Postoperative pain control is an important responsibility of the anaesthesiologist. Effective postoperative pain control might help to decrease pain-related complications, enable mobilization and food intake and thereby improve postoperative outcome.1,2 Several nociceptive mechanisms might influence the pathophysiology of postoperative pain.3 Therefore, opioids are combined with supplemental analgesics to utilize additive or synergistic effects4,5 and to decrease their consumption.6–8 A reduction in the amount of systemic opioids lowers the incidences of common side effects such as sedation, respiratory depression, nausea, vomiting, rash and urinary retention.6,7,9
The effect of supplemental analgesics may vary in different types of surgery. After breast surgery, paracetamol resulted in a significant reduction in the number of patients requiring opioids to provide adequate pain control compared with metamizol,10 whereas the analgesic effect of paracetamol was found to be less than metamizol during the first 2 h after lumbar disc surgery.11 After septorhinoplasty, lornoxicam patient-controlled analgesia (PCA) was found to be more effective than metamizol PCA,12 but the analgesic potency of intramuscular administration of lornoxicam was comparable to metamizol after septoplasty.13 The analgesic effect of lornoxicam was reported to be better than paracetamol after radical prostatectomy.14
In our clinical practice, we often use morphine with metamizol or paracetamol or NSAIDs, such as lornoxicam, as supplemental analgesics for postoperative pain management after lumbar disc surgery. Determining the most advantageous supplemental analgesic according to the type of surgical procedure is important for effective postoperative pain management. We aimed to determine the optimum supplemental analgesic for postoperative pain relief after lumbar disc surgery.
This prospective, placebo-controlled, double-blind study was conducted to compare the analgesic effects of intravenous (i.v.) metamizol or paracetamol or lornoxicam in combination with morphine PCA during the first 24 h following lumbar disc surgery. In addition, the differences in opioid consumption and morphine-related side effects were investigated.
With informed consent and after approval from the Ethics Committee of the Cerrahpasa Medical Faculty, 80 patients scheduled for elective lumbar disc surgery under general anaesthesia were included in the study. All patients were of American Society of Anesthesiologists (ASA) status 1 or 2. Anaesthesia was induced with propofol (1.5–2 mg kg−1), vecuronium (0.1 mg kg−1) and remifentanil, (0.1 μg kg−1), and maintained with isoflurane in oxygen/air [fraction of inspired oxygen (FiO2) of 0.40], remifentanil and vecuronium infusions. Peroperative analgesia was maintained with remifentanil alone. Residual muscle relaxation was reversed with atropine (0.01 mg kg−1) and neostigmine (0.02 mg kg−1) at the end of surgery. Patients were not eligible for the study if they had known or suspected spinal tumours, allergies to any of the drugs used in this study, hepatic dysfunction or emergency surgery or if they were unable to give consent (e.g. dementia).
Patients were randomized to one in four groups using opaque envelopes. The groups received supplemental i.v. injections of either 1 mg metamizol or 1 mg paracetamol or 8 mg lornoxicam or 0.9% isotonic saline as control. The drugs were dissolved in 100 ml 0.9% isotonic saline and were administered via i.v. infusion over 15 min. The study solutions were prepared by a nurse, whereas postoperative data were collected by a blinded anaesthesiologist. At the time of wound closure, the first bolus i.v. injections of metamizol, paracetamol and lornoxicam were given and then repeated every 6 h in the paracetamol and metamizol group and every 12 h in the lornoxicam group. The colour of lornoxicam solution is yellow; to maintain blinding, all solutions were covered by aluminium foil during administration. The lornoxicam group received 0.9% isotonic saline at the 6 and 18 h time points. All patients, previously instructed on the use of the PCA pumps (Abbott Provider, Chicago, Illinois, USA), received morphine using a PCA device for 24 h postoperatively. The PCA solution contained 100 mg morphine in 100 ml isotonic saline. The PCA was set to administer a bolus dose of 1 mg on demand, with a lockout period of 7 min. Patients did not receive antiemetic prophylaxis. Postoperative nausea and vomiting were treated by 8 mg ondansetron.
Patients were assessed for pain using a visual analogue scale (VAS) from 0 to 10, with 0 being no pain and 10 being the worst pain imaginable. Sedation was evaluated according to the Ramsay score.15 VAS, total morphine consumption, Ramsay score, adverse effects (including rash, pruritus, urinary retention, nausea and vomiting), blood pressure, heart rate and respiratory rate were recorded at 1, 2, 6, 12 and 24 h postoperatively. Operations were performed by neurosurgery faculty members and neurosurgery residents. The experience level of the surgeon was accepted as ‘experienced’ if the surgery was performed by a neurosurgery faculty member and ‘inexperienced’ if the surgery was performed by a neurosurgery resident who was supervised by a faculty member.
A previous study by Grundmann et al.11 investigated the effect of a single dose of parecoxib, paracetamol and metamizol versus placebo on pain scores after lumbar disc surgery. The investigators found a reduction in pain scores of 16 units in the metamizol group (SD ± 15) versus placebo (SD ± 20), measured on a VAS from 0 to 100. On the basis of these data and the assumption that a difference of 2 units on a VAS from 0 to 10 in postoperative pain scores is clinically relevant, we carefully defined the effect size to be 2, with an estimated SD of ±2. Setting α equal to 0.05 (two-sided) and β equal to 0.9, we calculated a sample size of 18 patients per group. To adjust for the fact that the effect size for paracetamol and lornoxicam is likely to be smaller and to compensate for dropouts, we increased our sample size to 20 patients per group.
Statistical analyses were performed using Stata (Stata 10 edition for Windows; StataCorp LP, College Station, Texas, USA). Differences between the groups were analysed by using one-way analysis of variance (ANOVA) with the post-hoc Bonferroni correction test for continuous variables and the chi-squared test for binomial outcomes. The differences in height, body weight and BMI between groups were analysed by using one-way ANOVA. The pain scores over time and their interaction with the intervention were analysed by means of ANOVA for repeated measures. The values are shown as mean ± SD. A probability value of less than 0.05 was considered to be statistically significant.
Eighty patients were enrolled in the study. One patient from the control group had to be excluded because of a technical failure of the PCA pump. One patient in the metamizol group developed a rash with morphine administration, and a second patient developed fever and therefore received an antipyretic drug. Therefore, a total of three patients were excluded from the per-protocol analysis. A comparison of four groups with respect to age, sex, height, body weight, BMI, nonsmoking status and other preoperative characteristics showed no statistically significant difference (P > 0.05 for all comparisons, Table 1).
Analysing the whole study period (24 h after surgery), repeated measures ANOVA revealed that pain was reduced in the metamizol (P = 0.001) and paracetamol (P = 0.04) groups, but not in the lornoxicam (P = 0.20) group compared with the control group (Fig. 1).
Further analysing the differences between the intervention groups, repeated measures ANOVA revealed that pain scores in the metamizol group were statistically significantly lower than in the lornoxicam group (P = 0.031) (Fig. 1).
Table 2 shows the mean (±SD) pain scores and morphine requirements for pain relief at each time point. ANOVA with the post-hoc Bonferroni correction test showed no statistical differences with respect to cumulative morphine consumption between the four groups at determined time points (P > 0.05). Cumulative opioid consumption increased significantly over time (P < 0.001), with no statistically significant difference between the groups (Table 2). However, the rate of morphine consumption significantly decreased over 24 h in the paracetamol group (P < 0.001) (Fig. 2).
Postoperative nausea, vomiting, antiemetic rescue medication, pruritus and respiratory rate were similar between the groups (P > 0.05 for all comparisons).
The results of this study showed that metamizol and paracetamol provide effective analgesia when used as a supplemental analgesic to morphine PCA during 24 h following lumbar disc surgery, but lornoxicam does not.
Metamizol is a commonly used injectable nonopioid analgesic for postoperative pain treatment. Although it is widely used in Europe and South America, it has been banned in some countries because of its potential to cause agranulocytosis.16 Recent studies showed that the risk of agranulocytosis depends on genetic factors17 and the risk ratio ranges from 0.8 to 23.7.18 The incidence of NSAID-related side effects, such as gastrointestinal mucosal damage, renal tubular dysfunction, liver dysfunction and allergic reactions, is related to age, drug dosage and duration of use. It has been shown that the risk of gastrointestinal and operative side bleeding associated with ketorolac is higher when it is used in high doses, for more than 5 days, and in elderly patients.19 A study20 comparing the risk of serious adverse effects after the use of paracetamol, diclofenac, aspirin and metamizol estimated excess mortality for each drug: paracetamol, 20 out of 100 million; diclofenac, 592 out of 100 million; aspirin, 185 out of 100 million; and metamizol, 25 out of 100 million. Therefore, metamizol is relatively well tolerated compared with the potential side effects of NSAIDs. Grundmann et al.11 compared metamizol, precoxib, paracetamol and placebo for postoperative pain relief during the first postoperative 2 h following lumbar disc surgery and showed that metamizol is superior to precoxib and paracetamol. In our study, we evaluated a longer postoperative period than the study by Grundmann et al.,11 and our results indicated that both the metamizol and paracetamol groups revealed significant pain reduction.
Although the best pain relief was obtained in the metamizol group, the associated risk of agranulocytosis should be taken into consideration.
There are numerous studies6–8 regarding the morphine-sparing effect of paracetamol. In our study, although the rate of morphine consumption in the paracetamol group was significantly decreased over time, the total amounts of morphine consumed in 24 h were not significantly different between the groups. Cakan et al.21 studied the efficacy of paracetamol following lumbar disc surgery, and, similar to our study results, paracetamol decreased VAS scores but did not decrease morphine consumption. Although consistent with the existing literature, the reason for the fact that paracetamol reduces VAS scores but not morphine consumption remains unclear. A possible explanation might be the limited sample size in our study. The study was powered to detect differences of more than 2 units in the VAS and might be underpowered to detect differences in morphine consumption. In our opinion, whether paracetamol has a morphine-sparing effect or not, it may be considered as an effective analgesic drug for postoperative pain relief following lumbar disc surgery due to the proven reduction in VAS scores.
NSAIDs are commonly used for postoperative analgesia following spinal surgery. Lornoxicam was compared with morphine for postoperative pain relief following lumbar disc surgery by Rosenow et al.22 They found a 36 mg daily dose of lornoxicam to be as effective as morphine and found it to be better tolerated. Another study12 found that lornoxicam (24 mg day−1) is more effective than metamizol (5 g day−1) when administered by PCA for postoperative analgesia after septorhinoplasty. The total daily dose of lornoxicam recommended by guidelines is 16 mg. Therefore, we used lornoxicam 16 mg daily in two divided doses and did not obtain an analgesic effect better than placebo. The morphine requirement in 24 h was also comparable to placebo. Consistent with our results, it was found that intramuscular administration of lornoxicam in 16 mg daily doses for postoperative pain relief following septoplasty did not cause any difference in opioid requirement when compared with intramuscular diclofenac (150 mg day−1), ketoprofen (200 mg day−1) or metamizol (3 g day−1).13 Variations in results when compared with recent studies could be due to the differences in drug administration routes, use of PCA devices, daily doses and types of surgeries. The meta-analysis carried out by Jirarattanaphochai and Jung23 assessed the efficacy and safety of NSAIDs added to opioid analgesics for postoperative pain management in lumbar spine surgery. They found a greater reduction in morphine consumption in patients operated for spinal fusion than in patients who have undergone disc surgery. They concluded that the type of surgery is one of the important factors for postoperative pain severity, and determining a significant reduction in opioid use may be more difficult in patients who have undergone discectomy. In our study, we could demonstrate a difference in pain scores evaluated by VAS between the groups, but we could not demonstrate any differences in morphine consumption. A possible explanation is patients after lumbar disc surgery do not require very high doses of morphine; therefore, determining differences in morphine consumption between groups might require a larger sample size than in our study. The meta-analysis carried out by Jirarattanaphochai and Jung23 has only one study that compared the pain relief effect of lornoxicam with placebo after disc surgery.24 Similar to our study results, they showed that lornoxicam provides inadequate pain relief after disc surgery.
The duration of operation, the number of herniated discs, the performance of a hemilaminectomy procedure and the experience level of the surgeon might have an effect on postoperative pain scores. However, there were no significant differences between the groups in our study.
The present study has certain limitations. In our clinic, patients are discharged 1 day after lumbar disc surgery; therefore, the study period ended 24 h postoperatively. Additionally, we evaluated the pain intensity only at rest; thus, it remains uncertain whether there would be similar results for movement-related pain relief. Although patients were monitored for side effects during the entire study period, we did not use a categorical evaluation for side effects including routine blood cell analysis after discharge to detect metamizol-related agranulocytosis. However, so far, we have not received any feedback from our patients due to haematological problems.
The study showed that metamizol and paracetamol provide effective analgesia when used as supplemental analgesics to morphine PCA during 24 h following lumbar disc surgery, but lornoxicam does not. The current safety profile of paracetamol makes it the preferred first choice supplemental analgesic after lumbar disc surgery.
1 White PF. The changing role of non-opioid analgesic techniques in the management of postoperative pain. Anesth Analg 2005; 101(5 Suppl):S5–S22.
2 Kehlet H, Dahl JB. Anaesthesia, surgery, and challenges in postoperative recovery. Lancet 2003; 362:1921–1928.
3 Carr DB, Goudas LC. Acute pain. Lancet 1999; 353:2051–2058.
4 White PF. Multimodal analgesia: its role in preventing postoperative pain. Curr Opin Investig Drugs 2008; 9:76–82.
5 White PF, Kehlet H, Neal JM, et al
. The role of the anesthesiologist in fast-track surgery: from multimodal analgesia toperioperative medical care. Anesth Analg 2007; 104:1380–1396.
6 Peduto VA, Ballabio M, Stefanini S. Efficacy of propacetamol in the treatment of postoperative pain. Morphine-sparing effect in orthopedic surgery. Italian Collaborative Group on Propacetamol. Acta Anaesthesiol Scand 1998; 42:293–298.
7 Remy C, Marret E, Bonnet F. Effects of acetaminophen on morphine side-effects and consumption after major surgery: meta-analysis of randomized controlled trials. Br J Anaesth 2005; 94:505–513.
8 Hernandez-Palazon J, Tortosa JA, Martínez-Lage JF, Pérez-Flores D. Intravenous administration of propacetamol reduces morphine consumption after spinal fusion surgery. Anesth Analg 2001; 92:1473–1476.
9 Jin F, Chung F. Multimodal analgesia for postoperative pain control. J Clin Anesth 2001; 13:524–539.
10 Ohnesorge H, Bein B, Hanss R, et al
in the treatment of postoperative pain after breast surgery: a randomized, controlled trial. Eur J Anaesthesiol 2009; 26:648–653.
11 Grundmann U, Wornle C, Biedler A, et al
. The efficacy of the nonopioid analgesics parecoxib, paracetamol
for postoperative pain relief after lumbar microdiscectomy. Anesth Analg 2006; 103:217–222.
12 Sener M, Yilmazer C, Yilmaz I, et al
. Patient-controlled analgesia with lornoxicam
vs. dipyrone for acute postoperative pain relief after septorhinoplasty: a prospective, randomized, double-blind, placebo-controlled study. Eur J Anaesthesiol 2008; 25:177–182.
13 Sener M, Yilmazer C, Yilmaz I, et al
. Efficacy of lornoxicam
for acute postoperative pain relief after septoplasty: a comparison with diclofenac, ketoprofen, and dipyrone. J Clin Anesth 2008; 20:103–108.
14 Mazaris EM, Varkarakis I, Chrisofos M, et al
. Use of nonsteroidal anti-inflammatory drugs after radical retropubic prostatectomy: a prospective, randomized trial. Urology 2008; 72:1293–1297.
15 Ramsay MA, Savege TM, Simpson BR, Goodwin R, et al
. Controlled sedation with alphaxalone-alphadolone. Br Med J 1974; 2:656–659.
16 Edwards JE, Meseguer F, Faura CC, et al
. Single-dose dipyrone for acute postoperative pain. Cochrane Database Syst Rev
17 Vlahov V, Bacracheva N, Tontcheva D, et al
. Genetic factors and risk of agranulocytosis from metamizol
. Pharmacogenetics 1996; 6:67–72.
18 Bentur Y, Cohen O. Dipyrone overdose. J Toxicol Clin Toxicol 2004; 42:261–265.
19 Strom BL, Berlin JA, Kinman JL, et al
. Parenteral ketorolac and risk of gastrointestinal and operative site bleeding. A postmarketing surveillance study. JAMA 1996; 275:376–382.
20 Andrade SE, Martinez C, Walker AM. Comparative safety evaluation of non narcotic analgesics. J Clin Epidemiol 1998; 51:1357–1365.
21 Cakan T, Inan N, Culhaoglu S, et al
. Intravenous paracetamol
improves the quality of postoperative analgesia but does not decrease narcotic requirements. J Neurosurg Anesthesiol 2008; 20:169–173.
22 Rosenow DE, Albrechtsen M, Stolke D. A comparison of patient-controlled analgesia with lornoxicam
versus morphine in patients undergoing lumbar disk surgery. Anesth Analg 1998; 86:1045–1050.
23 Jirarattanaphochai K, Jung S. Nonsteroidal anti inflammatory drugs for postoperative pain management after lumbar spine surgery: a meta-analysis of randomized controlled trials. J Neurosurg Spine 2008; 9:22–31.
24 Thienthong S, Jirarattanaphochai K, Krisanaprakornkit W, et al
. Treatment of pain after spinal surgery in the recovery room by single dose lornoxicam
: a randomized, double blind, placebo-controlled trial. J Med Assoc Thai 2004; 87:650–655.