Abstract
Objectives
Multimodal pain management is one component in enhanced recovery after surgery protocol. Here we evaluate the efficacy of tramadol–paracetamol in acute postoperative pain and pain outcome at 12 months after spine surgery in randomized, double-blind, placebo-controlled trial.
Methods
We randomized 120 patients undergoing spine surgery to receive, for add-on pain management, two tramadol–paracetamol 37.5 mg/325 mg (n = 61) or placebo tablets (n = 59) twice a day for 5 postoperative days. In the hospital, multimodal pain management consisted of dexketoprofen and oxycodone. After discharge, patients were prescribed ibuprofen 200 mg, maximum 1,200 mg/day. Pain, analgesic use, and satisfaction with pain medication were followed up with the Brief Pain Inventory questionnaire before surgery and at 1 and 52 weeks after surgery. The primary outcome was patients’ satisfaction with pain medication 1 week after surgery.
Results
At 1 week after surgery, patients’ satisfaction with pain medication was similarly high in the two groups, 75% [interquartile range, 30%] in the placebo group and 70% [40%] in the tramadol–paracetamol group (p = 0.949) on a scale: 0% = not satisfied, 100% = totally satisfied. At 1 week, ibuprofen dose was lower in the placebo group 200 mg [1,000] compared to the tramadol–paracetamol group, 800 mg [1,600] (p = 0.016). There was no difference in the need for rescue oxycodone. Patients in the tramadol–paracetamol group had more adverse events associated with analgesics during the first postoperative week (relative risk = 1.8, 95% confidence interval, 1.2–2.6).
Conclusion
Add-on pain treatment with tramadol–paracetamol did not enhance patients’ satisfaction with early pain management after back surgery.
1 Introduction
Back pain is a health burden and the leading cause of years lived with disability [1,2]. In Finland, the 30-day prevalence of neck pain is 37% among men and 51% among women, and for lower back pain, it is 45% among men and 49% among women [3]. Conservative management is often sufficient for nonmalignant back pain, but for a minority of patients, surgery is indicated. In Finland, the annual prevalence of cervical spine surgery is 28/100,000 person-years, and that for lumbar spine surgery is 107/100,000 person-years [4,5].
Efficient perioperative pain management is a necessity in an early phase of postoperative recovery. Opioid analgesics are highly effective in acute nociceptive pain but are associated with a risk of severe adverse effects, opioid-induced hyperalgesia, and high addiction potential [6]. Tramadol misuse is less common compared to pure opioid analgesics [7]. Tramadol is a synthetic opioid with low affinity for the μ-opioid receptor, but its primary active metabolite, O-desmethyltramadol, possesses 200 times higher receptor affinity. Tramadol and O-desmethyltramadol also inhibit the reuptake of the neurotransmitters serotonin and norepinephrine. Based on this monoaminergic mechanism, tramadol is also effective in treating neurogenic pain, which is an important feature for spine surgery patients who often have both nociceptive and neuropathic postoperative pain [8]. Tramadol analgesic potency in nociceptive pain is approximately one-tenth that of morphine, but in neuropathic pain, the potency ratio is 1−2:1 [9].
Tramadol–paracetamol coadministration is one of the proposed methods in postoperative multimodal analgesia in the era of the opioid epidemic [10]. In postoperative pain management, tramadol monotherapy does not usually provide adequate analgesia, but in coadministration with paracetamol, it can be highly effective. Tramadol–paracetamol coadministration has a supra-additive efficacy in preventing hyperalgesia [11], and as tramadol and paracetamol doses in the commercial combination products are relatively low, they are commonly well tolerated [12]. The tramadol–paracetamol combination product has analgesic efficacy in patients with both subacute and chronic low back pain and is effective in sustaining these patient’s physical functioning and quality of life [13,14].
The aim of this placebo-controlled, double-blinded, clinical trial was to estimate the benefits and harms of tramadol–paracetamol combination product in early postoperative pain after spine surgery. The primary outcome measure was patients’ satisfaction with pain medication 1 week after surgery.
2 Methods
2.1 Study design and subjects
This was a prospective, randomized, double-blind, placebo-controlled trial in 120 patients undergoing elective lumbar or cervical spine surgery between September 2019 and February 2021 at Kuopio University Hospital. The inclusion criteria were as follows: patients scheduled for elective primary cervical or lumbar spine surgery, age of 18–75 years, and body mass index of 18–35 kg m−2. Pregnant and lactating patients were excluded, as were those with sleep apnea, severe lung disease, severe heart disease, peptic ulcer, epilepsy, tendency of bleeding, severe renal or liver failure, and patients with hypersensitivity to tramadol, ibuprofen, paracetamol, or any of the excipients of the study compounds. Patients with a history of drug or alcohol abuse were also excluded. The patients were given oral and written information about the study, and 125 patients gave their informed consent. The surgery was canceled in five patients, and the final study population consisted of 120 patients (Figure 1).
Flow chart: patient exclusions and recruitment. PACU = postanesthesia care unit; POD = postoperative day.
2.2 Perioperative care
Standardized general anesthesia was used; premedication oral paracetamol, i.v. midazolam and propofol to induced anesthesia, rocuronium to facilitate orotracheal intubation, and a remifentanil-infusion for intraoperative analgesia (adjusted to maintain the Surgical Pleth Index at 20–50 (Carescape™ B650; GE Healthcare, Helsinki, Finland)), the maintenance of anesthesia with a propofol-infusion or sevoflurane-inhalation (adjusted to maintain the response entropy at 40–50 (Carescape™ B650)), and at the end of the anesthesia, sugammadex to reverse muscle relaxation.
2.3 Study compounds and study group allocation
After giving written informed consent, the participants were randomized, using a random sequence generator (www.randomization.com), into two parallel groups, and given double-blinded either two tramadol–paracetamol 37.5 mg/325 mg tablets (TRAMPALGIN®, Weifa, Oslo, Norway), the tramadol–paracetamol group, or two near-matched placebo tablets, the placebo group. The study compounds were purchased from commercial sources. Allocation concealment was achieved using the closed, opaque envelope method. To ensure blinding, an independent pharmacy dispensed the study medicines in pouches containing two tablets each, and the pouches were labeled study compound 1 (placebo tablets) and study compound 2 (tramadol–paracetamol tablets). The success of the blinding was tested by asking patients to guess their study group allocation at 7 days after surgery but researchers and patients were blinded to their study group allocation up to 12 months postoperative.
The first two study tablets were given in the morning before surgery, the next two tablets in the evening after the surgery, and then two tablets at 8 am and two tablets at 8 pm as long as they had moderate or severe pain for a maximum of 5 days. Each patient had a total of 20 tramadol–paracetamol or placebo tablets.
2.4 Rescue analgesia
For postoperative pain in the hospital, all patients had a standardized multimodal analgesia with dexketoprofen/ibuprofen and oxycodone with a target to keep patient’s pain on an 11-point numeric rating scale (NRS, 0 = no pain, 10 = worst pain) at rest <3/10 and dynamic pain <5/10. At discharge, the patients were given 30 ibuprofen 200 mg tablets (BURANA®, Orion Corporation, Espoo, Finland) to be used a maximum of six tablets a day if the pain relief with the study medicine was insufficient. The ibuprofen tablets were kindly provided by Orion Corporation, but this was an academic study, and Orion Corporation was neither involved in the design of the study, collecting, or analyzing the data, nor in writing the report.
After the first 5 postoperative days, pain treatment was prescribed according to the medical judgment of the attending physician.
2.5 Data collection
Pre- and perioperative data were collected by questionnaires before surgery and at discharge on the first postoperative morning and from the hospital’s medical record system. The questionnaires before surgery and at discharge were completed by the subjects themselves, and one of the authors (EL, MK, and PT) ensured the completeness of the forms and was available to consult to ensure understanding of the questions. After discharge, patients were interviewed by phone call (EL and PT) at 7 days and 52 weeks.
Patients’ satisfaction with pain medication, pain intensity, amount of rescue analgesic use, and adverse events were evaluated using the Brief Pain Inventory (BPI) questionnaire [15]. Patients’ satisfaction with pain medication was measured with NRS 0–100%. Pain intensity was measured as patients’ worst, least, and average pain during the past 24 h and pain right now.
Analgesic use during hospitalization was collected using the hospital’s medical record system. The use of ibuprofen for rescue analgesia was evaluated by recording the total number of ibuprofen tablets used during the first postoperative week.
Adverse events were collected from the hospital’s medical record system and with the BPI questionnaire.
2.6 Outcome measures
Our primary outcome measure was patients’ satisfaction with pain medication measured on a scale of 0% = not satisfied and 100% = totally satisfied at 1 week after surgery.
Secondary outcomes were the need for rescue pain medication and adverse events at the first postoperative week, pain intensity on an NRS of 0–10 (0 = no pain, 10 = worst pain) at 1 week after surgery and pain at 52 weeks.
2.7 Statistics
The sample size was calculated based on the pain-relieving efficacy of tramadol–paracetamol and placebo after dental surgery, where 47% of patients in the tramadol–paracetamol group compared to 5% of patients in the placebo group evaluated the efficacy as good or excellent overall [16]. The data were entered and analyzed with the Statistical Package for Social Sciences software (IBM SPSS Statistics 27, International Business Machines Corporation, Armonk, NY, USA). The distribution normality of continuous variables was tested by visual inspection of the histograms and using the Shapiro‒Wilk test. The continuous variables were analyzed with the Mann‒Whitney test or Wilcoxon test, and the binomial and categorical variables were analyzed with the chi-square test or McNemar test as appropriate and calculated relative risk (RR) with 95% confidence interval (CI). Continuous data are reported as the median with interquartile range (IQR), and categorical data are reported as the number of cases (percentages). p-Values under 0.05 were considered statistically significant.
3 Results
3.1 Patient characteristics, study compounds use, and pain outcome
Patient characteristics are listed in Table 1. Forty-seven of the 59 (80%) patients in the placebo group and 45 of the 61 (74%) patients in the tramadol–paracetamol group used all 20 study tablets (p = 0.446). The reasons for the cessation of study product use were no need for further analgesics (placebo group n = 6, tramadol–paracetamol group n = 4), suspected adverse event(s) (n = 3 vs n = 8), and lack of efficacy (n = 3 vs n = 2). Two patients in the tramadol–paracetamol tramadol–paracetamol group did not give any specific reason for cessation.
Patient characteristics. Data are median [IQR] or number of cases (%)
| Baseline factors | Placebo group, n = 59 | Tramadol–paracetamol group, n = 61 |
|---|---|---|
| Sex, male/female, n (%) | 37 (63%)/22 (37%) | 37 (61%)/24 (39%) |
| Age, years, median [IQR] | 58 [12] | 52 [13] |
| Weight, kg, median [IQR] | 82 [21] | 83 [17] |
| Height, cm, median [IQR] | 175 [14] | 174 [12] |
| Operation type, lumbar/cervical, n (%) | 28 (47%)/31 (53%) | 30 (49%)/31 (51%) |
| Patients’ preoperative satisfaction with pain medication 0–100%*, median [IQR] | 60% [30%] | 60% [40%] |
| Patients’ preoperative pain intensity NRS 0–10**, median [IQR] | ||
| Worst pain | 6 [4] | 7 [3] |
| Least pain | 2 [2] | 2 [2] |
| Average pain | 5 [4] | 5 [4] |
| Right now | 4 [5] | 4 [5] |
*0% = not satisfied, 100% = totally satisfied.
**NRS = numeric rating scale, 0 = no pain, 10 = worst pain.
Fifty-three (90%) patients in the placebo group required supplemental oxycodone during the first 24 postoperative hours, with a median dose of 24 mg [IQR, 30], compared to 54 (89%) patients (p = 0.818) in the tramadol–paracetamol group, with a median dose of 20 mg [32] (p = 0.528), requiring oxycodone for postoperative pain.
3.2 Primary outcome measure
Primary and secondary outcome measures are listed in Table 2 and expressed in Figure 2. Patients’ satisfaction with pain medication at 7 days after surgery was similarly high in the two groups, the median on a scale of 0–100% was 75% [30%] in the placebo group and 70% [40%] in the tramadol–paracetamol group (p = 0.949). Within group comparison patients’ satisfaction with pain medication increased in both groups, placebo group p = 0.036 and tramadol–paracetamol group p = 0.033.
Patients’ satisfaction with pain medication, pain intensity, and need for rescue ibuprofen at 1 week after surgery
| Parameter | Placebo group n = 58 | Tramadol–paracetamol group n = 61 |
|---|---|---|
| Satisfaction with pain medication, 0–100%*, median [IQR] | 75% [30%] | 70% [40%] |
| Pain intensity, NRS 0–10**, median [IQR] | ||
| Worst pain | 4 [4]# | 5 [5] |
| Least pain | 0 [2] | 1 [2] |
| Average pain | 2 [3]# | 3 [4] |
| Pain right now | 2 [3] | 2 [3] |
| Need for rescue pain medication | ||
| Had ibuprofen, n (%) | 30 (52%) | 44 (72%) |
| Ibuprofen (mg), median [IQR] | 200 mg [1,000]# | 800 mg [1,600] |
Data are median [IQR].
# p-value < 0.05 between the groups.
*0% = not satisfied, 100% = totally satisfied.
**NRS = numeric rating scale, 0 = no pain, 10 = worst pain.
A box and whisker plot presentation of patients’ satisfaction with pain medication in the two groups before surgery and 1 week after surgery. The boxes represent 25 and 75% interquartile ranges, medians, and means (X) and the whiskers represent minimum and maximum, ● represents two outliers, 0%. Between groups comparison NS = non-significant. Within groups comparison *, the placebo group p = 0.036 and the tramadol–paracetamol group p = 0.033.
3.3 Secondary outcome measures
One week after surgery during the past 24 h, patients in the placebo group used less ibuprofen, median 200 mg [1,000] than patients in the tramadol–paracetamol group, median 800 mg [1,600] (p = 0.016).
Patients used other analgesics also, but there was no difference in paracetamol use, median 0 g [1] in the placebo group and 0 g [1] in the tramadol–paracetamol group (p = 0.256), or in opioid use, oxycodone equivalents 0 mg [0] in the placebo group and 0 mg [0] in the tramadol–paracetamol group (p = 0.654).
Sixty patients (50%) had adverse events after surgery during the first postoperative week, more commonly in the tramadol–paracetamol group (39/61, 64%) than in the placebo group (21/59, 36%) (RR = 1.8, 95% CI, 1.2–2.6). Suspected adverse events are listed in Table 3.
Suspected adverse events during the first postoperative week
| Placebo group, n = 59 | Tramadol–paracetamol group, n = 61 | |
|---|---|---|
| Subjects with adverse events, n (%) | 21 (36%) | 39 (64%)* |
| Total number of adverse events, n | 35 | 92* |
| Nausea | 6 (10%) | 18 (30%)* |
| Fatigue | 3 (5%) | 18 (30%)* |
| Dizziness | 1 (2%) | 11 (18%)* |
| Mental confusion | 2 (3%) | 8 (13%) |
| Constipation | 7 (12%) | 7 (11%) |
| Dry mouth | 2 (3%) | 4 (7%) |
| Sweating | 1 (2%) | 4 (7%) |
| Itching | 1 (2%) | 3 (5%) |
| Headache | — | 3 (5%) |
| Difficult urination | 2 (3%) | 2 (3%) |
| Muscle weakness | — | 2 (3%) |
| Nightmares | 2 (3%) | 1 (2%) |
| Arrythmia | 2 (3%) | — |
| Abdominal pain | 1 (2%) | 1 (2%) |
| Vomiting | 1 (2%) | 1 (2%) |
| Diarrhoea | 1 (2%) | 1 (2%) |
| Others | 3# | 8## |
| Total | 35 | 92 |
#Herpes simplex virus activation, pulmonary embolism, allergic reaction.
##Chills, muscle cramps, agitation, flatulence, blurred vision, alternating blood pressure, insomnia, withdrawal symptom.
*p-value < 0.05 between groups.
At 12 months, the prevalence of persistent spinal pain syndrome (PSPS) was lower in patients with tramadol–paracetamol; 6/56 (11%) patients in the tramadol–paracetamol group and 13/57 (23%) patients in the placebo group (RR 0.47, 95% CI 0.19–1.15) had pain exacerbated compared to pain reported before surgery. At 12 months, patients had fewer radicular pain symptoms than before surgery in both groups: 51/59 (86%) vs 17/56 (30%) patients in the placebo group (RR 0.3, 95% CI 0.2–0.5) and 50/61 (82%) vs 25/57 (44%) patients in the tramadol–paracetamol group (RR 0.4, 95% CI 0.3–0.6).
At 12 months after surgery, the prevalence of at least moderate worst pain (NRS ≥ 4/10) during the past 24 h was significantly lower than that before surgery in both groups: 27/56 (48%) vs 45/59 (76%) patients in the placebo group (RR 0.6, 95% CI 0.4–0.8) and 32/57 (56%) vs 54/61 (89%) patients in the tramadol–paracetamol group (RR 0.5, 95% CI 0.3–0.7).
4 Discussion
In the present study, tramadol–paracetamol combination product did not increase patients’ satisfaction with their early pain medication and caused increased harm. Furthermore, tramadol–paracetamol did not decrease early postoperative pain or the need for other analgesics during the first postoperative week after spine surgery. At 1 week after surgery, pain scores were little higher in the tramadol–paracetamol group but were modest in the majority of the patients in both groups. At 12 months, the prevalence of PSPS was nonsignificantly lower in patients with tramadol–paracetamol (n = 6) than in the placebo group (n = 13, RR 0.47, 95% CI 0.19–1.15).
The tramadol–paracetamol combination product has been shown to be effective in many clinical indications, including postoperative pain and low back pain [14,17]. However, to our knowledge, this is the first placebo-controlled study evaluating the efficacy of tramadol–paracetamol combination product in spine surgery patients. We assume that the rather low doses of paracetamol and tramadol used in our study may explain our results that the combination did not enhance patients’ satisfaction with their pain medication 1 week after surgery. The peroral tramadol dose of 150 mg/24 h and paracetamol dose of 1.3 g/24 h are half of the approved maximum daily dose of the combination product, but our justification for dose selection was that higher dosages could have been associated with more adverse effects [18]. Previously, coadministration of tramadol and paracetamol has been evaluated in an active-controlled study in microdiscectomy patients [18]. In that study, the follow-up was only for the first four postoperative hours, the number of adverse events was increased with a higher dose of tramadol compared to coadministration of a lower dose with paracetamol, and analgesic efficacy was similar in the two groups [18]. In a recent open-label study, coadministration of i.v. paracetamol 1 g every 6 h enhanced pain relief achieved with i.v. tramadol during the first 24 postoperative hours after spine surgery [19]. In the present study, some of the suspected opioid-related adverse effects and early study compound cessations were more common in the tramadol–paracetamol -group. This is consistent with Rawal and colleagues’ study on hand surgery patients, where nausea and vomiting and study compound cessations were relatively high among patients randomized to have tramadol for postoperative pain management [20].
In our previous study in a similar patient population and similar settings, we compared oxycodone and oxycodone-naloxone controlled-release tablets in postoperative multimodal pain management after spine surgery. In that study, more efficient pain relief was achieved with oxycodone products compared to the present study [21]. This may indicate that pure opioid analgesics could be a better choice for early pain management after spine surgery but that patients may benefit in long-term outcomes from tramadol–paracetamol combination products coadministered as a part of a multimodal approach.
As a strength of the evidence, our study was conducted using a randomized, double-blind, placebo-controlled protocol. We performed all analyses for the primary outcome measures on an intention-to-treat basis, and based on a high response rate, 93–95%, in both groups, we assume that our data are soundly based. Since pain is a multidimensional experience, we used patient-reported outcomes with validated questionnaires using several variables: patients’ satisfaction with pain medication, pain intensity, analgesic use, and adverse events [15]. Each interview was performed by one of the same three trained researchers to decrease bias. One of the strengths of the present study was that it was an academic study, and no companies were involved in either research planning, data collection, in analyzing, or reporting the results.
There are limitations that should be considered. Our study population was relatively small, and a few subjects had low treatment compliance concerning the use of study compounds. However, the study protocol allowed study compound cessation if the patients did not have pain. Second, we did not use the maximum approved daily dose of tramadol–paracetamol combination product. Higher doses may have enhanced the analgesic efficacy but also, we assumed, increased the risk of adverse effects [19]. The most commonly reported adverse effects with the combination product, nausea, and dizziness were also commonly observed in the present study [12]. Third, in the follow-up after surgery, some patients might report pain outcomes that are not related to their spine disease, which might have affected the results. However, in BPI, patients are asked to mark their pain location(s) on front/back body diagrams and to describe their pain perception. Thus, we believe our data are soundly based [15]. However, as we made multiple statistical comparisons between the two groups there was a risk of a type 1 error, i.e., falsely rejecting the null hypothesis.
Further studies on tramadol–paracetamol combination are warranted as all patients in our study had NSAIDs as a part of their multimodal pain management protocol. Recent UK Biobank study indicated that patients reporting acute back pain and taking NSAIDs have elevated risk of pain persistence [22]. Whether this is the case with back surgery patients also, and whether tramadol–paracetamol combination product without concomitant NSAID would perform better, should be evaluated. In this study, half of the patients in the placebo group and one-third in the tramadol–paracetamol group had ceased ibuprofen 1 week after surgery and the daily dose for those still having ibuprofen was modest, 800 mg in both groups. In a post hoc analysis, it was found that the postoperative use of ibuprofen was similar in patients with PSPS and that in those who recovered without pain exacerbation in follow-up. Further studies are warranted to evaluate factors to prevent PSPS, which is a chronic or recurrent pain condition of spinal origin usually combined with neuropathic pain symptoms, e.g., paresthesia, numbness, stiffness, and muscle weakness or spams, and could be associated with spine surgery [23].
5 Conclusion
Coadministration of tramadol–paracetamol with NSAIDs and oxycodone did not enhance satisfaction with early pain medication at 1 week after spine surgery and the addition of tramadol–paracetamol was associated with increased harm.
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Research ethics: Research involving human subjects complied with all relevant national regulations, institutional policies and is in accordance with the tenets of the Helsinki Declaration (as amended in 2013), and has been approved by the Research Ethics Committee of Northern Savo Hospital District, Kuopio, Finland (No. 511/2018, April 10, 2018) and the Finnish Medicines Agency was notified (No. 20/2018, March 21, 2018). The study had organizational approval, and it was recorded in the European Clinical Trial database (EudraCT no 2017-004711-39) and in the Clinicaltrials.gov database (NCT04533009).
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Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
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Informed consent: Informed consent has been obtained from all individuals included in this study.
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Competing interests: Authors state no conflict of interest.
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Research funding: EL has received funding granted by the Finnish Cultural Foundation and the Finnish Medical Foundation. For the remaining authors, none were declared.
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Data availability: The raw data can be obtained on request from the corresponding author.
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Supplementary material: Table S1: CONSORT 2010 checklist of information to include when reporting a randomised trial.
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