Inguinal herniorrhaphy is one of the most frequently performed general surgical procedures.1 The postoperative pain intensity may vary from moderate to severe, causing the patient discomfort and delaying recovery and discharge after herniorrhaphy.2 Prolonged postoperative pain may also lead to difficulty with returning to normal daily activities and work.3 A combination of analgesics and adjuvants with different mechanisms of action may improve postoperative pain management while reducing the number of doses needed and the analgesic-related side-effects.4,5
α2-Agonists are sympatholytic and centrally acting antihypertensive agents. In addition to their hypotensive effect, α2-agonists are also used in anaesthetic practice for their sedative and analgesic effects.6–9 The α2-agonists dexmedetomidine and clonidine have been extensively investigated in the context of multimodal analgesia; additional studies with different drug combinations are also needed.6–9,10
Tizanidine is a centrally acting α2-agonist with muscle relaxant, sedative and anxiolytic properties. This drug is widely used for the treatment of spasticity and has recently been used to treat musculoskeletal pain conditions.11 The role of tizanidine in anaesthesia has been evaluated in several studies. According to these studies, oral premedication with tizanidine attenuates the hypertensive response during laryngoscopy, reduces the induction dose of midazolam, the maintenance dose of propofol and the minimum alveolar concentration of sevoflurane, and prolongs spinal anesthesia.12–15 The postoperative analgesic effect of tizanidine has been demonstrated in a rat model, but to our knowledge, the role of tizanidine in postoperative pain treatment has not yet been investigated.16
The primary objective of this study was to compare the efficacy of tizanidine with placebo in the context of postoperative pain treatment in patients undergoing inguinal herniorrhaphy. The primary outcome measure was the postoperative visual numerical rating scale (NRS) values for pain. The secondary outcome measures were analgesic consumption, return to normal daily activity scores (first week) and the health-related quality-of-life scores (first month).
This prospective, randomised, double-blind study was conducted after obtaining institutional ethical approval (Ministry of Health Diskapi Yildirim Beyazit Training and Research Hospital Ethical Committee, Chairperson Prof. M. Alper on 17 December 2012, no: 06/35) and informed written patient consent between November 2013 and June 2014. Adult men of American Society of Anesthesiologists’ (ASA) physical status 1 to 3 scheduled to undergo day-case surgery for unilateral inguinal hernia repair under general anaesthesia were enrolled in the study. Patients with a history of chronic pain, bleeding disorders, sleep disturbances, renal or hepatic insufficiency, hypertension, peptic ulcer and those with known hypersensitivity to the study medications, or taking chronic nonsteroidal anti-inflammatory medications, antihypertensive drugs, sedatives or α2-agonists, and patients with recurrent hernia and emergency cases were excluded. Age, BMI and the ASA physical status were recorded for all patients. The visual NRS for pain (0, no pain; 10, the worst imaginable pain) was explained to the patients, and the presence of preoperative inguinal pain was determined.
Simple randomisation was used to allocate patients into one of two equal groups who received either tizanidine (Group T) or placebo (Group P). The patients in Group T received 4 mg of tizanidine (Sirdalud 2 mg tablets; Novartis, Saglik, Istanbul) orally twice per day during the first postoperative week and the first dose was administered 1 h before surgery. The patients in Group P received the same treatment with an identical placebo pill prepared by the hospital pharmacist. An anaesthetic nurse prepared the analgesic packs and performed patient randomisation. A table of computer-generated random numbers and sequentially numbered sealed opaque envelopes were used for randomisation. Patients were randomised after being assessed for eligibility, having signed informed consent and being registered on the study. The nurse delivered the analgesic pack according to group allocation, administered the first dose of either tizanidine or placebo and assigned a code to each patient. The patients were blinded to group allocation. The surgeons and the investigator who assessed pain, sedation, patient diaries and recovery had access to patient information but not to the randomisation list containing the codes. The patient codes were revealed after the 1-month postoperative visit had taken place.
Concurrent with the study drugs, both the groups received standard pain treatment with dexketoprofen and paracetamol. A 25-mg dose of dexketoprofen was administered intravenously prior to the induction of anaesthesia, and the same dose was administered orally three times per day during the first postoperative week. A 1-g dose of paracetamol was intravenously administered approximately 15 min prior to the end of surgery. Supplemental analgesia with paracetamol was provided if the NRS scores were at least 4 cm, in a dose of 1 g intravenous during the hospital stay (maximum daily dose 4 g) and 500 mg orally up to four times per day after discharge. The time to first analgesic request was recorded.
The patients were not premedicated. Heart rate (HR), mean arterial pressure (MAP), peripheral oxygen saturation, end-tidal desflurane concentration (EtDes) and the bispectral index (BIS) were monitored, and the baseline values of these variables were recorded. Anaesthesia induction and muscle relaxation were standardised with propofol, fentanyl and rocuronium. Anaesthesia was maintained with oxygen in nitrous oxide and desflurane. The desflurane concentration was titrated to a BIS value of 40 to 60, and the EtDes concentrations were recorded. Hypotension was defined as a decrease of at least 20% in the MAP from baseline values and was treated with intravenous ephedrine 5 mg. Bradycardia was defined as a HR of less than 45 beats per minute and was treated with intravenous atropine 0.5 mg. Hypertension and tachycardia were defined as increases in the MAP or HR of at least 20% from baseline values. Fentanyl 1 μg kg−1 was used for intraoperative rescue analgesia if hypertension and/or tachycardia was observed while the BIS value was within the range of 40 to 60. Local anaesthesia was not used. Surgery was performed by an experienced surgeon. All patients underwent open anterior mesh repair.
At the end of surgery, the patients were transferred to the postanaesthesia care unit (PACU). Postoperative pain was evaluated using the NRS on arrival in the PACU and at 6, 12 and 24 h postoperatively. NRS scores were recorded at rest and during movement (the observer asked the patients to cough, rise or walk during pain assessment). Pain intensity was graded as follows: NRS scores 0 to 3 cm, mild pain; 4 to 6 cm, moderate pain and at least 7 cm, severe pain. The patients were also assessed for sedation using a four-point sedation scale (0, awake; 1, responding to verbal commands; 2, responding to tactile stimulus; 3, deep sleep, difficult to arouse) at the time of the pain evaluation.
The patients were discharged with an analgesic pack containing dexketoprofen, paracetamol and either tizanidine or placebo and were instructed to record their NRS scores and analgesic consumption in a diary. The patients brought their analgesic packs and diaries to a visit which was scheduled 1 week after surgery. Pain intensity at home, total analgesic consumption and analgesic-related adverse events (e.g. dry mouth, dizziness, drowsiness, headache, nausea, vomiting, dyspepsia or bleeding) were determined during this visit. The patients were also evaluated as to whether they had experienced difficulty in performing daily activities because of pain in the past week. A five-point daily activity score (1, no difficulty; 2, mild difficulty; 3, difficulty; 4, severe difficulty or 5, unable to perform daily activities) was used to assess difficulty with normal daily activities (feeding, toileting, dressing and bathing). Health-related quality of life was evaluated 1 month after surgery using the short form-36. The short form-36 contains 36 questions concerning the patient's physical and mental health. The patient's scores are transformed into a total score of 1 to 100. The scores are presented with a physical component score (PCS) and a mental component score.
Statistical analyses were performed using the Statistical Package for Social Sciences (SPSS) software version 21.0 (SPSS Inc., Chicago, Illinois, USA). Continuous variables are presented as mean ± SD or median (range). Categorical variables are summarised as frequencies and percentages. The normality of continuous variables was evaluated using the Shapiro–Wilk test. Differences in continuous variables between the two groups were evaluated using the independent samples t test or the Mann–Whitney U test, and Friedman two-way analysis of variance was used wherever appropriate. Categorical variables were compared using the Pearson χ2 or Fisher's exact tests. A P value less than 0.05 was considered significant. Sample size was determined with a pilot study; 27 patients in each group were required to achieve 90% power with α = 0.05 (Group T, NRS 3.3 ± 1.2 cm; Group P, NRS 4.3 ± 1.0 cm). The minimal clinically important difference in acute pain after herniorrhaphy was considered a NRS score difference of 1.0 cm.17 Thirty patients were recruited for each group to account for possible dropouts.
Sixty patients were randomised to receive the study medications. The study flow chart is shown in Fig. 1. All patients returned their analgesic packs and diaries 1 week after surgery. However, five patients in Group T and seven patients in Group P were lost during follow-up; the short form-36 questionnaires of these patients were not obtained. No significant differences in patient characteristics or surgical data were observed between the two groups. The BIS values and EtDes values of the two groups were also similar (Table 1).
The postoperative NRS scores of the patients were comparable only at the time of arrival at the PACU; the NRS scores during the 6, 12 and 24 h postoperatively were significantly lower in Group T than in Group P, both at rest and during movement (Table 2, Fig. 2). The pain intensity was mild to moderate among the patients in Group T, and none of the patients in Group T reported severe pain. In contrast, 10 (33%) of the patients in Group P experienced severe pain. Groups were also different with respect to pain intensity after discharge on days 1, 2, 3 and 4 (P < 0.001, P < 0.001, P < 0.001 and P = 0.001, respectively) (Fig. 3). The effect size of the NRS differences and the power of these results are shown in Table 3. The median time to the first request for supplemental analgesia was longer in Group T than in Group P [20 (15 to 22) h vs. 10 (6 to 12) h, respectively; P = 0.005]. The paracetamol consumption was lower in patients who received tizanidine. The number of patients requiring paracetamol during their hospital stay was 11 in Group P and three in Group T (P = 0.033). The mean rescue analgesia dose was 1 g of paracetamol in both the groups. Twenty-two of the patients in Group T and 21 patients in Group P completed their analgesia diary fully. The amounts of the used and reported analgesics were consistent. The NRS scores of eight patients in Group T and nine patients in Group P were not complete after day 4. All available data were included in the analysis. Patients in Group T also had significantly lower paracetamol consumption after discharge. In Group T, 20 patients (66%) used no paracetamol and 10 patients (33%) consumed paracetamol on postoperative days 1, 2 or 3; the maximum dose was 1 g within 24 h. In contrast, seven patients (23%) in Group P required no supplemental analgesia and 23 (76%) patients in this group consumed paracetamol on postoperative days 1, 2, 3 or 4; the maximum dose was 1.5 g within 24 h (P < 0.001). None of the patients used the maximum allowed doses of paracetamol. The sedation scores of the patients were comparable in the two groups (P = 1.000); the patients were awake or easily aroused with verbal stimulation.
The ability to perform daily activities scores was lower in Group T than in Group P (P < 0.001). Fifteen patients in Group T had no difficulty performing normal daily activities and 13 patients experienced mild difficulty. Ten patients in Group P reported difficulty and six patients reported severe difficulty when performing daily activities. One patient in Group P was unable to perform daily activities. In contrast, none of the patients in Group T reported severe difficulty (Table 4).
The intraoperative HR alterations were similar in the two treatment groups; HR values were 67.6 ± 10.3 beats per minute in Group T and 68.3 ± 9.8 beats per minute in Group P (P = 0.804). However, the groups differed in respect of intraoperative MAP alterations. The MAP was lower in Group T than in Group P (93 ± 5.1 vs. 97.9 ± 10.7 mmHg; P = 0.031). Atropine and ephedrine were not used in either group. The mean postoperative HR and MAP values of the two treatment groups were similar.
The groups were similar with respect to the incidence of side-effects. Five patients (16.6%) in Group T and one patient (3.3%) in Group P reported having a dry mouth (P = 0.195). Dizziness was reported by three patients (6.6%) in Group T and two patients (1%) in Group P (P = 1.000). The number of patients who experienced fatigue was four (14%) in Group T and three (3.3%) in Group P (P = 1.000). None of the patients reported headache, nausea, vomiting or dyspepsia. Bleeding was not observed in any group.
A comparison of the short form-36 scores between the groups revealed significant differences in one of the physical dimensions. The bodily pain scores were 74 (74 to 100) in Group T and 74 (31 to 80) in Group P (P < 0.001). The PCS was 39 (36 to 60) in Group T and 38 (31 to 48) in Group P (P = 0.001). The effect sizes of the difference between the bodily pain scores and PCS scores were large and the power of these results was high (Cohen's d = 1.41, r = 0.58, power = 0.99; and Cohen's d = 0.93, r = 0.42, power = 0.86, respectively).
α2-Agonists are clinically used to provide analgesia.6–9 The spinal cord is the site of action and both peripheral and supraspinal mechanisms are also involved. α2-Agonists change neuronal ion channel functioning through multiple mechanisms and finally lead to central modulation of nociceptive transmission.5,18–20 Tizanidine is an α2-agonist mainly used for the treatment of pain related to muscular spasms. Tizanidine is also effective for myofascial pain and neuropathic pain, and has been used for back pain and headache.21–25
The results of our study demonstrated significantly lower NRS scores in patients treated with tizanidine compared with those who received placebo. The postoperative analgesic consumption in the tizanidine group was one-third of that in the placebo group and the time to first analgesic request was longer in Group T. The pain scores were comparable at the time of arrival in the PACU; there was a 1-cm difference in NRS scores in the first 24 h; the NRS difference increased to 2 cm or more after discharge. The most likely explanation for this escalating effect in time is the dose and timing of the first dose of tizanidine. Administering tizanidine earlier or using a higher dose could have resulted in a more significant and earlier onset of effect. Although a 2-cm NRS difference is considered substantial, a 1-cm NRS difference can be criticised as being not clinically important.26 Nonetheless, the authors of the previous studies regarded this degree of decrease in NRS scores as clinically significant. A NRS score difference of 1.0 cm is considered as the minimal clinically important difference in acute pain after herniorrhaphy.17 In a meta-analysis on α-agonists and postoperative analgesia, a 1.5 and 0.7 cm reduction on a 10-cm visual analogue scale were considered to be clinically relevant changes in pain scores.7 We consider this extent of decrease in pain to be important because, beyond lesser pain perception and decreased analgesic consumption, the daily activity scores and quality-of-life scores were improved in patients receiving tizanidine.
Recovery and pain are associated.27 Return to daily activity was measured with a subjective scale to assess recovery from the patients’ point of view. Quality of life was assessed using the short form-36, which is a validated tool for patients undergoing herniorrhaphy.28 The short form-36 dimension concerning pain and the physical health score was significantly higher in the group treated with tizanidine.
We have reported the effect size and power of our NRS and short form-36 score results although some of the patients did not complete their pain diaries after discharge and we could not complete the short form-36 questionnaire in all patients. Despite the lost follow-up, we detected that the effect sizes of the NRS and short form-36 score differences between the groups were large and the power of these results is high. These results provide another quantitative estimate of the difference in pain intensity between the treatment groups and emphasise the positive effect of tizanidine on postoperative analgesia.
α2-Agonists are useful adjuvants to anaesthesia as they provide sedation, anxiolysis, sympatholysis and analgesia.7 Clonidine is the prototype α2-agonist. The role of clonidine in postoperative analgesia is well established. Clonidine provides postoperative pain relief when administered parenterally and as an adjuvant to regional anaesthesia.19 Systemically administered clonidine decreases postoperative opioid consumption and pain intensity, and extends the time to first analgesia.7,29 Clonidine and tizanidine have not been previously compared in terms of postoperative analgesia, but the antinociceptive property of tizanidine is weaker compared with clonidine and the side-effects of tizanidine are well tolerated.14,30 The sedative and haemodynamic effects of tizanidine and clonidine have been investigated in healthy volunteers.31 According to that study, both drugs achieved modest sedation and reduced arterial blood pressure and salivation; however, the effects of tizanidine were short lasting. Tizanidine 4 mg caused a 9% reduction in SBP.31
In general, the incidence of side-effects with our pain management strategy was low; the intensity was mild and required no treatment. The MAP decreased only during the intraoperative period. The alterations in HR and MAP were within the predetermined limits; no treatment was required in either group. The MAP alterations in the tizanidine group were in accordance with the previous studies reporting on the larger safety margin of tizanidine.31
Several features of the study protocol need discussion. This was the first study investigating the role of tizanidine in postoperative pain management. The effective dose and timing of tizanidine in this context is not known, so a low dose was intentionally used. In addition to the low side-effect profile of tizanidine, the low dose used in our study and the timing of the first dose of tizanidine may be the reason for the low side-effect incidence that we have encountered. The same reasons may also explain why the EtDes values were similar in both the groups. The paracetamol doses used in our study were lower than the usual recommended doses, consistent with the purpose of multimodal analgesia, and it is worth noting that none of the patients used the maximum permitted doses of paracetamol.32,33 The patients were not provided with opioids for postoperative analgesia to avoid opioid-related side-effects. In addition to causing patient discomfort, these side-effects could have interfered with the side-effects of tizanidine. We aimed to eliminate a possible confounder by avoiding opioids and we suggest that the detected incidence of side-effects was entirely because of tizanidine.
This study was conducted on patients undergoing inguinal herniorrhaphy. Postoperative pain is not exclusively nociceptive pain related to tissue trauma; herniorrhaphy involves many muscular layers, and surgically induced skeletal muscle spasms and subsequent lactic acidosis may also contribute to pain. After herniorrhaphy, patients may keep themselves in a protective position, causing regional muscle spasms. We suggest that both the central modulation of nociceptive transmission and the muscle relaxant effect of tizanidine might have improved analgesia.
The study limitations are as follows. First, the study was not powered to compare the treatment groups with respect to adverse events and the study protocol prevented the participation of patients who were at risk of developing side-effects related to the analgesic management; our results concerning adverse events are inconclusive. Second, because we did not provide our patients with opioids, we were unable to demonstrate a reduction in opioid consumption, which would be complimentary. Furthermore, the patients were not evaluated with a fatigue or sleep diary after discharge. It was suggested that the patients would have difficulties with scoring more than one scale, and thus a scale was used only for the primary outcome measure. However, the short form-36 questionnaire includes many questions regarding fatigue. We did not observe any difference between groups concerning these dimensions. None of the patients complained about their sleep quality but we cannot present direct data regarding sleep.
In conclusion, the present study demonstrated that the addition of tizanidine to postoperative pain therapy decreased postoperative pain and analgesic consumption; the improved analgesia resulted in earlier return to normal daily activities among patients undergoing inguinal herniorrhaphy. Quality of life was also improved in terms of pain and physical health.
Acknowledgements relating to this article
Assistance with the study: none.
Financial support and sponsorship: none.
Conflicts of interest: none.
Presentation: preliminary results from this study were presented at the 1st World Congress on Abdominal Wall Hernia Surgery, Milan, Italy, 2015.
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