ORIGINAL ARTICLE
Pregabalin reduces opioid consumption and hyperalgesia but not pain intensity after laparoscopic donor nephrectomy M. Myhre1,2
, L. Romundstad2 and A. Stubhaug3,1
1
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway Department of Anesthesiology, Division of Emergencies and Critical Care, Oslo University Hospital, Rikshospitalet, Oslo, Norway 3 Department of Pain Management and Research, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway 2
Correspondence M. Myhre, Oslo University Hospital, Rikshospitalet, P.O. Box 4950 Nydalen, NO-0424 Oslo, Norway E-mail: [email protected] Conflict of interest The authors have no conflict of interest. Clinical trial number: NCT01059331 Responsible ethics committee: Regional for medisinsk og helsefaglig komite forskningsetikk Sør-Øst (REK Sør-Øst D), P.O. Box 1130 Blindern, NO-0318 Oslo. Document number given by ethics committee: 2009/1286 Submitted 6 July 2017; accepted 2 August 2017; submission 31 March 2017. Citation Myhre M, Romundstad L, Stubhaug A. Pregabalin reduces opioid consumption and hyperalgesia but not pain intensity after laparoscopic donor nephrectomy. Acta Anaesthesiologica Scandinavica 2017 doi: 10.1111/aas.12963
Background: Gabapentinoids are increasingly used to reduce acute postoperative pain, opioid consumption and opioid-related adverse effects. We explored the opioid-sparing, analgesic and anti-hyperalgesic effect of perioperative administered pregabalin in laparoscopic living donor nephrectomy. Methods: In this randomized controlled trial, 80 patients were recruited and randomized to receive pregabalin 150 mg twice daily or placebo on the day of surgery and the first postoperative day as part of a multimodal analgesic regimen. Primary outcome was opioid consumption 0–48 h after surgery. Secondary outcomes were pain intensity at rest and with movement 0–48 h after surgery using the 0–10 Numeric Rating Scale and incisional hyperalgesia measured 24 h post-surgery and at hospital discharge. Further secondary outcomes were adverse effects. Persistent post-surgical pain was registered 6 weeks, 6 and 12 months after surgery. Results: Pregabalin significantly reduced opioid consumption compared with placebo 0–48 h after surgery (median mg [25th, 75th percentile]); 29.0 (22.0–45.5) vs. 41.8 (25.8–63.6) (P = 0.04). Pain intensity 0–48 h after surgery calculated as area under the pain (NRS) vs. time curve was not statistically different between groups at rest (P = 0.12) or with movement (P = 0.21). Pregabalin decreased incisional hyperalgesia 24 h after surgery (median cm [25th, 75th percentile] 8.5 (1.0–18.5) vs. 15.5 (9.5–24.0) (P = 0.02). Nausea (P ≤ 0.01), use of antiemetics (P ≤ 0.01) and pain-related sleep interference (P = 0.02) were reduced with pregabalin. Conclusions: Perioperative pregabalin added to a multimodal analgesic regimen was opioid-sparing, but made no difference to pain intensity score 0–48 h after surgery. Pregabalin may reduce incisional hyperalgesia on the first day after surgery.
Editorial comment
In this trial, perioperative pregabalin, added to a multimodal analgesic regimen with local anesthetic wound infiltration, dexamethasone, paracetamol and opioids as required, was opioid-sparing and reduced incisional hyperalgesia on the first day after surgery. No effect on immediate postoperative pain 0–48 h after surgery, or persistent post-surgical pain at 6 weeks, or 6 and 12 months after surgery was demonstrated. Acta Anaesthesiologica Scandinavica (2017) ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
An international journal of anaesthesiology, intensive care, pain, and critical emergency medicine
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Laparoscopic living donor nephrectomy is a standardized surgical procedure performed in healthy individuals.1 Although the surgery has become less invasive changing from open surgery to minimally invasive laparoscopic techniques, many patients still experience moderate to strong pain and opioid-related adverse effects in the immediate postoperative period.2,3 The patients are healthy, often young, compassionately donating a kidney to a close family member or spouse. Thus, it is of great importance to reduce the total perioperative burden and sequelae as far as possible. Postoperative multimodal pain treatment is today standard of care.4 The regime involves the use of well-known agents such as opioids, paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, regional analgesia and the newer gabapentinoids.5,6 Although systematic reviews have demonstrated reduced opioid consumption in patients receiving pregabalin perioperatively,7 the analgesic efficacy in acute postoperative pain remains controversial.8 In spite of that, the use of gabapentinoids is recommended in the new American postoperative pain guidelines9 and widely implemented in postoperative pain protocols to relieve pain, spare opioids and thereby hasten recovery and reduce hospital stay. Lately, there has been increased focus on adverse effects caused by drugs and drug combinations used in postoperative pain treatment.10 Sedation, dizziness and visual disturbances are all associated with pregabalin,11 and recent studies have reported respiratory depressive effects.12,13 Thus, to prove their usefulness in a multimodal pain protocol, the analgesic advantages of pregabalin must outweigh potential adverse effects. Acute postoperative pain is most often regarded as inflammatory and nociceptive pain. Neurogenic mechanisms also contribute to the acute phase and reversible neuropathic pain may dominate from the late acute phase.14 Acute pain models have demonstrated analgesic effect of pregabalin.12 Consequently, there are reasons to believe that pregabalin is useful in early postoperative pain management. An analgesic effect of pregabalin will substantiate as reduced opioid consumption, reduced pain intensity or both. We hypothesized that pregabalin will reduce early opioid consumption.
There is evidence that the presence of postoperative sensory disturbances, especially hyperphenomena like hyperesthesia and hyperalgesia, is associated with chronic postoperative pain.15 Pregabalin may have anti-hyperalgesic properties5,16 and is by these mechanisms a candidate for prevention of persistent post-surgical pain. Hence, our primary aim was to investigate whether pregabalin 150 mg twice daily on the day of surgery and the consecutive day reduces opioid consumption. Secondly, we wanted to explore the effect of pregabalin on postoperative pain, incisional hyperalgesia and adverse effects. Materials and methods The clinical trial was conducted at Oslo University Hospital, Rikshospitalet, from January 2010 until October 2012 after approval was received by the Regional Committee for Medical Research Ethics for Eastern Norway and the Norwegian Medicines Agency. The study was registered at EudraCT (2009-015316-17) and www.clinicaltrials.gov (NCT01059331, 28 January 2010), and the results are reported in accordance with the CONSORT statement for randomized trials17 and the latest Declaration of Helsinki. Population Patients undergoing elective hand-assisted laparoscopic living donor nephrectomy with ASA classification I – II, aged 18–75 years, were eligible. At admission, the patients received oral and written information, and were enrolled in the study if a written consent was given. Exclusion criteria were known allergy to any of the test drugs, daily use of analgesics or sedative medications, or unfamiliarity with oral or written Norwegian. Randomization and blinding This was a randomized, placebo-controlled and parallel group study. A person not involved in the treatment or follow-up randomized the patients in sex-stratified blocks of 4–6 to one of two groups (1 : 1 ratio), using a computerized randomization program (DatInf RandList Acta Anaesthesiologica Scandinavica (2017)
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PREGABALIN AND POSTOPERATIVE ANALGESIA
version 1.2, DatInf GmbH, T€ ubingen, Germany). Block size and randomization code were unknown to all investigators (LR, AS, MM), and the treatment allocation was concealed in opaque, sealed and sequentially numbered envelopes for use in potential emergencies only (no envelopes opened). The participants were assigned to the next consecutive participant number and given study medication marked with the corresponding number. The study drug consisting of pregabalin 75 mg capsules and placebo capsules of identical appearance were produced by Oslo University Hospital Pharmacy, and pre-packed in sequentially numbered and identical containers according to the randomization list and labeled with identical study information. Patients and healthcare providers involved in the treatment of the patients were all blinded to the test drug, and the randomization code was not revealed to the investigators before all measurements were registered and entered into a database. Anesthesia and surgery All patients were premedicated with diazepam 10 mg orally in the morning before surgery. A three-lead electrocardiography, noninvasive blood pressure and peripheral pulse oximetry were applied for monitoring, and two intravenous cannulas were inserted for infusion of crystalloids. General anesthesia was induced and maintained by the use of infusion pumps (IVAC Syringe Pump, Model P7000, Alaris, Cardinal Health, Rolle, Switzerland) delivering propofol (mg/kg/h) and remifentanil (lg/kg/ min) as total intravenous anesthesia (TIVA). One hour after induction of anesthesia, postoperative nausea and vomiting prophylaxis was administered intravenously consisting of ondansetron 4 mg IV and droperidol 0.625 mg IV in addition to the previously mentioned dexamethasone 8 mg. The surgical procedure was a hand-assisted laparoscopic right- or left-sided nephrectomy.18 A 10-cm incision was made directly proximal to the pubic symphysis in addition to three incisions on the right or left side of abdomen for handling instruments. The kidney was dissected free from the retroperitoneal tissue, and removed through the incision near the
symphysis. Thirty minutes before the anticipated end of surgery, an intravenous bolus of fentanyl 50 lg (patients ≤ 60 kg) or 100 lg (patients ≥ 61 kg) was administered intravenously in addition to paracetamol 1 g. After closure of the surgical incision bupivacaine 5 mg/ml + epinephrine 5 lg/ml, 20 ml was infiltrated in the wound area. Perioperative pain management The participants were randomly assigned to receive either pregabalin or placebo in addition to a standard multimodal postoperative analgesic regimen comprising local anesthetic wound infiltration, dexamethasone 8 mg IV, paracetamol 1 g every 6th h and opioids as required. The study medication, consisting of two capsules a 75 mg (totally 150 mg) of either pregabalin or placebo, was administered 1 h before induction of anesthesia on the day of surgery, in the evening on the day of surgery, as well as in the morning and in the evening on the first postoperative day. Immediately after surgery, a patient-controlled analgesia (PCA) device (CADD-Legacy 6300 PCA Pump, Smiths Medical, Kent, UK) was connected delivering boluses of 1 mg ketobemidone19 intravenously on request, with a lock out time for 8 min between each bolus, and a maximum dose of 7 mg ketobemidone per hour. The total opioid consumption was retrieved from the PCA device and recorded daily by a trained nurse. The PCA device was stopped 48 h after surgery if the total opioid consumption was ≤ 20 mg for the last 24 h. If the patients required ≥ 21 mg ketobemidone, the PCA device was continued for another 24 h. After discontinuing the PCA device, oral oxycodone 5 mg or 10 mg was administered regularly twice daily and on request, to achieve adequate pain control. For statistical analyses, the opioids were converted to intravenous morphine equivalents.20 Opioid consumption The primary outcome was the opioid consumption in the early postoperative period predefined as 0–48 h after surgery. In this time period, all patients were using the PCA device.
Acta Anaesthesiologica Scandinavica (2017) ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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Pain assessment
Long-term follow-up
Postoperative pain was assessed using an 11point, 0–10 Numeric Rating Scale (NRS) where 0 = no pain and 10 = worst pain imaginable. Pain intensity was measured every hour at rest and with standardized movement (coughing) during the first 6 h postoperatively and in the evening on the day of surgery, followed by four times during the first postoperative day (09.00, 13.00, 17.00 and 21.00). The data collection was performed by a trained nurse in the postoperative unit and on the ward.
Finally, a long-term follow-up was carried out using questionnaires registering persistent postsurgical pain at rest and during activity in the last 24 h and during the last 7 days. The postal questionnaires were answered by the patients at 6 weeks, 6 and 12 months after surgery, and the number of patients reporting pain was used for further analysis.
Incisional hyperalgesia The area of incisional hyperalgesia was mapped21 by pin-prick stimuli to the skin with a handheld von Frey glass-fiber monofilament (Optihair 256 mN, Marstocknervtest, Marburg, Germany) twice. The first test was performed 24 h after surgery (around noon the day after surgery), and the second test was performed on the day of hospital discharge 4–6 days after the last drug administration. The tactile stimulation with the von Frey monofilament started above the pubic symphysis outside the hyperalgesic area and continued in steps of 5 mm along five trajectories toward the incision until a distinct change in sensation (painful, sore or sharper feeling) was registered. If no change in sensation appeared, the stimulus stopped 5 mm before the incision. The sum of the five distances around the wound was summarized and used as a surrogate for the hyperalgesic area. The hyperalgesia tests were performed by one of the investigators (MM). Adverse effects Sedation, dizziness, nausea, headache and painrelated sleep interference were registered by a trained ward nurse in the evening on the day of surgery, and four times (09.00, 13.00, 17.00 and 21.00) 24–48 h post-surgery and scored on a 0–10 NRS scale. In addition, vomiting, recovery of bowel function and mobilization (graded in coughing, upright in bed, standing/sitting in chair, walking) were recorded. Furthermore, the patients were asked to report any symptoms or discomfort during the hospital stay.
Statistical methods Sample size was calculated based on results from a similar study on pain and postoperative opioid usage after similar surgery in the same institution.22 We considered 20% difference between the groups in opioid usage, the primary efficacy variable, as clinically meaningful. With a mean opioid usage of 50 mg (SD 15) in the control group, a two sided a = 0.05 and 80% statistical power, 36 patients would be required in each group. To compensate for dropouts, we included 80 patients. Data were assessed for normality of distribution by Shapiro–Wilk test and visual inspection of the residuals using QQ-plots and histograms. Data are reported as median (25th to 75th percentile) unless otherwise is stated. Differences between groups for normally distributed continuous data (demographics, intraoperative data) were analyzed using the independent sample t-test. Non-normal distributed continuous data (opioid consumption, pain intensity, hyperalgesia, pain-related sleep interference and persistent post-surgical pain) were analyzed using the Mann–Whitney U-test. To compare repeated pain intensity measurements between the groups over time, we calculated the area under the curve (AUC). Categorical data (adverse effects, persistent post-surgical pain and demographic variables) were tested using the chi-square for independence test (with continuity correction) and confirmed with Fisher’s exact test when necessary. For multiple comparisons between groups, level of significance was corrected with Bonferroni adjustments with a factor of n comparisons. Data analyses were performed with IBM SPSS Statistics 24 (SPSS Inc., Chicago, IL, USA). Acta Anaesthesiologica Scandinavica (2017)
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PREGABALIN AND POSTOPERATIVE ANALGESIA
Results In the study period 1 February 2010 to 30 October 2011, 108 patients were operated with laparoscopic donor nephrectomy. Sixteen patients were not assessed due to lack of dedicated study personnel. Ninety-two patients were assessed for eligibility, and twelve patients were excluded (Fig. 1). Eighty patients were randomized to one of the treatments (40 patients in each group).Seventy-nine patients completed the in-hospital part of the study with only a few protocol violations. In the pregabalin group, one patient received diclofenac 50 mg 9 2 on the second postoperative day, while one patient received inhalation anesthesia with sevoflurane 90 min before changing to TIVA. One patient received erroneously higher boluses of opioids from the patient-controlled analgesia (PCA) device and was treated with naloxone. This patient was excluded from the efficacy analyses but maintained in the analyses of adverse events. In the follow-up at 6 weeks, 6 and 12 months after surgery, 76 (95%), 72 (90%) and 70 (87.5%) patients answered the questionnaires, respectively. Demographic variables are shown in Table 1. Pregabalin reduced the opioid consumption 0–48 h after surgery compared with placebo; 29.0 mg (22.0–45.5) mg vs. 41.8 mg (25.8–63.6) (P = 0.04) (Fig. 2). The difference was most evident 0–24 h after surgery; 16.3 mg (12.0–28.0) vs. 26.8 mg (15. 3–37.5) (P = 0.04), followed by 13.0 mg (8.0–22.5) vs. 17.5 mg (10.0–26.1) (P = 0.06) in the time period 24–48 after surgery. The PCA device was used in all patients during the first 0–48 h after surgery, and only a few patients received additionally oxycodone OR (0–24 h; N = 2, 24–48 h; N = 9). On the second postoperative day, 48–72 h after surgery, a large proportion of the patients (N = 35) stopped using the PCA device and started treatment with oral oxycodone. Opioid consumption after 48 h did not differ between groups (data not shown). Pain intensity are presented as NRS scores (median, 25th, 75th percentile) (Fig. 3). Area under the pain (NRS) vs. time curve (AUC) 0– 48 h after surgery were numerically but not significantly lower in the pregabalin group compared with the placebo group in rest; 46 (25–90)
vs. 64 (49–95) (P = 0.12) and with movement; 177 (130–208) vs. 185 (140–224) (P = 0.21). In the time period 0–24 h and 24–48 h, there were also no significant differences between the pregabalin group and the placebo group in rest or with movement; (P = 0.52, P = 0.89) and (P = 0.06, P = 0.18), respectively. Incisional hyperalgesia was tested 24 h after surgery and by hospital discharge. Thirty five patients in the pregabalin group and 27 in the placebo group (Fig. 4) were tested on each day. Nausea and pain were main reasons for refusing testing. The hyperalgesic area was significantly smaller in the pregabalin group compared with the placebo group 24 h after surgery 1; 8.5 cm (1.0–18.5) vs. 15.5 cm (9.5–24.0) (P = 0.02) but not at 5–7 days after surgery; 7.5 cm (0–20.0) vs. 15.5 cm (4.0–23.0) (P = 0.10). Adverse effects are presented in Table 2. Nausea was reduced in the pregabalin group compared with placebo group 24–48 h (P ≤ 0.01), and the number of patients receiving antiemetics was lower in the pregabalin group (N); 8 vs. 21 (P ≤ 0.01). Sedation and dizziness were insignificant between groups 0–24 h and 24–48 h after surgery. Pain-related sleep interference was significantly reduced in the pregabalin group 0–24 h (median NRS (25th, 75th percentile); 2.5 (0.0–4.0) vs. 4.0 (1.5–5.0) (P = 0.02) and 24–48 h after surgery; 1.0 (0.0– 3.0) vs. 2.0 (1.0–4.5) (P = 0.02). No significant differences were observed in time to mobilization. Four patients reported diplopia: three in the pregabalin group and one in the placebo group. Persistent post-surgical pain was assessed at rest and during activity at 6 weeks, 6 and 12 months after surgery (Table 3). There were no significant differences between groups after Bonferroni correction (P = 0.017). Discussion In this placebo-controlled study, pregabalin reduced opioid consumption during the first 48 h after surgery, while no difference in reported pain intensity score was found between the groups. Our findings are in accordance with a recent meta-analysis showing opioid-sparing effects in patients treated with 150– 300 mg pregabalin perioperatively.11 In this
Acta Anaesthesiologica Scandinavica (2017) ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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Fig. 1. CONSORT flow diagram of enrollment, treatment allocation and analysis. Acta Anaesthesiologica Scandinavica (2017)
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PREGABALIN AND POSTOPERATIVE ANALGESIA
Table 1 Demographics and intraoperative data.
Variables
Pregabalin (n = 40)
Placebo (n = 40)
Age (years) Gender (M/F) Body mass index (BMI) Propofol (mg) Remifentanil (mg) Duration of anesthesia (min) Duration of surgery (min)
47.4 10.5 12/28 25.5 3.4 1514 (504) 3.9 (1.3) 207 27 140 23
47.3 13.6 13/27 24.5 3.3 1679 (629) 4.2 (1.6) 209 30 143 29
Data are expressed as means (SD) and numbers. No significant differences were found between the treatment groups. Level of significance: P < 0.05.
meta-analysis, mean reduction in the pregabalin group was 16%, while the results in our study showed a 39% and 26% lower median opioid consumption in the pregabalin group at 0–24 h and 24–48 h, respectively. The effect of pregabalin on pain intensity has differed between studies. In one meta-analysis,23 pregabalin 150–300 mg reduced pain at rest and with movement 2 and 24 h postoperatively, while another meta-analysis could only confirm pain reduction in certain types of surgery, and specifically not in abdominal surgery.11 In the current study, all patients were treated with a robust multimodal standardized analgesic regimen consisting of paracetamol, opioids, glucocorticoids and local infiltration anesthesia possibly obscuring the analgesic
Fig. 2. Opioid consumption. Data are presented as median opioid consumption (25th, 75th percentile). Pregabalin significantly reduced opioid consumption 0–24 h after surgery (*P = 0.04), but not 24–48 h after surgery (P = 0.06). Level of significance: ≤ 0.05.
effect of the test medication. The opioids administered intravenously with a patient-controlled analgesia (PCA) device resulted in relatively low pain scores in both groups, indicating that the PCA-device algorithm, and instructions for use, worked well. Our results show numerically lower pain scores with pregabalin 0–48 h after surgery, but the difference was clinically and statistically insignificant. Nevertheless, the overall significantly reduced opioid consumption during the period when the test drug was administered, and the numerically lower pain scores, must be interpreted as an analgesic effect of pregabalin. Pain-related sleep interference was significantly lower in patients receiving pregabalin, further supporting the above interpretation.
Fig. 3. (A and B) Pain intensity at rest and with movement. Data are presented as median NRS scores (25th,75th percentile). Pain intensity 0–48 h after surgery calculated as area under the pain (NRS) vs. time curve were not statistically different between the treatment groups in rest (P = 0.12) or with movement (P = 0.21). Level of significance: ≤ 0.05. Acta Anaesthesiologica Scandinavica (2017) ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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Table 2 Incidence of main adverse effects.
Fig. 4. Incisional hyperalgesia. Data are presented as sum of the five distances around the wound. Horizontal line represents the median. The boxes represents 25th and 75th percentile, and the whiskers represents the range. Pregabalin reduced incisional hyperalgesia significantly 24 h after surgery (*P = 0.02), but not at hospital discharge 5–7 days after surgery (P = 0.10). Bonferroni-corrected level of significance: ≤ 0.025.
An anti-hyperalgesic effect of pregabalin has been demonstrated in animal24 and human pain models25 but is not well documented in clinical studies.26 In a small comparable study (N = 13 per group) in patients undergoing transperitoneal nephrectomy, a single preoperative dose of 300 mg pregabalin decreased the hyperalgesic area 48 h after surgery.27 In the present study, the incisional hyperalgesic area was significantly reduced in patients receiving pregabalin on the first postoperative day but not at hospital discharge 5–7 days after surgery. However, some patients, mostly in the placebo group, refused testing because of pain and nausea, resulting in several missing values. These incomplete data collections weaken the reported findings and underscore the need of further studies. The aim of multimodal pain management is to ensure optimal analgesia and reduce the need for opioids and thus opioid-related adverse effects. Nevertheless, pregabalin per se has been associated with unpleasant adverse effects like sedation, dizziness and visual disturbances.11 In this study, we found no significant difference between the groups in sedation or dizziness
0–24 h after surgery Sedation (n, %) Dizziness (n, %) Nausea (n, %) Antiemetics (n, %) Headache (n, %) Vomiting (n, %) Recovery of bowel function (n, %) Pain-related sleep interference (median [25th to 75th percentile]) 24–48 h after surgery Sedation (n, %) Dizziness (n, %) Nausea (n, %) Antiemetics (n, %) Headache (n, %) Vomiting (n, %) Recovery of bowel function (n, %) Pain-related sleep interference (median [25th to 75th percentile])
Pregabalin
Placebo
39 16 7 11 8 1 0
36 12 11 15 4 4 1
(97.5) (41.0) (17.5) (28.9) (20.0) (2.5) (0)
P-value
(94.7) (30.8) (27.5) (38.5) (10.3) (10.0) (2.5)
0.96 0.48 0.42 0.52 0.37 0.36 1.000
2.5 (0.0–4.0)
4.0 (1.5–5.0)
0.02*
36 29 9 8 6 6 1
39 29 23 21 16 11 2
(94.7) (74.4) (23.1) (20.0) (15.4) (15.0) (2.6)
1.0 (0.0–3.0)
(97.5) (74.4) (57.5) (52.5) (40.0) (27.5) (5.1)
2.0 (1.0–4.5)
0.96 1.000 < 0.01* < 0.01* 0.03 0.27 1.000 0.02*
Data are presented as number of patients (n, %) experiencing the adverse effect at least once or median NRS score (25th, 75th percentile). Bonferroni-corrected level of significance: ≤ 0.025. *P ≤ 0.025.
scores while the patients received pregabalin. Our findings are somewhat surprising as sedation induced by pregabalin has been reported in other studies28 but low adverse effect scores could be due both to reduced opioid consumption and to the combination with steroids. In a recent study in patients scheduled for hip arthroplasty,29 the sedative side effect of 300 mg pregabalin was diminished when adding 8 mg dexamethasone, suggesting that glucocorticoids might counteract this common side effect of pregabalin. In concert with previous studies,30 our results show reduced nausea and use of antiemetics in the pregabalin group. This may be the result of an opioid-sparing and subsequently antiemetic effect of pregabalin. Furthermore, it should be noted that the beneficial side effect profile seen in this study could be explained by the fact that the study population Acta Anaesthesiologica Scandinavica (2017)
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PREGABALIN AND POSTOPERATIVE ANALGESIA
Table 3 Persistent post-surgical pain.
Rest 6 weeks last 24 h last 7 days 6 months last 24 h last 7 days 12 months last 24 h last 7 days Movement 6 weeks last 24 h last 7 days 6 months last 24 h last 7 days 12 months last 24 h last 7 days
Pregabalin (n, %)
Placebo (n, %)
P-value
10 (26.3) 12 (30.8)
11 (29.7) 13 (35.1)
0.943 0.872
6 (16.7) 5 (55.6)
4 (11.1) 4 (11.1)
0.733 1.000
3 (8.3) 2 (5.6)
4 (11.8) 4 (11.8)
0.706 0.422
16 (42.1) 19 (48.7)
16 (43.2) 19 (51.4)
1.00 1.00
10 (27.8) 10 (27.8)
7 (19.4) 8 (22.2)
0.58 0.79
1 (2.8) 2 (5.6)
7 (20.6) 7 (20.6)
0.03 0.08
Data are presented as number of patients (n, %) experiencing wound-related pain in rest and with movement at 6 weeks, 6 and 12 months after surgery. Bonferroni-corrected level of significance: ≤ 0.017.
was relatively young and healthy and had received dexamethasone. Some studies have investigated the effect of perioperatively administered pregabalin on the incidence and intensity of chronic post-surgical pain.31 The area of incisional hyperalgesia has been found to predict persistent pain,32 and reduction of this area has been associated with reduced prevalence of persistent pain after surgery.33 In this study, the patients were followed up until 1 year after surgery. There were no differences in pain scores between the groups at 6 weeks or 6 months after surgery, while more patients in the placebo group reported activityrelated pain 1 year after surgery. Even if our study was not sized to find differences in persistent post-surgical pain, the results may add power to later systematic reviews on this issue. The strength of this study is very standardized surgery and perioperative care in healthy subjects without comorbidities. The study has
several limitations. First, only one-dose regimen was tested. Thus, the present study cannot answer what is the optimal dose and treatment length. Second, a few subjects (N = 9) received oral oxycodone as a supplement to PCA-ketobemidone, especially from 24 to 48 h post-surgery, and this had to be converted to i.v. opioid equivalents. Further, the number of patients tested for incisional hyperalgesia at 24 h postsurgery was lower in the placebo-group because of pain and nausea. The reduced and unequal sample size may have biased the test results on this outcome. Finally, it has to be emphasized that the number of patients in this study is too small to allow conclusions concerning the effect of pregabalin on persistent post-surgical pain after laparoscopic nephrectomy. In summary, this study shows that perioperatively administered pregabalin added to a robust multimodal analgesic regimen has an opioid-sparing effect, while pain intensity score is not reduced. Pregabalin may have anti-hyperalgesic effect the first day after surgery. Together with improved sleep and less nausea, these results support the use of perioperative pregabalin in patients undergoing laparoscopic donor nephrectomy. Acknowledgements The authors thank the many patients involved in this study, Leiv Arne Rosseland, M.D., Ph.D., Prof., Department of Anaesthesia, Division of Emergencies and Critical Care, Oslo University Hospital, Rikshospitalet, Oslo, Norway, for kind assistance with randomization, and the surgical team and nurses all affiliated at the Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway, for the excellent support and collaboration. Lien My Diep, M.Sc., Oslo center for Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Oslo, Norway, provided valuable advice and help on statistical issues. References 1. Dols LF, Kok NF, Ijzermans JN. Live donor nephrectomy: a review of evidence for surgical techniques. Transpl Int 2010; 23: 121–30.
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2. Perry KT, Freedland SJ, Hu JC, Phelan MW, Kristo B, Gritsch AH, Rajfer J, Schulam PG. Quality of life, pain and return to normal activities following laparoscopic donor nephrectomy versus open miniincision donor nephrectomy. J Urol 2003; 169: 2018–21. 3. Ergun M, Berkers AW, van der Jagt MF, Langenhuijsen JF, van Ozdemir-Brunschot D, van der Vliet JA, D’Ancona FC, Warle MC. Components of pain assessment after laparoscopic donor nephrectomy. Acta Anaesthesiol Scand 2014; 58: 219–22. 4. Kehlet H, Dahl JB. The value of “multimodal” or “balanced analgesia” in postoperative pain treatment. Anesth Analg 1993; 77: 1048–56. 5. Dahl JB, Nielsen RV, Wetterslev J, Nikolajsen L, Hamunen K, Kontinen VK, Hansen MS, Kjer JJ, Mathiesen O. Post-operative analgesic effects of paracetamol, NSAIDs, glucocorticoids, gabapentinoids and their combinations: a topical review. Acta Anaesthesiol Scand 2014; 58: 1165–81. 6. Romundstad L, Breivik H, Niemi G, Helle A, Stubhaug A. Methylprednisolone intravenously 1 day after surgery has sustained analgesic and opioid-sparing effects. Acta Anaesthesiol Scand 2004; 48: 1223–31. 7. Engelman E, Cateloy F. Efficacy and safety of perioperative pregabalin for post-operative pain: a meta-analysis of randomized-controlled trials. Acta Anaesthesiol Scand 2011; 55: 927–43. 8. Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. CochraneDatabaseSystRev 2009. CD007076. 9. Chou R, Gordon DB, de Leon-Casasola OA, Rosenberg JM, Bickler S, Brennan T, Carter T, Cassidy CL, Chittenden EH, Degenhardt E, Griffith S, Manworren R, McCarberg B, Montgomery R, Murphy J, Perkal MF, Suresh S, Sluka K, Strassels S, Thirlby R, Viscusi E, Walco GA, Warner L, Weisman SJ, Wu CL. Management of postoperative pain: a clinical practice guideline from the American Pain Society, the American Society of Regional Anesthesia and Pain Medicine, and the American Society of Anesthesiologists’ Committee on Regional Anesthesia, Executive Committee, and Administrative Council. J Pain 2016; 17: 131–57. 10. Hoffer D, Smith SM, Parlow J, Allard R, Gilron I. Adverse event assessment and reporting in trials of newer treatments for post-operative pain. Acta Anaesthesiol Scand 2016; 60: 842–51. 11. Eipe N, Penning J, Yazdi F, Mallick R, Turner L, Ahmadzai N, Ansari MT. Perioperative use of
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pregabalin for acute pain-a systematic review and meta-analysis. Pain 2015; 156: 1284–300. Myhre M, Diep LM, Stubhaug A. Pregabalin has analgesic, ventilatory, and cognitive effects in combination with remifentanil. Anesthesiology 2016; 124: 141–9. Weingarten TN, Jacob AK, Njathi CW, Wilson GA, Sprung J. Multimodal analgesic protocol and postanesthesia respiratory depression during phase I recovery after total joint arthroplasty. Reg Anesth Pain Med 2015; 40: 330–6. Martinez V, Ben Ammar S, Judet T, Bouhassira D, Chauvin M, Fletcher D. Risk factors predictive of chronic postsurgical neuropathic pain: the value of the iliac crest bone harvest model. Pain 2012; 153: 1478–83. Kaasa T, Romundstad L, Roald H, Skolleborg K, Stubhaug A. Hyperesthesia one year after breast augmentation surgery increases the odds for persisting pain at four years: a prospective fouryear follow-up study. Scand J Pain 2010; 1: 75–81. Wilder-Smith OHG, Arendt-Nielsen L. Postoperative hyperalgesia: its clinical importance and relevance. Anesthesiology 2006; 104: 601–7. Moher D, Hopewell S, Schulz K, Montori V, Gotzsche P, Devereaux P. CONSORT 2010 explanation and elaboration: updated guidelines for reporting parallel group randomised trials. BMJ 2010; 340: c869. Oyen O, Line PD, Pfeffer P, Edwin B, Jorgensen PF, Foss A, Lien B, Bentdal O, Husberg B, Brekke IB. Laparoscopic living donor nephrectomy: introduction of simple hand-assisted technique (without handport). Transplant Proc 2003; 35: 779– 81. Tamsen A, Bondesson U, Dahlstrom B, Hartvig P. Patient-controlled analgesic therapy, Part III: pharmacokinetics and analgesic plasma concentrations of ketobemidone. Clin Pharmacokinet 1982; 7: 252–65. Svendsen K, Borchgrevink P, Fredheim O, Hamunen K, Mellbye A, Dale O. Choosing the unit of measurement counts: the use of oral morphine equivalents in studies of opioid consumption is a useful addition to defined daily doses. Palliat Med 2011; 25: 725–32. Stubhaug A, Breivik H, Eide PK, Kreunen M, Foss A. Mapping of punctuate hyperalgesia around a surgical incision demonstrates that ketamine is a powerful suppressor of central sensitization to pain following surgery. Acta Anaesthesiol Scand 1997; 41: 1124–32. Acta Anaesthesiologica Scandinavica (2017)
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22. Andersen MH, Mathisen L, Oyen O, Edwin B, Digernes R, Kvarstein G, Tonnessen TI, Wahl AK, Hanestad BR, Fosse E. Postoperative pain and convalescence in living kidney donors-laparoscopic versus open donor nephrectomy: a randomized study. Am J Transplant 2006; 6: 1438–43. 23. Mishriky BM, Waldron NH, Habib AS. Impact of pregabalin on acute and persistent postoperative pain: a systematic review and meta-analysis. Br J Anaesth 2015; 114: 10–31. 24. Jokinen V, Lilius TO, Laitila J, Niemi M, Rauhala PV, Kalso EA. Pregabalin enhances the antinociceptive effect of oxycodone and morphine in thermal models of nociception in the rat without any pharmacokinetic interactions. Eur J Pain 2016; 20: 297–306. 25. Chizh BA, Gohring M, Troster A, Quartey GK, Schmelz M, Koppert W. Effects of oral pregabalin and aprepitant on pain and central sensitization in the electrical hyperalgesia model in human volunteers. Br J Anaesth 2007; 98: 246–54. 26. Lederer AJ, Bornemann-Cimenti H, Wejbora M, Kern-Pirsch C, Michaeli K, Sandner-Kiesling A. Pregabalin and postoperative hyperalgesia. A review. Schmerz 2011; 25: 12–8. 27. Bornemann-Cimenti H, Lederer AJ, Wejbora M, Michaeli K, Kern-Pirsch C, Archan S, RumpoldSeitlinger G, Zigeuner R, Sandner-Kiesling A. Preoperative pregabalin administration significantly reduces postoperative opioid consumption and mechanical hyperalgesia after
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transperitoneal nephrectomy. Br J Anaesth 2012; 108: 845–9. White PF, Tufanogullari B, Taylor J, Klein K. The effect of pregabalin on preoperative anxiety and sedation levels: a dose-ranging study. AnesthAnalg 2009; 108: 1140–5. Mathiesen O, Jacobsen LS, Holm HE, Randall S, Adamiec-Malmstroem L, Graungaard BK, Holst PE, Hilsted KL, Dahl JB. Pregabalin and dexamethasone for postoperative pain control: a randomized controlled study in hip arthroplasty. Br J Anaesth 2008; 101: 535–41. Grant MC, Betz M, Hulse M, Zorrilla-Vaca A, Hobson D, Wick E, Wu CL. The effect of preoperative pregabalin on postoperative nausea and vomiting: a meta-analysis. Anesth Analg 2016; 123: 1100–7. Martinez V, Pichard X, Fletcher D. Perioperative pregabalin administration does not prevent chronic postoperative pain. Systematic review with a metaanalysis of randomized trials. Pain 2017; 158: 775–83. Boogaard S, Heymans MW, de Vet HC, Peters ML, Loer SA, Zuurmond WW, Perez RS. Predictors of persistent neuropathic pain–a systematic review. Pain Physician 2015; 18: 433–57. Lavand’homme P, De Kock M, Waterloos H. Intraoperative epidural analgesia combined with ketamine provides effective preventive analgesia in patients undergoing major digestive surgery. Anesthesiology 2005; 103: 813–20.
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Pregabalin reduces opioid consumption and hyperalgesia but not pain intensity after laparoscopic donor nephrectomy M. Myhre1,2
, L. Romundstad2 and A. Stubhaug3,1
1
Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway Department of Anesthesiology, Division of Emergencies and Critical Care, Oslo University Hospital, Rikshospitalet, Oslo, Norway 3 Department of Pain Management and Research, Division of Emergencies and Critical Care, Oslo University Hospital, Oslo, Norway 2
Correspondence M. Myhre, Oslo University Hospital, Rikshospitalet, P.O. Box 4950 Nydalen, NO-0424 Oslo, Norway E-mail: [email protected] Conflict of interest The authors have no conflict of interest. Clinical trial number: NCT01059331 Responsible ethics committee: Regional for medisinsk og helsefaglig komite forskningsetikk Sør-Øst (REK Sør-Øst D), P.O. Box 1130 Blindern, NO-0318 Oslo. Document number given by ethics committee: 2009/1286 Submitted 6 July 2017; accepted 2 August 2017; submission 31 March 2017. Citation Myhre M, Romundstad L, Stubhaug A. Pregabalin reduces opioid consumption and hyperalgesia but not pain intensity after laparoscopic donor nephrectomy. Acta Anaesthesiologica Scandinavica 2017 doi: 10.1111/aas.12963
Background: Gabapentinoids are increasingly used to reduce acute postoperative pain, opioid consumption and opioid-related adverse effects. We explored the opioid-sparing, analgesic and anti-hyperalgesic effect of perioperative administered pregabalin in laparoscopic living donor nephrectomy. Methods: In this randomized controlled trial, 80 patients were recruited and randomized to receive pregabalin 150 mg twice daily or placebo on the day of surgery and the first postoperative day as part of a multimodal analgesic regimen. Primary outcome was opioid consumption 0–48 h after surgery. Secondary outcomes were pain intensity at rest and with movement 0–48 h after surgery using the 0–10 Numeric Rating Scale and incisional hyperalgesia measured 24 h post-surgery and at hospital discharge. Further secondary outcomes were adverse effects. Persistent post-surgical pain was registered 6 weeks, 6 and 12 months after surgery. Results: Pregabalin significantly reduced opioid consumption compared with placebo 0–48 h after surgery (median mg [25th, 75th percentile]); 29.0 (22.0–45.5) vs. 41.8 (25.8–63.6) (P = 0.04). Pain intensity 0–48 h after surgery calculated as area under the pain (NRS) vs. time curve was not statistically different between groups at rest (P = 0.12) or with movement (P = 0.21). Pregabalin decreased incisional hyperalgesia 24 h after surgery (median cm [25th, 75th percentile] 8.5 (1.0–18.5) vs. 15.5 (9.5–24.0) (P = 0.02). Nausea (P ≤ 0.01), use of antiemetics (P ≤ 0.01) and pain-related sleep interference (P = 0.02) were reduced with pregabalin. Conclusions: Perioperative pregabalin added to a multimodal analgesic regimen was opioid-sparing, but made no difference to pain intensity score 0–48 h after surgery. Pregabalin may reduce incisional hyperalgesia on the first day after surgery.
Editorial comment
In this trial, perioperative pregabalin, added to a multimodal analgesic regimen with local anesthetic wound infiltration, dexamethasone, paracetamol and opioids as required, was opioid-sparing and reduced incisional hyperalgesia on the first day after surgery. No effect on immediate postoperative pain 0–48 h after surgery, or persistent post-surgical pain at 6 weeks, or 6 and 12 months after surgery was demonstrated. Acta Anaesthesiologica Scandinavica (2017) ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
An international journal of anaesthesiology, intensive care, pain, and critical emergency medicine
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Laparoscopic living donor nephrectomy is a standardized surgical procedure performed in healthy individuals.1 Although the surgery has become less invasive changing from open surgery to minimally invasive laparoscopic techniques, many patients still experience moderate to strong pain and opioid-related adverse effects in the immediate postoperative period.2,3 The patients are healthy, often young, compassionately donating a kidney to a close family member or spouse. Thus, it is of great importance to reduce the total perioperative burden and sequelae as far as possible. Postoperative multimodal pain treatment is today standard of care.4 The regime involves the use of well-known agents such as opioids, paracetamol, nonsteroidal anti-inflammatory drugs (NSAIDs), glucocorticoids, regional analgesia and the newer gabapentinoids.5,6 Although systematic reviews have demonstrated reduced opioid consumption in patients receiving pregabalin perioperatively,7 the analgesic efficacy in acute postoperative pain remains controversial.8 In spite of that, the use of gabapentinoids is recommended in the new American postoperative pain guidelines9 and widely implemented in postoperative pain protocols to relieve pain, spare opioids and thereby hasten recovery and reduce hospital stay. Lately, there has been increased focus on adverse effects caused by drugs and drug combinations used in postoperative pain treatment.10 Sedation, dizziness and visual disturbances are all associated with pregabalin,11 and recent studies have reported respiratory depressive effects.12,13 Thus, to prove their usefulness in a multimodal pain protocol, the analgesic advantages of pregabalin must outweigh potential adverse effects. Acute postoperative pain is most often regarded as inflammatory and nociceptive pain. Neurogenic mechanisms also contribute to the acute phase and reversible neuropathic pain may dominate from the late acute phase.14 Acute pain models have demonstrated analgesic effect of pregabalin.12 Consequently, there are reasons to believe that pregabalin is useful in early postoperative pain management. An analgesic effect of pregabalin will substantiate as reduced opioid consumption, reduced pain intensity or both. We hypothesized that pregabalin will reduce early opioid consumption.
There is evidence that the presence of postoperative sensory disturbances, especially hyperphenomena like hyperesthesia and hyperalgesia, is associated with chronic postoperative pain.15 Pregabalin may have anti-hyperalgesic properties5,16 and is by these mechanisms a candidate for prevention of persistent post-surgical pain. Hence, our primary aim was to investigate whether pregabalin 150 mg twice daily on the day of surgery and the consecutive day reduces opioid consumption. Secondly, we wanted to explore the effect of pregabalin on postoperative pain, incisional hyperalgesia and adverse effects. Materials and methods The clinical trial was conducted at Oslo University Hospital, Rikshospitalet, from January 2010 until October 2012 after approval was received by the Regional Committee for Medical Research Ethics for Eastern Norway and the Norwegian Medicines Agency. The study was registered at EudraCT (2009-015316-17) and www.clinicaltrials.gov (NCT01059331, 28 January 2010), and the results are reported in accordance with the CONSORT statement for randomized trials17 and the latest Declaration of Helsinki. Population Patients undergoing elective hand-assisted laparoscopic living donor nephrectomy with ASA classification I – II, aged 18–75 years, were eligible. At admission, the patients received oral and written information, and were enrolled in the study if a written consent was given. Exclusion criteria were known allergy to any of the test drugs, daily use of analgesics or sedative medications, or unfamiliarity with oral or written Norwegian. Randomization and blinding This was a randomized, placebo-controlled and parallel group study. A person not involved in the treatment or follow-up randomized the patients in sex-stratified blocks of 4–6 to one of two groups (1 : 1 ratio), using a computerized randomization program (DatInf RandList Acta Anaesthesiologica Scandinavica (2017)
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version 1.2, DatInf GmbH, T€ ubingen, Germany). Block size and randomization code were unknown to all investigators (LR, AS, MM), and the treatment allocation was concealed in opaque, sealed and sequentially numbered envelopes for use in potential emergencies only (no envelopes opened). The participants were assigned to the next consecutive participant number and given study medication marked with the corresponding number. The study drug consisting of pregabalin 75 mg capsules and placebo capsules of identical appearance were produced by Oslo University Hospital Pharmacy, and pre-packed in sequentially numbered and identical containers according to the randomization list and labeled with identical study information. Patients and healthcare providers involved in the treatment of the patients were all blinded to the test drug, and the randomization code was not revealed to the investigators before all measurements were registered and entered into a database. Anesthesia and surgery All patients were premedicated with diazepam 10 mg orally in the morning before surgery. A three-lead electrocardiography, noninvasive blood pressure and peripheral pulse oximetry were applied for monitoring, and two intravenous cannulas were inserted for infusion of crystalloids. General anesthesia was induced and maintained by the use of infusion pumps (IVAC Syringe Pump, Model P7000, Alaris, Cardinal Health, Rolle, Switzerland) delivering propofol (mg/kg/h) and remifentanil (lg/kg/ min) as total intravenous anesthesia (TIVA). One hour after induction of anesthesia, postoperative nausea and vomiting prophylaxis was administered intravenously consisting of ondansetron 4 mg IV and droperidol 0.625 mg IV in addition to the previously mentioned dexamethasone 8 mg. The surgical procedure was a hand-assisted laparoscopic right- or left-sided nephrectomy.18 A 10-cm incision was made directly proximal to the pubic symphysis in addition to three incisions on the right or left side of abdomen for handling instruments. The kidney was dissected free from the retroperitoneal tissue, and removed through the incision near the
symphysis. Thirty minutes before the anticipated end of surgery, an intravenous bolus of fentanyl 50 lg (patients ≤ 60 kg) or 100 lg (patients ≥ 61 kg) was administered intravenously in addition to paracetamol 1 g. After closure of the surgical incision bupivacaine 5 mg/ml + epinephrine 5 lg/ml, 20 ml was infiltrated in the wound area. Perioperative pain management The participants were randomly assigned to receive either pregabalin or placebo in addition to a standard multimodal postoperative analgesic regimen comprising local anesthetic wound infiltration, dexamethasone 8 mg IV, paracetamol 1 g every 6th h and opioids as required. The study medication, consisting of two capsules a 75 mg (totally 150 mg) of either pregabalin or placebo, was administered 1 h before induction of anesthesia on the day of surgery, in the evening on the day of surgery, as well as in the morning and in the evening on the first postoperative day. Immediately after surgery, a patient-controlled analgesia (PCA) device (CADD-Legacy 6300 PCA Pump, Smiths Medical, Kent, UK) was connected delivering boluses of 1 mg ketobemidone19 intravenously on request, with a lock out time for 8 min between each bolus, and a maximum dose of 7 mg ketobemidone per hour. The total opioid consumption was retrieved from the PCA device and recorded daily by a trained nurse. The PCA device was stopped 48 h after surgery if the total opioid consumption was ≤ 20 mg for the last 24 h. If the patients required ≥ 21 mg ketobemidone, the PCA device was continued for another 24 h. After discontinuing the PCA device, oral oxycodone 5 mg or 10 mg was administered regularly twice daily and on request, to achieve adequate pain control. For statistical analyses, the opioids were converted to intravenous morphine equivalents.20 Opioid consumption The primary outcome was the opioid consumption in the early postoperative period predefined as 0–48 h after surgery. In this time period, all patients were using the PCA device.
Acta Anaesthesiologica Scandinavica (2017) ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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Pain assessment
Long-term follow-up
Postoperative pain was assessed using an 11point, 0–10 Numeric Rating Scale (NRS) where 0 = no pain and 10 = worst pain imaginable. Pain intensity was measured every hour at rest and with standardized movement (coughing) during the first 6 h postoperatively and in the evening on the day of surgery, followed by four times during the first postoperative day (09.00, 13.00, 17.00 and 21.00). The data collection was performed by a trained nurse in the postoperative unit and on the ward.
Finally, a long-term follow-up was carried out using questionnaires registering persistent postsurgical pain at rest and during activity in the last 24 h and during the last 7 days. The postal questionnaires were answered by the patients at 6 weeks, 6 and 12 months after surgery, and the number of patients reporting pain was used for further analysis.
Incisional hyperalgesia The area of incisional hyperalgesia was mapped21 by pin-prick stimuli to the skin with a handheld von Frey glass-fiber monofilament (Optihair 256 mN, Marstocknervtest, Marburg, Germany) twice. The first test was performed 24 h after surgery (around noon the day after surgery), and the second test was performed on the day of hospital discharge 4–6 days after the last drug administration. The tactile stimulation with the von Frey monofilament started above the pubic symphysis outside the hyperalgesic area and continued in steps of 5 mm along five trajectories toward the incision until a distinct change in sensation (painful, sore or sharper feeling) was registered. If no change in sensation appeared, the stimulus stopped 5 mm before the incision. The sum of the five distances around the wound was summarized and used as a surrogate for the hyperalgesic area. The hyperalgesia tests were performed by one of the investigators (MM). Adverse effects Sedation, dizziness, nausea, headache and painrelated sleep interference were registered by a trained ward nurse in the evening on the day of surgery, and four times (09.00, 13.00, 17.00 and 21.00) 24–48 h post-surgery and scored on a 0–10 NRS scale. In addition, vomiting, recovery of bowel function and mobilization (graded in coughing, upright in bed, standing/sitting in chair, walking) were recorded. Furthermore, the patients were asked to report any symptoms or discomfort during the hospital stay.
Statistical methods Sample size was calculated based on results from a similar study on pain and postoperative opioid usage after similar surgery in the same institution.22 We considered 20% difference between the groups in opioid usage, the primary efficacy variable, as clinically meaningful. With a mean opioid usage of 50 mg (SD 15) in the control group, a two sided a = 0.05 and 80% statistical power, 36 patients would be required in each group. To compensate for dropouts, we included 80 patients. Data were assessed for normality of distribution by Shapiro–Wilk test and visual inspection of the residuals using QQ-plots and histograms. Data are reported as median (25th to 75th percentile) unless otherwise is stated. Differences between groups for normally distributed continuous data (demographics, intraoperative data) were analyzed using the independent sample t-test. Non-normal distributed continuous data (opioid consumption, pain intensity, hyperalgesia, pain-related sleep interference and persistent post-surgical pain) were analyzed using the Mann–Whitney U-test. To compare repeated pain intensity measurements between the groups over time, we calculated the area under the curve (AUC). Categorical data (adverse effects, persistent post-surgical pain and demographic variables) were tested using the chi-square for independence test (with continuity correction) and confirmed with Fisher’s exact test when necessary. For multiple comparisons between groups, level of significance was corrected with Bonferroni adjustments with a factor of n comparisons. Data analyses were performed with IBM SPSS Statistics 24 (SPSS Inc., Chicago, IL, USA). Acta Anaesthesiologica Scandinavica (2017)
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Results In the study period 1 February 2010 to 30 October 2011, 108 patients were operated with laparoscopic donor nephrectomy. Sixteen patients were not assessed due to lack of dedicated study personnel. Ninety-two patients were assessed for eligibility, and twelve patients were excluded (Fig. 1). Eighty patients were randomized to one of the treatments (40 patients in each group).Seventy-nine patients completed the in-hospital part of the study with only a few protocol violations. In the pregabalin group, one patient received diclofenac 50 mg 9 2 on the second postoperative day, while one patient received inhalation anesthesia with sevoflurane 90 min before changing to TIVA. One patient received erroneously higher boluses of opioids from the patient-controlled analgesia (PCA) device and was treated with naloxone. This patient was excluded from the efficacy analyses but maintained in the analyses of adverse events. In the follow-up at 6 weeks, 6 and 12 months after surgery, 76 (95%), 72 (90%) and 70 (87.5%) patients answered the questionnaires, respectively. Demographic variables are shown in Table 1. Pregabalin reduced the opioid consumption 0–48 h after surgery compared with placebo; 29.0 mg (22.0–45.5) mg vs. 41.8 mg (25.8–63.6) (P = 0.04) (Fig. 2). The difference was most evident 0–24 h after surgery; 16.3 mg (12.0–28.0) vs. 26.8 mg (15. 3–37.5) (P = 0.04), followed by 13.0 mg (8.0–22.5) vs. 17.5 mg (10.0–26.1) (P = 0.06) in the time period 24–48 after surgery. The PCA device was used in all patients during the first 0–48 h after surgery, and only a few patients received additionally oxycodone OR (0–24 h; N = 2, 24–48 h; N = 9). On the second postoperative day, 48–72 h after surgery, a large proportion of the patients (N = 35) stopped using the PCA device and started treatment with oral oxycodone. Opioid consumption after 48 h did not differ between groups (data not shown). Pain intensity are presented as NRS scores (median, 25th, 75th percentile) (Fig. 3). Area under the pain (NRS) vs. time curve (AUC) 0– 48 h after surgery were numerically but not significantly lower in the pregabalin group compared with the placebo group in rest; 46 (25–90)
vs. 64 (49–95) (P = 0.12) and with movement; 177 (130–208) vs. 185 (140–224) (P = 0.21). In the time period 0–24 h and 24–48 h, there were also no significant differences between the pregabalin group and the placebo group in rest or with movement; (P = 0.52, P = 0.89) and (P = 0.06, P = 0.18), respectively. Incisional hyperalgesia was tested 24 h after surgery and by hospital discharge. Thirty five patients in the pregabalin group and 27 in the placebo group (Fig. 4) were tested on each day. Nausea and pain were main reasons for refusing testing. The hyperalgesic area was significantly smaller in the pregabalin group compared with the placebo group 24 h after surgery 1; 8.5 cm (1.0–18.5) vs. 15.5 cm (9.5–24.0) (P = 0.02) but not at 5–7 days after surgery; 7.5 cm (0–20.0) vs. 15.5 cm (4.0–23.0) (P = 0.10). Adverse effects are presented in Table 2. Nausea was reduced in the pregabalin group compared with placebo group 24–48 h (P ≤ 0.01), and the number of patients receiving antiemetics was lower in the pregabalin group (N); 8 vs. 21 (P ≤ 0.01). Sedation and dizziness were insignificant between groups 0–24 h and 24–48 h after surgery. Pain-related sleep interference was significantly reduced in the pregabalin group 0–24 h (median NRS (25th, 75th percentile); 2.5 (0.0–4.0) vs. 4.0 (1.5–5.0) (P = 0.02) and 24–48 h after surgery; 1.0 (0.0– 3.0) vs. 2.0 (1.0–4.5) (P = 0.02). No significant differences were observed in time to mobilization. Four patients reported diplopia: three in the pregabalin group and one in the placebo group. Persistent post-surgical pain was assessed at rest and during activity at 6 weeks, 6 and 12 months after surgery (Table 3). There were no significant differences between groups after Bonferroni correction (P = 0.017). Discussion In this placebo-controlled study, pregabalin reduced opioid consumption during the first 48 h after surgery, while no difference in reported pain intensity score was found between the groups. Our findings are in accordance with a recent meta-analysis showing opioid-sparing effects in patients treated with 150– 300 mg pregabalin perioperatively.11 In this
Acta Anaesthesiologica Scandinavica (2017) ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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Fig. 1. CONSORT flow diagram of enrollment, treatment allocation and analysis. Acta Anaesthesiologica Scandinavica (2017)
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Table 1 Demographics and intraoperative data.
Variables
Pregabalin (n = 40)
Placebo (n = 40)
Age (years) Gender (M/F) Body mass index (BMI) Propofol (mg) Remifentanil (mg) Duration of anesthesia (min) Duration of surgery (min)
47.4 10.5 12/28 25.5 3.4 1514 (504) 3.9 (1.3) 207 27 140 23
47.3 13.6 13/27 24.5 3.3 1679 (629) 4.2 (1.6) 209 30 143 29
Data are expressed as means (SD) and numbers. No significant differences were found between the treatment groups. Level of significance: P < 0.05.
meta-analysis, mean reduction in the pregabalin group was 16%, while the results in our study showed a 39% and 26% lower median opioid consumption in the pregabalin group at 0–24 h and 24–48 h, respectively. The effect of pregabalin on pain intensity has differed between studies. In one meta-analysis,23 pregabalin 150–300 mg reduced pain at rest and with movement 2 and 24 h postoperatively, while another meta-analysis could only confirm pain reduction in certain types of surgery, and specifically not in abdominal surgery.11 In the current study, all patients were treated with a robust multimodal standardized analgesic regimen consisting of paracetamol, opioids, glucocorticoids and local infiltration anesthesia possibly obscuring the analgesic
Fig. 2. Opioid consumption. Data are presented as median opioid consumption (25th, 75th percentile). Pregabalin significantly reduced opioid consumption 0–24 h after surgery (*P = 0.04), but not 24–48 h after surgery (P = 0.06). Level of significance: ≤ 0.05.
effect of the test medication. The opioids administered intravenously with a patient-controlled analgesia (PCA) device resulted in relatively low pain scores in both groups, indicating that the PCA-device algorithm, and instructions for use, worked well. Our results show numerically lower pain scores with pregabalin 0–48 h after surgery, but the difference was clinically and statistically insignificant. Nevertheless, the overall significantly reduced opioid consumption during the period when the test drug was administered, and the numerically lower pain scores, must be interpreted as an analgesic effect of pregabalin. Pain-related sleep interference was significantly lower in patients receiving pregabalin, further supporting the above interpretation.
Fig. 3. (A and B) Pain intensity at rest and with movement. Data are presented as median NRS scores (25th,75th percentile). Pain intensity 0–48 h after surgery calculated as area under the pain (NRS) vs. time curve were not statistically different between the treatment groups in rest (P = 0.12) or with movement (P = 0.21). Level of significance: ≤ 0.05. Acta Anaesthesiologica Scandinavica (2017) ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
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Table 2 Incidence of main adverse effects.
Fig. 4. Incisional hyperalgesia. Data are presented as sum of the five distances around the wound. Horizontal line represents the median. The boxes represents 25th and 75th percentile, and the whiskers represents the range. Pregabalin reduced incisional hyperalgesia significantly 24 h after surgery (*P = 0.02), but not at hospital discharge 5–7 days after surgery (P = 0.10). Bonferroni-corrected level of significance: ≤ 0.025.
An anti-hyperalgesic effect of pregabalin has been demonstrated in animal24 and human pain models25 but is not well documented in clinical studies.26 In a small comparable study (N = 13 per group) in patients undergoing transperitoneal nephrectomy, a single preoperative dose of 300 mg pregabalin decreased the hyperalgesic area 48 h after surgery.27 In the present study, the incisional hyperalgesic area was significantly reduced in patients receiving pregabalin on the first postoperative day but not at hospital discharge 5–7 days after surgery. However, some patients, mostly in the placebo group, refused testing because of pain and nausea, resulting in several missing values. These incomplete data collections weaken the reported findings and underscore the need of further studies. The aim of multimodal pain management is to ensure optimal analgesia and reduce the need for opioids and thus opioid-related adverse effects. Nevertheless, pregabalin per se has been associated with unpleasant adverse effects like sedation, dizziness and visual disturbances.11 In this study, we found no significant difference between the groups in sedation or dizziness
0–24 h after surgery Sedation (n, %) Dizziness (n, %) Nausea (n, %) Antiemetics (n, %) Headache (n, %) Vomiting (n, %) Recovery of bowel function (n, %) Pain-related sleep interference (median [25th to 75th percentile]) 24–48 h after surgery Sedation (n, %) Dizziness (n, %) Nausea (n, %) Antiemetics (n, %) Headache (n, %) Vomiting (n, %) Recovery of bowel function (n, %) Pain-related sleep interference (median [25th to 75th percentile])
Pregabalin
Placebo
39 16 7 11 8 1 0
36 12 11 15 4 4 1
(97.5) (41.0) (17.5) (28.9) (20.0) (2.5) (0)
P-value
(94.7) (30.8) (27.5) (38.5) (10.3) (10.0) (2.5)
0.96 0.48 0.42 0.52 0.37 0.36 1.000
2.5 (0.0–4.0)
4.0 (1.5–5.0)
0.02*
36 29 9 8 6 6 1
39 29 23 21 16 11 2
(94.7) (74.4) (23.1) (20.0) (15.4) (15.0) (2.6)
1.0 (0.0–3.0)
(97.5) (74.4) (57.5) (52.5) (40.0) (27.5) (5.1)
2.0 (1.0–4.5)
0.96 1.000 < 0.01* < 0.01* 0.03 0.27 1.000 0.02*
Data are presented as number of patients (n, %) experiencing the adverse effect at least once or median NRS score (25th, 75th percentile). Bonferroni-corrected level of significance: ≤ 0.025. *P ≤ 0.025.
scores while the patients received pregabalin. Our findings are somewhat surprising as sedation induced by pregabalin has been reported in other studies28 but low adverse effect scores could be due both to reduced opioid consumption and to the combination with steroids. In a recent study in patients scheduled for hip arthroplasty,29 the sedative side effect of 300 mg pregabalin was diminished when adding 8 mg dexamethasone, suggesting that glucocorticoids might counteract this common side effect of pregabalin. In concert with previous studies,30 our results show reduced nausea and use of antiemetics in the pregabalin group. This may be the result of an opioid-sparing and subsequently antiemetic effect of pregabalin. Furthermore, it should be noted that the beneficial side effect profile seen in this study could be explained by the fact that the study population Acta Anaesthesiologica Scandinavica (2017)
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ª 2017 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd
PREGABALIN AND POSTOPERATIVE ANALGESIA
Table 3 Persistent post-surgical pain.
Rest 6 weeks last 24 h last 7 days 6 months last 24 h last 7 days 12 months last 24 h last 7 days Movement 6 weeks last 24 h last 7 days 6 months last 24 h last 7 days 12 months last 24 h last 7 days
Pregabalin (n, %)
Placebo (n, %)
P-value
10 (26.3) 12 (30.8)
11 (29.7) 13 (35.1)
0.943 0.872
6 (16.7) 5 (55.6)
4 (11.1) 4 (11.1)
0.733 1.000
3 (8.3) 2 (5.6)
4 (11.8) 4 (11.8)
0.706 0.422
16 (42.1) 19 (48.7)
16 (43.2) 19 (51.4)
1.00 1.00
10 (27.8) 10 (27.8)
7 (19.4) 8 (22.2)
0.58 0.79
1 (2.8) 2 (5.6)
7 (20.6) 7 (20.6)
0.03 0.08
Data are presented as number of patients (n, %) experiencing wound-related pain in rest and with movement at 6 weeks, 6 and 12 months after surgery. Bonferroni-corrected level of significance: ≤ 0.017.
was relatively young and healthy and had received dexamethasone. Some studies have investigated the effect of perioperatively administered pregabalin on the incidence and intensity of chronic post-surgical pain.31 The area of incisional hyperalgesia has been found to predict persistent pain,32 and reduction of this area has been associated with reduced prevalence of persistent pain after surgery.33 In this study, the patients were followed up until 1 year after surgery. There were no differences in pain scores between the groups at 6 weeks or 6 months after surgery, while more patients in the placebo group reported activityrelated pain 1 year after surgery. Even if our study was not sized to find differences in persistent post-surgical pain, the results may add power to later systematic reviews on this issue. The strength of this study is very standardized surgery and perioperative care in healthy subjects without comorbidities. The study has
several limitations. First, only one-dose regimen was tested. Thus, the present study cannot answer what is the optimal dose and treatment length. Second, a few subjects (N = 9) received oral oxycodone as a supplement to PCA-ketobemidone, especially from 24 to 48 h post-surgery, and this had to be converted to i.v. opioid equivalents. Further, the number of patients tested for incisional hyperalgesia at 24 h postsurgery was lower in the placebo-group because of pain and nausea. The reduced and unequal sample size may have biased the test results on this outcome. Finally, it has to be emphasized that the number of patients in this study is too small to allow conclusions concerning the effect of pregabalin on persistent post-surgical pain after laparoscopic nephrectomy. In summary, this study shows that perioperatively administered pregabalin added to a robust multimodal analgesic regimen has an opioid-sparing effect, while pain intensity score is not reduced. Pregabalin may have anti-hyperalgesic effect the first day after surgery. Together with improved sleep and less nausea, these results support the use of perioperative pregabalin in patients undergoing laparoscopic donor nephrectomy. Acknowledgements The authors thank the many patients involved in this study, Leiv Arne Rosseland, M.D., Ph.D., Prof., Department of Anaesthesia, Division of Emergencies and Critical Care, Oslo University Hospital, Rikshospitalet, Oslo, Norway, for kind assistance with randomization, and the surgical team and nurses all affiliated at the Department of Transplantation Medicine, Oslo University Hospital, Rikshospitalet, Oslo, Norway, for the excellent support and collaboration. Lien My Diep, M.Sc., Oslo center for Biostatistics and Epidemiology, Research Support Services, Oslo University Hospital, Oslo, Norway, provided valuable advice and help on statistical issues. References 1. Dols LF, Kok NF, Ijzermans JN. Live donor nephrectomy: a review of evidence for surgical techniques. Transpl Int 2010; 23: 121–30.
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