The new antiepileptics gabapentin and pregabalin act on the α2δ1-subunits of the presynaptic voltage-dependent calcium channels.1 These drugs exert their analgesic effect via mechanisms different from opioids, NSAIDs or local anaesthetics and may be useful as adjuncts to control postsurgical pain.2
Originally, perioperative treatment with gabapentin in patients undergoing modified radical mastectomy aimed to prevent or ameliorate chronic postoperative pain, particularly associated with brachial plexus injury. However, this treatment decreased analgesic requirements and acute postoperative pain as well as the incidence of burning pain 3 months postoperatively.3
Since then, gabapentin and, later, pregabalin have been used preoperatively or perioperatively as adjuvants aiming to reduce opioid requirements and/or pain postoperatively. Data from meta-analysis articles provide evidence that gabapentin has an opioid-sparing effect and is efficacious in controlling perioperative pain. Although this drug decreased opioid requirements postoperatively, opioid side-effects such as nausea and/or vomiting were not affected.4
The evidence available for pregabalin efficacy as an adjuvant in postoperative pain control suggests that the drug decreases opioid requirements but not postoperative pain intensity.5 In contrast to a systematic review for gabapentin,4 pregabalin decreases opioid-related adverse effects such as vomiting, but is associated with side-effects such as visual disturbances.5 Patients with prevailing acute neuropathic pain after surgery and treated with pregabalin are expected to benefit more than those with inflammatory postoperative pain. Pregabalin may prevent or ameliorate the development of chronic postsurgical pain when surgery involves also the neuropathic component of pain, but more evidence-based data are required to support this assumption.6
We hypothesised that perioperative treatment with pregabalin would decrease morphine consumption perioperatively and the incidences of late and chronic pain associated with abdominal hysterectomy or myomectomy.
The present study was designed to investigate the impact of treatment with pregabalin on opioid requirements and pain intensity after myomectomy or abdominal hysterectomy, the intensity of acute pain and the presence of chronic postoperative pain.
Ethical approval for this double-blind randomised study (Ethical Committee M-13) was provided by the Ethical Committee of Aretaieio University Hospital, Athens, Greece (Chairperson Professor P. Demakakos) on 2 November 2006.
Patients and randomisation
The study started on 29 May 2007 and finished on 23 July 2009. Patients aged between 30 and 60 years, American Society of Anesthesiologists physical status I or II scheduled for total abdominal hysterectomy or myomectomy under general anaesthesia gave their written informed consent to participate in the study. The visual analogue scale (VAS) score for pain assessment (0 to 100 mm, 0 for no pain and 100 for excruciating pain) and the use of the patient-controlled analgesia (PCA) pump (Freedom 5, Vygon, Ecouen, France) for postoperative analgesia were explained to all patients during the preoperative visit. Exclusion criteria were body weight more than 20% of ideal weight, central or peripheral nervous disease, diabetes mellitus, chronic pain and intake of analgesics, hypnotics, antidepressants, sedatives, anxiolytics or calcium channel blockers.
Patients were randomised to the control or treatment group using sealed envelopes, containing odd and even numbers obtained from a computer-generated table; for odd numbers, patients were allocated to the control (code A) group and for even numbers to the pregabalin (code B) group. The active and placebo capsules were coded accordingly and kept in two different containers. Placebo capsules were prepared by emptying the pregabalin capsules and filling them with thin sugar. Capsule preparation and allocation into the containers (containers coded as A for the placebo and as B for the pregabalin capsules) were undertaken by an anaesthesiologist who did not participate in the study data collection or analysis. Anaesthesiologists, surgeons and patients were not aware of the contents of capsules.
Patients received pregabalin capsules 150 mg 8-hourly starting on the day before surgery at 14 : 00 hours and continuing for the first five postoperative days. The control group was treated similarly, but with placebo capsules instead.
Premedication was omitted. On arrival at the operating room, a 16-gauge catheter was inserted into a peripheral vein and 50 mg of ranitidine, 0.75 mg of droperidol and 10 mg of metoclopramide were administered intravenously. Metoclopramide increases the tone of the lower oesophageal sphincter; the combination with droperidol has a more powerful antiemetic effect than ondansetron 4 mg and is a low-cost regimen.7
Standard monitoring of oxygen saturation, ECG, heart rate and non-invasive blood pressure (S/5 Anaesthesia Monitor, GE Healthcare Finland Oy, Helsinki, Finland) was implemented. To monitor the depth of anaesthesia, a Bispectral Index (BIS) sensor was attached to the patient's forehead and connected to a BIS monitor (BIS A-2000, Aspect Medical Systems Inc., Newton, Massachusetts, USA).
All patients were pre-oxygenated with 100% oxygen via a tightly fitting face mask for 3 min. Anaesthesia was induced with fentanyl 5 μg kg−1, thiopental 4 to 5 mg kg−1 and cis-atracurium 0.15 mg kg−1 to facilitate intubation of the trachea, and maintained with sevoflurane in a 50% nitrous oxide/oxygen mixture, targeting BIS values of 40 to 50.
Postoperative pain and analgesic requirements
For the first two postoperative days, all patients had access to a 60-ml PCA pump (Freedom 5, Vygon) containing morphine 1 mg ml−1 with a lockout interval of 7 min and release dose of 1 mg.
While patients were using PCA morphine, they received intravenous ranitidine 50 mg every 12 h and intravenous metoclopramide 10 mg every 8 h to protect against gastric acid hypersecretion and to prevent possible nausea and vomiting due to morphine. If metoclopramide was not effective in preventing postoperative nausea and vomiting, patients were treated with 4 mg of intravenous ondansetron.
During the third, fourth and fifth postoperative days, patients received Lonalgal (Boehringer Ingelheim, Ingelheim, Germany) tablets (30 mg of codeine with 500 mg of paracetamol) on demand for pain relief due to surgery.
Morphine consumption was recorded 2, 4, 8, 24 and 48 h postoperatively and Lonalgal tablet consumption on the third, fourth and fifth postoperative days. VAS pain scores at rest and on coughing were recorded at 2, 4, 8, 24 and 48 h postoperatively as well as on the third to fifth postoperative days. To assess pain during coughing, the patient was asked to cough three times. Patients recorded pain at rest and during coughing by drawing a vertical line on a 100 mm horizontal line with 0 corresponding to no pain and 100 to intractable intolerable pain.
The presence or absence of dizziness, ataxia, diplopia and blurred vision were assessed before pregabalin administration and during the first five postoperative days. Sedation and anxiety (scored as 0 to 100 mm using visual analogue scales) were assessed before pregabalin administration, on the day of surgery 1 h after pregabalin intake, 2, 4, 8, 24 and 48 h postoperatively as well as on the third to fifth days after surgery.
Before discharge from hospital, all patients were asked to record at home the presence of pain and the analgesics required specifically due to surgery. One and 3 months later, patients were interviewed by telephone to identify the presence of late and chronic pain, hyperaesthesia or hypoaesthesia around the wound area and analgesic consumption due to surgery.
Our hypothesis was that pregabalin may decrease opioid requirements postoperatively and ameliorate late and chronic postoperative pain, which some patients may develop after surgery. The primary outcome of the study was the amount of morphine consumed during the first 48 h after surgery. Secondary outcomes were the intensity of acute pain, the presence of late and chronic pain as well as sedation, anxiety, dizziness, ataxia, diplopia and blurred vision during pregabalin intake.
Power analysis was based on a previous study8 in which mean morphine consumption in the control group after hysterectomy over the first 48 h was 50 mg. On the basis of this study, we assumed that at least 15 mg less morphine consumption representing a 30% reduction is a satisfactory clinical outcome. Therefore, in order to detect a 15 mg difference in cumulative morphine consumption at 48 h postoperatively, with a within-group SD of 22, a total sample of 58 patients was considered necessary to have a power of 0.80 with α-error of 0.05 for a two-tailed test.
We used an intention to treat analysis with a linear mixed model for morphine consumption and VAS scores at rest and on coughing postoperatively. The model was designed to assess differences between the two groups over time, with time and treatment as fixed effects, and a random effect to compensate for the correlation between repeated measurements. Interaction between treatment and time was also included in the model. In this model, the estimated coefficient suggests how much lower (negative sign) or higher (positive sign) is the measured variable in one group compared with the other.
The same model was applied for sedation and anxiety scores. If a significant difference was found, post-hoc individual comparisons between the two groups at each time point were carried out, adjusted with Bonferroni correction. To compare dizziness, ataxia, diplopia and blurred vision between the groups as well as the number of Lonalgal tablets consumed, we used the χ2-test. The presence of pain, loss of, or decreased sensation in the wound area and analgesic consumption 1 and 3 months postoperatively between the two groups were compared with the χ2-test. The statistical program used was IBM SPSS 19 (SPSS Inc., Chicago, Illinois, USA).
The mean (± SD) age of patients in the control and pregabalin groups was 42 ± 7 and 41 ± 7 years respectively. Body weight was 63.0 ± 7.1 and 63.4 ± 9.4 kg, and height was 163 ± 5 and 164 ± 5 cm respectively. The duration of surgery was 92 ± 26 and 95 ± 20 min in the control and the treatment groups respectively. The two groups did not differ in the number of patients who underwent abdominal hysterectomy; 19 of 41 (46.3%) patients in the control group had abdominal hysterectomy and 13 of 39 (33.3%) patients in the pregabalin group. Similarly, the number of myomectomies did not differ between the two groups: 22 of 41 (53.6%) versus 26 of 39 (66.6%) in the control and the pregabalin groups respectively (χ2 = 1.40, P = 0.234).
The flow diagram of the study is shown in Fig. 1.
Analgesic requirements and acute postoperative pain
The overall morphine consumption differed between the two groups [estimated coefficient = 18.40, 95% confidence intervals (CI) 8.81 to 27.99, P = 0.0001]. The pregabalin group had a significantly lower morphine consumption at time points 4, 8, 24 and 48 h postoperatively (P = 0.001, P = 0.0001, P = 0.0001 and P = 0.0001, respectively) (Fig. 2). Consumption of Lonalgal tablets during postoperative days 3 to 5 did not differ between the two groups (χ2 = 5.645, P = 0.582) (Table 1).
The mean VAS scores at rest (estimated coefficient = 1.9, CI −5.61 to 9.42, P = 0.615) and on coughing (estimated coefficient = 5.40, CI 4.83 to 15.63, P = 0.214) are shown in Table 2.
Sedation and anxiety scores did not differ overall between the control and the pregabalin groups (estimated coefficient 0.196, CI −0.22 to 0.61, P = 0.713 and 0.14, CI −0.31 to 0.61, P = 0.082 for the sedation and the anxiety scores, respectively). Patients in the control group had lower incidences of dizziness [11 of 38 (29%) versus 19 of 33 (58%), χ2 = 5.933, P = 0.015], ataxia [zero of 34 (0%) versus six of 33 (18%), χ2 = 6.711 P = 0.011], blurred vision [two of 33 (6%) versus nine of 35 (26%), χ2 = 4.839 P = 0.028)] or diplopia [zero of 34 (0%) versus five of 32 (16%), χ2 = 5.748 P = 0.023] compared with the pregabalin group.
Late and chronic pain
In the first and third months postoperatively, patients in the control and the pregabalin groups reported VAS scores for pain of 20.5 ± 18.7 and 27.0 ± 23.4 mm (P = 0.21) and 5.7 ± 1.0 and 4.8 ± 8.9 mm (P = 0.772), respectively. The results for late and chronic pain are shown in Table 3.
Perioperative administration of pregabalin decreased morphine consumption during the first 48 h after surgery, but had no effect on early, late or chronic pain.
The evidence available supporting the postoperative analgesic effect of pregabalin after hysterectomy is controversial or at least insufficient. A single dose of pregabalin 300 mg and 1 g of paracetamol given 1 h before abdominal hysterectomy had no effect on postoperative opioid consumption or pain scores during the first 24 h postoperatively.9
Jokela et al. reported that pregabalin 300 mg given 1 h before laparoscopic hysterectomy and repeated 12 h after surgery was associated with less oxycodone requirements for the interval 12 to 24 h postoperatively when compared with pregabalin 150 mg and repeated at the same time points. Intensity of pain did not differ between patients who received either diazepam 10 mg or a total dose of pregabalin of 300 or 600 mg. The incidences of dizziness, headache and blurred vision were higher in the 600-mg pregabalin group in comparison with the 10-mg diazepam group.10
The results of the studies by Mathiesen et al.9 and Jokela et al.10 imply that a single dose or two doses of pregabalin failed to decrease the postoperative consumption of opioids or other analgesics recorded during the first 24 h. However in another study, women undergoing abdominal hysterectomy and treated with 300 mg of pregabalin 1 h before surgery consumed less morphine during the first 24 h postoperatively and experienced less pain when compared with women treated with 0.5 mg of lorazepam as an active control.11
Women undergoing day-case gynaecological laparoscopy received either 5 mg of diazepam as an active control, or 75 mg of pregabalin, or 150 mg of pregabalin, given 1 h before surgery. Eight hours postoperatively, pregabalin 150 mg had no effect on analgesic requirements, but postoperative pain during the first 8 h both at rest and during movement was less compared with pain recorded after 5 mg of diazepam.12 Paech et al.13 found no effect of a single dose of 100 mg of pregabalin administered 1 h preoperatively to patients undergoing minor gynaecological procedures. These results are not comparable with the results of the present study, as the type of surgery and the dose of pregabalin differ.
In the above studies, patients were treated only with one dose of pregabalin, except for one study that used two doses, and the assessment of postoperative analgesic consumption and pain lasted for a limited period (maximum 24 h). To prevent or ameliorate chronic pain development, the surgical insult must be controlled postoperatively for as long as possible. For this reason, we continued the administration of the antiepileptic drug for the first 5 postoperative days. The dose and duration of treatment with pregabalin are consistent with our previous studies with gabapentin.3,8 In the present study, we found a significant reduction in opioid requirements in patients who received pregabalin. This study differs from our previous ones in that we administered high doses of pregabalin earlier and continued to administer the drug postoperatively for 5 days.
Although the number of Lonalgal tablets consumed during the third to the fifth postoperative days was twice as high as the number of tablets consumed by the control group (58 versus 29), the difference is not statistically significant. A possible explanation might be that, on the third to the fifth postoperative days, pain due to surgery was less intense. Also, the higher consumption of morphine during the first 48 h in the control group might have attenuated further sensitisation, resulting in similar analgesic requirements with the pregabalin group on the following days.14 Our results are consistent with the results of the systematic review demonstrating that pregabalin decreases postoperative opioid consumption, but has no effect on postoperative acute pain intensity.6
With regard to late and chronic pain, gabapentin and pregabalin up-regulate the α2δ1-subunits of the voltage-gated calcium channels, so interfering with the hypersensitisation process,15 and have been used clinically to treat neuropathic pain in various conditions.1–2,16 However, we found no difference in the incidence of late and chronic postoperative pain. Possible explanations may be the method of assessment (patients were interviewed by telephone), lack of statistical power to detect the presence of chronic pain (the study was powered for morphine consumption), and the number of dropouts (reducing the number of patients eligible for assessment for late and chronic pain).
Including patients who had myomectomy and abdominal hysterectomy might have influenced the results of the study, as hysterectomy may affect women psychologically and cause more anxiety than myomectomy. Anxiety enhances the affective component of pain.17 However, the numbers of myomectomies and hysterectomies were similar in the two groups, as were the anxiety scores recorded perioperatively; thus, the type of surgery is unlikely to have influenced the results.
We administered the total daily dose of 450 mg of pregabalin 8-hourly instead of 12-hourly for the convenience of our patients (a capsule of 150 mg 8-hourly instead of capsules of 150 and 75 mg 12 hourly), and to simplify the preparation of placebo capsules, requiring placebo only for the 150 mg active drug capsule. Kinetics of pregabalin at steady state are predictable and the Cmax, the apparent oral clearance and the apparent volume of distribution are similar for 600 mg given either as 200 mg 8-hourly or as 300 mg 12-hourly, although the terminal elimination half-life is shorter after 8-hourly administration of pregabalin.18
In conclusion, under the present study design, perioperative administration of pregabalin in women undergoing total abdominal hysterectomy or myomectomy, decreased morphine requirements during the first 48 h postoperatively, but had no effect on the consumption of Lonalgal tablets during postoperative days 3 to 5, or on acute, late or chronic pain during that period. More studies are required using different doses of pregabalin in the perioperative period and with chronic pain prevention or attenuation as the primary objectives.
Assistance with the study: none declared.
Financial support and sponsorship: this work was supported by Departmental funds (Aretaieio Hospital, University of Athens, Athens, Greece).
Conflicts of interest: none declared.
Comment from the Editor: AF is an editor of the European Journal of Anaesthesiology.
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