandCON, n=43ITM, n=44Exp(B)p
      Needing diclofenac sodium suppositoryDay1215.000
      Day2720.3640.022
      Day3300
      Needing intravenous parecoxibDay1120/.000
      Day230/.12
      Day300/>0.999

      Postoperative adverse events

      The incidences of morphine-associated adverse effects during the first 72 hours postoperatively are shown in Table 6. No patient had respiratory depression requiring treatment. There were no cases of pruritus severe enough to warrant treatment. There were no significant differences between the two groups in the incidences of headache, urinary retention, hypoxia, somnolence, pruritus, nausea, wound infection, and neurologic symptoms.
      Table 6Associated adverse effects (number of patients)
      Adverse eventCON, n=43ITM, n=44p
      Headache02.49
      Urinary retention00>.99
      Hypoxia00>.99
      Somnolence01>.99
      Pruritus03.24
      Nausea30.12
      Wound infection00>.99
      Neurologic symptoms00>.99
      The length of hospital stay and the time taken after surgery to regain the ability to walk unsupported are reported in Table 7. There were no significant differences between the two groups.
      Table 7Length of hospital stay and time taken to regain the ability to walk unsupported
      CON, n=43ITM, n=44p
      Length of hospital-stay (day)5.6±0.95.5±0.6.93
      Time to ambulation (h)61.0±8.563.1±6.7.20

      Patient satisfaction

      Regarding the comfort and satisfaction scores, the ITM group reported a greater degree of satisfaction with the whole hospitalization experience than the CON group (Fig. 5).
      Fig 5
      Fig. 5The ITM group reported greater satisfaction with the whole hospitalization experience than the CON group (2.4±0.6 vs 1.9±0.6; p=.000). CON, control; ITM, intrathecal morphine.

      Discussion

      The current clinical study showed that the preoperative administration of 0.2 mg of ITM significantly reduces analgesic requirements in the first 72 hours after lumbar spine surgery. Compared with the CON group, the ITM group had a significantly reduced consumption of intraoperative remifentanil, postoperative sufentanil in PCIA, and supplemental analgesics, and a significantly increased degree of patient satisfaction. Furthermore, preemptive ITM did not induce hemodynamic instability or increase the incidence of adverse effects.
      Posterior spine surgery can result in severe postoperative pain due to the extensive soft tissue dissection and muscle detachment required to obtain adequate exposure of the laminae, facet joints, and transverse processes [
      • Puvanesarajah V
      • Liauw JA
      • Lo SF
      • Lina IA
      • Witham TF
      • Gottschalk A
      • et al.
      Analgesic therapy for major spine surgery.
      ]. Historically, pain control regimens after spine surgery have relied heavily on the provision of opioid medications at intervals in response to patient-reported pain. Although opioids remain the cornerstone of the management of severe acute postoperative pain, intermittent opioid use may result in inadequate pain relief and substantial opioid-induced adverse effects. Opioid use is associated with a multitude of notable adverse effects, including respiratory depression, cardiovascular stress, altered cognition, delayed wound healing, urinary and gastrointestinal dysfunction, and acquired tolerance [
      • Wheeler M.
      • Oderda G.M.
      • Ashburn M.A.
      • Lipman A.G.
      Adverse events associated with postoperative opioid analgesia: a systematic review.
      ]. Administration of an analgesic drug before the occurrence of the pain stimulus can prevent the development of pain hypersensitization. There are many interventions available for possible use as preemptive analgesia in lumbar spinal surgery, including epidural analgesia [
      • Samagh N.
      • Pai R.K.
      • Mathews T.K.
      • Jangra K.
      • Varma R.G.
      Pre-emptive caudal epidural analgesia with ropivacaine for lumbosacral spine surgery: a randomized case control study.
      ], local anesthetic wound infiltration [
      • Ersayli D.T.
      • Gurbet A.
      • Bekar A.
      • Uckunkaya N.
      • Bilgin H.
      Effects of perioperatively administered bupivacaine and bupivacaine-methylprednisolone on pain after lumbar discectomy.
      ], systemic opioids [
      • Yukawa Y.
      • Kato F.
      • Ito K.
      • Terashima T.
      • Horie Y.
      A prospective randomized study of preemptive analgesia for postoperative pain in the patients undergoing posterior lumbar interbody fusion: continuous subcutaneous morphine, continuous epidural morphine, and diclofenac sodium.
      ], and systemic nonsteroidal anti-inflammatory drugs [
      • Siribumrungwong K.
      • Cheewakidakarn J.
      • Tangtrakulwanich B.
      • Nimmaanrat S.
      Comparing parecoxib and ketorolac as preemptive analgesia in patients undergoing posterior lumbar spinal fusion: a prospective randomized double-blinded placebo-controlled trial.
      ].
      The analgesia resulting from ITM is mediated by pre- and postsynaptic receptors in the substantia gelatinosa of the spinal cord dorsal horn cells and supraspinal levels [
      • Yaksh T.L.
      Opioid receptor systems and the endorphins: a review of their spinal organization.
      ]. Morphine contains hydroxyl groups that give it polar characteristics as a hydrophilic opiate, resulting in decreased bio-membrane permeability and delayed absorption by the cells and blood [
      • Cousins M.J.
      • Mather L.E.
      Intrathecal and epidural administration of opioids.
      ]. Thus, ITM has a longer acting duration and faster onset than other opioids. The onset of analgesia reportedly occurs approximately 30 minutes after the injection of ITM [
      • Fournier R.
      • Van Gessel E.
      • Macksay M.
      • Gamulin Z.
      Onset and offset of intrathecal morphine versus nalbuphine for postoperative pain relief after total hip replacement.
      ], and a single bolus of ITM is estimated to have an onset of 1 to 2 hours and a duration of 12 to 24 hours [
      • Roy J.D.
      • Massicotte L.
      • Sassine M.P.
      • Seal R.F.
      • Roy A.
      A comparison of intrathecal morphine/fentanyl and patient-controlled analgesia with patient-controlled analgesia alone for analgesia after liver resection.
      ]. Thus, in our study, a single preoperative injection of ITM showed a significant analgesic effect from the beginning of surgery that lasted for 24 hours postoperatively, which is consistent with previous reports [
      • Hida T
      • Yukawa Y
      • Ito K
      • et al.
      Intrathecal morphine for postoperative pain control after laminoplasty in patients with cervical spondylotic myelopathy.
      ]. As all patients in our study received subcutaneous local anesthesia, which provides analgesia for 4 to 6 hours, there were no differences between the two groups in the VAS score and sufentanil consumption prior to 6 hours postoperatively. After 6 hours, the ITM group had a significantly lower VAS score and lesser sufentanil requirement than the CON group until 24 hours postoperatively. With the offset of the analgesic effect of ITM, there were no significance differences between the two groups in the VAS score and sufentanil consumption after 24 hours postoperatively. It is worth noting that the Ramsay score was significantly lower in the CON group than in the ITM group only at 5 minutes after arrival at the PACU, but did not significantly differ between groups from 10 minutes onwards. This may be because ITM provided perfect analgesia in the ITM group, while the subcutaneous local anesthesia alone received by the CON group was unable to remit deep muscle pain before the initiation of PCIA. However, the VAS scores within the first hour postoperatively were not assessed in our study.
      A previous study reported a dosage of ITM of 0.3 mg or more [
      • Siribumrungwong K.
      • Cheewakidakarn J.
      • Tangtrakulwanich B.
      • Nimmaanrat S.
      Comparing parecoxib and ketorolac as preemptive analgesia in patients undergoing posterior lumbar spinal fusion: a prospective randomized double-blinded placebo-controlled trial.
      ], which may increase the risk of adverse effects compared with lower doses of ITM. In our study, we used only 0.2 mg of ITM, and found that this dose produced a satisfactory analgesic effect. Most previous studies administered morphine under direct visualization at the end of the operative procedure and before wound closure [
      • Pendi A
      • Lee YP
      • Farhan SAB
      • et al.
      Complications associated with intrathecal morphine in spine surgery: a retrospective study.
      ]; in contrast, we administered morphine in the operation theatre before the surgery, and showed the feasibility of preemptive analgesia via low-dose ITM. We found that preemptive ITM not only significantly reduced the analgesic requirements in the first postoperative day after lumbar spine surgery, which may reduce the incidences of opioid-related adverse effects, but also significantly decreased the intraoperative consumption of remifentanil. The significantly slower heart rate of the CON group compared with the ITM group may have been induced by the greater remifentanil requirement of the CON group perioperatively. Furthermore, the hyperpathia induced by high-dose intraoperative remifentanil infusion increases early postoperative analgesic consumption [
      • Kim D.
      • Lim H.S.
      • Kim M.J.
      • Jeong W.
      • Ko S
      High-dose intraoperative remifentanil infusion increases early postoperative analgesic consumption: a prospective, randomized, double-blind controlled study.
      ], and results in higher reports of worse pain and a lower degree of patient satisfaction [
      • Sanfilippo F
      • Conticello C
      • Santonocito C
      • et al.
      Remifentanil and worse patient-reported outcomes regarding postoperative pain management after thyroidectomy.
      ]. Therefore, our study provides one solution to decrease the adverse effect of hyperalgesia caused by the high-dose remifentanil-based anesthesia that is currently commonly used in surgery.
      The onset of analgesia for ITM is 30 minutes after injection [
      • Fournier R.
      • Van Gessel E.
      • Macksay M.
      • Gamulin Z.
      Onset and offset of intrathecal morphine versus nalbuphine for postoperative pain relief after total hip replacement.
      ,
      • Baraka A.
      • Noueihid R.
      • Hajj S.
      Intrathecal injection of morphine for obstetric analgesia.
      ]. Thus, single-shot ITM given preoperatively may show a significant analgesic effect from the beginning of surgery and could quite possibly decrease intraoperative anesthetic requirements. In our study, compared with the CON group, the ITM group required significantly less intraoperative remifentanil, while maintaining comparable intraoperative hemodynamic parameters and bispectral index values. Although a substantial decrease in the total amount of anesthetic agents administered intraoperatively may be beneficial to patients, we are concerned that the different dose of remifentanil between the two groups may affect the postoperative consumption of analgesics, as it is known that remifentanil may cause hyperalgesia [
      • Angst M.S.
      Intraoperative use of remifentanil for TIVA: postoperative pain, acute tolerance, and opioid-induced hyperalgesia.
      ]. However, the hyperalgesia caused by remifentanil is associated with a high infusion rate and long infusion time, and it appears that intraoperative remifentanil infusion rates of more than 0.25 µg kg−1 min−1 are associated with higher postoperative opioid consumption, suggesting tolerance, and infusion rates of greater than 0.2 µg kg−1 min−1 are characterized by lower mechanical/pressure/cold/pain thresholds, which suggests hyperalgesia [
      • Yu E.H.
      • Tran D.H.
      • Lam S.W.
      • Irwin M.G
      Remifentanil tolerance and hyperalgesia: short-term gain, long-term pain?.
      ]. Furthermore, a previous study found that remifentanil (0.16 µg kg−1 min−1) as an adjuvant to propofol in general anesthesia for adults undergoing a 3.9-hour spinal fusion surgery does not lead to acute opioid tolerance or hyperalgesia [
      • Yeom J.H.
      • Kim K.H.
      • Chon M.S.
      • Byun J.
      • Cho S.Y.
      Remifentanil used as adjuvant in general anesthesia for spinal fusion does not exhibit acute opioid tolerance.
      ]. Compared with the abovementioned studies, our study used much lower infusion rates of remifentanil (0.098±0.01 µg kg−1 min−1 in the CON group and 0.027±0.008 µg kg−1 min−1 in the ITM group) and involved a shorter duration of surgery (157.4±47.0 minutes in the CON group and 163.3±50.6 minutes in the ITM group); therefore, the amount of interference from remifentanil on postoperative pain and analgesic consumption is likely to have been negligible.
      The main limitation of the clinical use of ITM may be complications due to morphine use, such as nausea, vomiting, pruritus, and urinary retention. Pruritus is an opiate-specific complication. Morphine acts on the M-receptors of mast cells at the skin, provoking granulation, which elicits histamine release and results in skin rash and itching [
      • McCracken G.
      • Houston P.
      • Lefebvre G.
      Guideline for the management of postoperative nausea and vomiting.
      ]. The incidence of pruritus is reportedly 28% to 75% with epidural or intravenous morphine [
      • Liao CC
      • Chang CS
      • Tseng CH
      • et al.
      Efficacy of intramuscular nalbuphine versus diphenhydramine for the prevention of epidural morphine-induced pruritus after cesarean delivery.
      ]. However, the incidence of pruritus in our study was quite low, and there were no significant differences between the two groups in the incidences of other morphine-related adverse effects. This may be because the complications associated with morphine are dose-related [
      • Gehling M.
      • Tryba M.
      Risks and side-effects of intrathecal morphine combined with spinal anaesthesia: a meta-analysis.
      ], and only a low dose of morphine chloride was administered in our study. Furthermore, we did not observe any complications associated with the lumbar puncture procedure, such as headache.
      Few previous studies have reported the use of ITM for abdominal anesthesia and postoperative pain control [
      • Koning M.V.
      • Teunissen A.J.W.
      • van der Harst E.
      • Ruijgrok E.J.
      • Stolker R.J.
      Intrathecal morphine for laparoscopic segmental colonic resection as part of an enhanced recovery protocol: a randomized controlled trial.
      ,
      • Kjolhede P.
      • Bergdahl O.
      • Borendal Wodlin N.
      • Nilsson L.
      Effect of intrathecal morphine and epidural analgesia on postoperative recovery after abdominal surgery for gynecologic malignancy: an open-label randomised trial.
      ], and the present study is the first to investigate preemptive analgesia via ITM in posterior lumbar fusion surgery in accordance with the CONSORT recommendations to provide increased confidence with unbiased results in estimating the effectiveness of an intervention. Our sample size had adequate power to detect key intergroup effects. However, our study had some limitations. First, we did not assess the VAS scores within the first hour postoperatively. Second, we evaluated only a single low dose of ITM. Further studies on the analgesic efficacy of different doses of ITM and other opioids in preemptive analgesia are warranted. Third, in our study, we excluded patients with obesity for safety reasons. The total amount and dose of sufentanil in the PCIA pump were calculated based on the patient's body weight, and patients with obesity needed more sufentanil than those with a normal BMI. As a higher dose of sufentanil may lead to respiratory depression and patients with obesity are more likely to have sleep apnea syndrome than those with a normal BMI, administering a higher dose of sufentanil to patients with obesity carries a very high risk of respiratory depression. Therefore, the treatment regimen of the present study may not be applicable to patients with obesity.
      In conclusion, our study shows that, for patients undergoing posterior lumbar interbody fusion surgery, 0.2 mg of ITM before the induction of general anesthesia promotes better perioperative pain control with less PCIA consumption and no increase in adverse effects compared with no administration of ITM. Therefore, ITM may be a potentially useful adjunctive procedure for the management of pain after surgery that is known to induce a severe degree of pain.

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