Gen Thorac Cardiovasc Surg (2015) 63:99–104 DOI 10.1007/s11748-014-0466-y
ORIGINAL ARTICLE
Evaluation of postoperative pregabalin for attenuation of postoperative shoulder pain after thoracotomy in patients with lung cancer, a preliminary result Yukako Imai • Kazuhiro Imai • Tetsu Kimura • Takashi Horiguchi Toru Goyagi • Hajime Saito • Yusuke Sato • Satoru Motoyama • Toshiaki Nishikawa • Yoshihiro Minamiya
•
Received: 8 July 2014 / Accepted: 22 August 2014 / Published online: 29 August 2014 Ó The Japanese Association for Thoracic Surgery 2014
Abstract Objective Thirty-one to 97 % of patients who undergo thoracotomy for lung cancer experience ipsilateral shoulder pain, marring the otherwise excellent relief provided by thoracic epidural analgesia. The aim of this study was to test whether the addition of pregabalin to the treatment for shoulder pain would provide a significant benefit. Methods Twenty patients undergoing thoracic surgery for lung cancer were enrolled in the control group between May 2012 and December 2012, and 20 patients were enrolled in the pregabalin group between January 2013 and July 2013, consecutively. All patients had standard preand intraoperative care. Patients received pregabalin 150 mg po POD 1 and then non-steroidal anti-inflammatory drugs (NSAIDs) po 2 h later (pregabalin group), or they received only NSAIDs po at exactly the same times (control group). Pain severity was then measured using a 100-mm visual analog scale (VAS) scoring system. Results The VAS scores indicated that patients in the pregabalin group had significantly less shoulder pain on postoperative day (POD) 2 than those in the control group (control: 27.9 ± 28.1 vs. pregabalin: 11.8 ± 14.4; p = 0.030). No differences in pain were observed between Y. Imai Department of Anaesthesia, Nakadori General Hospital, Akita, Japan K. Imai (&) H. Saito Y. Sato S. Motoyama Y. Minamiya Department of General Thoracic Surgery (and Breast and Endocrine Surgery), Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan e-mail: [email protected] T. Kimura T. Horiguchi T. Goyagi T. Nishikawa Department of Anaesthesia, Akita University Graduate School of Medicine, Akita, Japan
the two groups on other POD. There were significant differences on only POD 2 in the patients with shoulder pain immediately after surgery. Three of the pregabalin-treated patients showed mild somnolence. Conclusions Postoperative administration of pregabalin provided significant relief of postoperative shoulder pain during earlier POD after thoracic surgery for lung cancer when received multimodal analgesia in combination with NSAIDs. Keywords Pregabalin Shoulder pain Thoracotomy Lung cancer
Introduction Thoracic surgery is a painful procedure. Thirty-one percent to 97 % of patients who undergo a thoracotomy during lung cancer surgery experience ipsilateral shoulder pain, marring the otherwise excellent relief provided by thoracic epidural analgesia [1]. Patients complain of a constant, moderate to severe, aching pain in the posterior deltoid and in the suprascapular region, ipsilateral to the surgery in spite of natural intraoperative shoulder position [1–6]. Although thoracic epidural analgesia has become a standard of care for postoperative pain management after a thoracotomy, shoulder pain is often difficult to manage, as it is relatively resistant to epidural infusion of local anesthetic and to intravenous opioids [5]. The most plausible mechanism, among several proposed to explain the occurrence of post-thoracotomy shoulder pain, appears to be pain referred from an irritation of the pericardium or pleural surfaces. In Mackenzie’s ‘‘convergence-facilitation’’ theory [7], a small stimulus passing down the somatic afferent suprascapular nerve becomes
123
100
amplified and distorted by incoming visceral pain from the diaphragm via the phrenic nerve. Ruch [8] had a similar ‘‘convergence-projection’’ theory in which somatic afferent signals and visceral pain converge on the same spinal neuron. The phrenic nerve arises mainly from the fourth cervical nerve and provides the sensory innervation for the mediastinal, diaphragmatic pleura, and the pericardium. The fourth cervical nerve also provides the cutaneous innervation for the skin over the shoulder. Disruption of the pericardial or diaphragmatic pleural surface during lung resection with lymph node dissection, or irritation such as inflammation of the pleural surface may provoke the shoulder pain [5, 7, 8]. The brain then misconstrues this as pain from the somatic shoulder area. That effective relief of shoulder pain after thoracotomy could be achieved by infiltrating local anesthetics around the phrenic nerve [5] confirms the role of referred pain via the phrenic nerve. Interscalene brachial plexus block has also been used to abolish ipsilateral shoulder pain after thoracotomy [9, 10], possibly as a result of concurrent phrenic nerve blockade. However, a potential problem with interscalene brachial plexus and phrenic nerve blocks is diaphragmatic dysfunction, and the associated risk of respiratory depression [5, 11]. In addition, complications such as pneumothorax, Horner’s syndrome and the systemic toxicity of local anesthetics must be kept in mind. Pregabalin, a derivative of c-aminobutyric acid (GABA), is a drug that exerts an analgesic effect by binding to Ca2? channels in nerve presynapses and suppressing release of neural transmitters [12]. Pregabalin has anticonvulsant, anti-hyperalgesic and anxiolytic properties similar to gabapentin, but it has a more favorable pharmacokinetic profile, including dose-independent absorption [13, 14]. There have been several reports describing the efficacy of pregabalin for treating neuropathic pain [15– 17]. In addition, in a recent meta-analysis that considered the amount of analgesic drug administered during the postoperative period and the postoperative pain at rest and during movement, perioperative pregabalin reduced opioid consumption and opioid-related adverse effects [18]. Multimodal analgesia [19], achieved through use of a combination of drugs that differ in their mechanism of action, is the standard practice for postoperative pain, and has shown significant benefits over opioids alone. These include better pain control, reduced opioid consumption, fewer opioid-related side effects and an earlier return to the activities of daily living [20, 21]. We therefore, investigated the analgesic effect of pregabalin in combination with non-steroidal anti-inflammatory drugs (NSAIDs) in comparison with NSAIDs alone for shoulder pain after thoracotomy. The aim of this comparative trail was to test whether the addition of pregabalin to the treatment of shoulder pain in
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patients who had undergone thoracic surgery for lung cancer would have a significant impact on the visual analog scale (VAS) scores.
Methods Patients This study was approved by the Institutional Review Boards at Akita University School of Medicine and Akita University Hospital. The study was a non-randomized, single-center prospective study. After obtaining written informed consent, 20 patients diagnosed with lung cancer were enrolled in the control group between May 2012 and December 2012, and 20 patients were enrolled in the pregabalin group between January 2013 and July 2013 consecutively. None of the patients received preoperative chemotherapy or radiotherapy. The patient’s characteristics are summarized in Table 1. Patients were excluded if they had preexisting shoulder pain, or had an ASA physical status of more than III. Methods All patients had standard pre- and intraoperative care, including noninvasive monitoring of blood pressure, Table 1 Patients’ characteristics Control group (n = 20)
Pregabalin group (n = 20)
p value
0.343
Age (year)
71 ± 10
69 ± 8
Gender (M/F)
13/7
9/11
Type of surgery
0.204 0.507
Lobectomy
12
14
Segmentectomy
8
6
Rib fracture (%)
30
25
0.727
Node dissection 2a (%)
75
90
0.139
Total skin incision length (cm)
25.3 ± 7.7
22.3 ± 7.8
0.076
Surgery duration (min)
200 ± 46
188 ± 47
0.756
Postoperative epidural anesthesia duration (days)
5.0 ± 2.0
4.6 ± 0.9
0.555
Intra-operative fentanyl citrate
109.2 ± 85.1
101.9 ± 100.4
0.372
IA
13
12
IB
4
5
IIA-IV
3
3
Pathological Stage
0.480
Rib fracture was included accidently fracture because of rib spreader
Gen Thorac Cardiovasc Surg (2015) 63:99–104
electrocardiography and pulse oximetry, and establishment of intravenous access. A thoracic epidural catheter (T5–T8) was placed before the induction of general anesthesia. The paramedian approach was used in all patients, and the epidural space was identified using the loss-of-resistance technique, after which the epidural catheter was inserted. A test dose of 3 mL of 1.5 % lidocaine with epinephrine 1:2,00,000 was administered via the epidural catheter and was followed first by a bolus dose of 1.5 % lidocaine and then by a continuous infusion of 4 mL/h of 0.2 % levobupivacaine with fentanyl 0.002 mg/mL. In both groups, general anesthesia was induced using propofol 1.5–2 mg/ kg and remifentanil 0.2–0.4 lg/kg/min. Tracheal intubation was facilitated by administration of rocuronium bromide 1 mg/kg. A left-sided double-lumen endobronchial tube (Mallinckrodt’s Broncho-Cath 32–37 Fr, Mallinckrodt Medical Ltd, Athlone, Ireland) was then inserted, and a fiberoptic bronchoscope was used to confirm the proper position of the tube. Anesthesia was maintained with 1–2 % sevoflurane and oxygen in air. All patients were placed in the standard lateral decubitus position. Padded rolls were placed under the dependent axilla, and the arms were flexed and supported by a soft-surface pillow. Care was taken to avoid excessive strain on the shoulder joint by ensuring that there was \ 90° of flexion of the upper arm. These lung cancer patients were treated with segmentectomy or lobectomy plus systematic nodal dissection. A standard surgical technique with respect to rib retraction and chest tube placement was used. Patients in the pregabalin group received pregabalin 150 mg po (divided into 2 oral applications every day) POD 1 followed by NSAIDs (loxoprofen sodium 180 mg/ day) po 2 h later. Patients in the control group received only NSAIDs po at exactly the same times after surgery (control group). Shoulder pain was assessed 30 min after surgery, 4 h after surgery (before postoperative analgesia with pregabalin and/or NSAIDs), 12 h after surgery (POD 1, after pregabalin po and before NSAIDs in the pregabalin group), and on POD 2, POD 3 and POD 7. Pain severity was measured using a 100-mm VAS, where 0 represented no pain and 100 represented the worst pain imaginable. Postoperative patients unable to understand the VAS scoring system, despite preoperative coaching, were also excluded from the study. A patient-controlled epidural analgesia (PCEA) bolus, a diclofenac sodium suppository (25 mg/body) or intramuscular pentazocine hydrochloride (15 mg/body) was administered as rescue medication if patients complained of severe wound or shoulder pain despite the oral administration of pregabalin and/or NSAIDs. The patients in both groups were allowed to change to other NSAIDS, and to add analgesic adjuvant drugs (e.g., tramadol hydrochloride/
101
acetaminophen combination tablet) after POD 4. The time and dose of the rescue medication were recorded. Statistics Group data were expressed as mean ± standard deviation. Continuous data were compared using the Wilcoxon signed ranks test, and categorical data were compared using the Chi squared test with continuity correction or Fisher’s exact test when applicable. Differences between the measured VAS scores in the pregabalin and control groups were examined using Welch’s t test. All statistical analyses were performed using JMP IN 8.0.2 (SAS Institute, Cary, NC, USA). Values of p \ 0.05 were considered significant.
Results Following radical pulmonary resection for lung cancer, pregabalin was administered to 20 of the patients recruited for this study. 16 of 20 patients in the control group had shoulder pain immediately after surgery, and 11 patients had VAS score of shoulder pain [50 mm before treatment. In contrast, 14 of 20 patients in the pregabalin group had it, and 11 patients had VAS score [50 mm, similarly. Rescue medication (time) was not significantly different between groups (control: 11 ± 10 vs. pregabalin: 9 ± 9;
Fig. 1 Visual analog scale scores for postoperative shoulder pain experienced in the pregabalin and control groups. VAS shoulder pain scores indicated that the pregabalin group (NSAIDs and pregabalin po) experienced significantly less pain on postoperative day 2 than the control group (only NSAIDs po). Patients in the pregabalin group received only pregabalin po without NSAIDs po when measuring VAS score on POD 1, and those patients received multimodal analgesia in combination with NSAIDs for the first time before POD 2. *p \ 0.05. NSAIDs non-steroidal anti-inflammatory drugs, VAS visual analog scale
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Table 2 Frequency of adverse events Side effect
Control group
Pregabalin group
Dizziness
0
0
Somnolence
0
3
Ataxia
0
0
Headache
0
0
Peripheral edema
0
0
p = 0.524). In addition, PCEA bolus (control: 10.6 ± 9.6 vs. pregabalin: 6.6 ± 6.3; p = 0.148) and other rescue (control: 1.5 ± 1.7 vs. pregabalin: 3.4 ± 5.2; p = 0.396) were not significantly different between groups. This treatment relieved the patient’s shoulder pain on POD 2 after their surgery when they received pregabalin in combination with NSAIDs (Fig. 1). Moreover, their VAS scores indicated the pregabalin group experienced significantly less shoulder pain on POD 2 than the control group (pregabalin: 11.8 ± 14.4 vs. control: 27.9 ± 28.1; p = 0.030). No differences were observed between the two groups on POD 3 or on POD 7, when the patients left the hospital. There were significant differences on only POD 2 between 16 patients with shoulder pain immediately after surgery in the control group and 14 patients with it in the pregabalin group (pregabalin: 16.0 ± 15.2 vs. control: 34.1 ± 27.9; p = 0.035). Three of the pregabalin-treated patients showed mild somnolence, and their dose of pregabalin was reduced to 75 mg divided into an oral application at night (Table 2). These were the only adverse events in patients from either group, as evidenced by their physical examinations, laboratory data, arterial blood gasses and chest X-rays.
Discussion The results of this pilot study indicate that pregabalin effectively relieves the shoulder pain associated with thoracotomy for pulmonary resection in patients with lung cancer. A significant beneficial effect was seen for POD 2 after surgery, and there were no major adverse events associated with using pregabalin po. This is the first study evaluating the efficacy of postoperative pregabalin for the attenuation of postoperative shoulder pain following thoracotomy in patients with lung cancer. Burgess et al. [1] was the first group to describe and better characterize prospective ipsilateral shoulder pain following thoracic surgery. They recommended the postoperative use of ketorolac, and suggested that transection of a major bronchus was the mechanism involved in this type of pain. Barak et al. [2] showed that intrarectal indomethacin reduced the intensity of the shoulder pain,
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which implied that inflammation plays an active role in the process. However, the complications associated with NSAIDs, including platelet inhibition, gastrointestinal bleeding and potential renal toxicity, render these drugs questionable for routine use. It is also being debated whether NSAIDs should be used in dehydrated patients, which includes those undergoing thoracic surgery for lung cancer. Another option for the management of post-thoracotomy pain is the use of opioids and suprascapular nerve block [2, 6, 22]. However, opioids are respiratory depressants and should be given with caution to patients following lobectomy or segmentectomy, which diminish pulmonary reserve, especially in patients who suffer from chronic obstructive pulmonary disease. And although it is a safe and reliable technique, suprascapular nerve block using 0.5 % bupivacaine is not effective for ipsilateral shoulder pain occurring after thoracotomy [6]. Thus, a safe and effective solution for the management of post-thoracotomy shoulder pain is still lacking. We suggest that there is a need for pharmacological treatment options that could be administered as multimodal analgesia to relieve postoperative incisional pain and shoulder pain. The widespread interest in two anticonvulsants, gabapentin and pregabalin, stems from their clinical versatility and has stimulated over 1,500 related publications in just the 5 years up to 2012 [23]. Gabapentin, which is a synthetic GABA analog originally used for the adjunctive treatment of seizure disorders, has also been used to treat chronic neuropathic pain, mainly in patients with either diabetic neuropathy or postherpetic neuralgia. However, Huot et al. [24] reported that gabapentin at a dose of 1,200 mg was no better than placebo for reducing the incidence or severity of shoulder pain after thoracotomy in patients receiving thoracic epidural analgesia. On the other hand, pregabalin is considered to be more potent than gabapentin. Two reasons for the lower dosage of pregabalin are its much higher bioavailability (90 % of pregabalin vs. 33–66 % of gabapentin) and its rapid absorption (peak blood levels: 1 h). In addition, plasma concentrations of pregabalin increase linearly with increasing dose [25]. In the present non-randomized preliminary study, pregabalin provided significant relief of postoperative shoulder pain during earlier POD after thoracotomy. The frequency and severity of adverse events in pregabalin-treated patients were similar to those reported in neuropathic studies and in a meta-analysis and review of surgical pain [18, 26–28]. The most commonly reported adverse events are somnolence, dizziness, ataxia, headache and peripheral edema, all of which appear to be doserelated and are generally mild to moderate. In three of the pregabalin-treated patients in the present study, the dose of pregabalin was reduced to 75 mg due to mild somnolence,
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but there were no major complications. Thus, pregabalin appears to reduce the intensity of shoulder pain after thoracotomy without increasing the frequency of severe adverse events. The limitations of our study are the small number of patients in the two groups and the study’s non-randomized design. It would have been difficult, if not impossible, to perform a randomized study of the uncertain effects of pregabalin on shoulder pain after thoracotomy, as this is the first evaluation of the efficacy of postoperative pregabalin for the prevention and attenuation of shoulder pain after thoracotomy in patients with lung cancer. Further investigation will be needed to more precisely define the role of pregabalin as a component of multimodal analgesia or a preanesthetic medication. Secondary, the patients in the pregabalin group had significantly less shoulder pain on only POD 2 than those in the control group. When measuring VAS score on POD 1, patients in the pregabalin group received only pregabalin po without NSAIDs po. Another limitation of our study is that water intake started on POD 1 according to clinical pathway in our hospital. Moreover, the shoulder pain might be improved spontaneously in both groups after POD 3. We therefore recommend multimodal analgesia of pregabalin in combination with NSAIDs at the early postoperative period. And we suggest administration of pregabalin as pre-anesthetics is the best schedule for preventing the shoulder pain after thoracic surgery.
Conclusions In sum, post-thoracotomy ipsilateral shoulder pain remains a significant problem, despite effective epidural analgesia. Postoperative administration of pregabalin significantly reduces shoulder pain during earlier POD after thoracic surgery when received multimodal analgesia. The efficacy of postoperative pregabalin for use after painful procedures and for the prevention of the shoulder pain should be investigated in future studies. In addition, future doubleblind randomized studies should explore the effects of using combinations of various anti-hyperalgesic and analgesic drugs with a low potential of adverse effects as protective premedications against shoulder pain after thoracotomy. Acknowledgments The authors are grateful to Prof. Hiroshi Nanjo (Department of Pathology, Akita University Graduate School of Medicine) and Prof. Akiteru Goto (Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine) for suggesting pathological diagnoses. And we thank Prof. Katsuyuki Murata (Department of Environmental Health Sciences, Akita University Graduate School of Medicine) for suggesting statistics.
103 Conflict of interest flict of interest.
Yukako Imai and his co-authors have no con-
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ORIGINAL ARTICLE
Evaluation of postoperative pregabalin for attenuation of postoperative shoulder pain after thoracotomy in patients with lung cancer, a preliminary result Yukako Imai • Kazuhiro Imai • Tetsu Kimura • Takashi Horiguchi Toru Goyagi • Hajime Saito • Yusuke Sato • Satoru Motoyama • Toshiaki Nishikawa • Yoshihiro Minamiya
•
Received: 8 July 2014 / Accepted: 22 August 2014 / Published online: 29 August 2014 Ó The Japanese Association for Thoracic Surgery 2014
Abstract Objective Thirty-one to 97 % of patients who undergo thoracotomy for lung cancer experience ipsilateral shoulder pain, marring the otherwise excellent relief provided by thoracic epidural analgesia. The aim of this study was to test whether the addition of pregabalin to the treatment for shoulder pain would provide a significant benefit. Methods Twenty patients undergoing thoracic surgery for lung cancer were enrolled in the control group between May 2012 and December 2012, and 20 patients were enrolled in the pregabalin group between January 2013 and July 2013, consecutively. All patients had standard preand intraoperative care. Patients received pregabalin 150 mg po POD 1 and then non-steroidal anti-inflammatory drugs (NSAIDs) po 2 h later (pregabalin group), or they received only NSAIDs po at exactly the same times (control group). Pain severity was then measured using a 100-mm visual analog scale (VAS) scoring system. Results The VAS scores indicated that patients in the pregabalin group had significantly less shoulder pain on postoperative day (POD) 2 than those in the control group (control: 27.9 ± 28.1 vs. pregabalin: 11.8 ± 14.4; p = 0.030). No differences in pain were observed between Y. Imai Department of Anaesthesia, Nakadori General Hospital, Akita, Japan K. Imai (&) H. Saito Y. Sato S. Motoyama Y. Minamiya Department of General Thoracic Surgery (and Breast and Endocrine Surgery), Akita University Graduate School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan e-mail: [email protected] T. Kimura T. Horiguchi T. Goyagi T. Nishikawa Department of Anaesthesia, Akita University Graduate School of Medicine, Akita, Japan
the two groups on other POD. There were significant differences on only POD 2 in the patients with shoulder pain immediately after surgery. Three of the pregabalin-treated patients showed mild somnolence. Conclusions Postoperative administration of pregabalin provided significant relief of postoperative shoulder pain during earlier POD after thoracic surgery for lung cancer when received multimodal analgesia in combination with NSAIDs. Keywords Pregabalin Shoulder pain Thoracotomy Lung cancer
Introduction Thoracic surgery is a painful procedure. Thirty-one percent to 97 % of patients who undergo a thoracotomy during lung cancer surgery experience ipsilateral shoulder pain, marring the otherwise excellent relief provided by thoracic epidural analgesia [1]. Patients complain of a constant, moderate to severe, aching pain in the posterior deltoid and in the suprascapular region, ipsilateral to the surgery in spite of natural intraoperative shoulder position [1–6]. Although thoracic epidural analgesia has become a standard of care for postoperative pain management after a thoracotomy, shoulder pain is often difficult to manage, as it is relatively resistant to epidural infusion of local anesthetic and to intravenous opioids [5]. The most plausible mechanism, among several proposed to explain the occurrence of post-thoracotomy shoulder pain, appears to be pain referred from an irritation of the pericardium or pleural surfaces. In Mackenzie’s ‘‘convergence-facilitation’’ theory [7], a small stimulus passing down the somatic afferent suprascapular nerve becomes
123
100
amplified and distorted by incoming visceral pain from the diaphragm via the phrenic nerve. Ruch [8] had a similar ‘‘convergence-projection’’ theory in which somatic afferent signals and visceral pain converge on the same spinal neuron. The phrenic nerve arises mainly from the fourth cervical nerve and provides the sensory innervation for the mediastinal, diaphragmatic pleura, and the pericardium. The fourth cervical nerve also provides the cutaneous innervation for the skin over the shoulder. Disruption of the pericardial or diaphragmatic pleural surface during lung resection with lymph node dissection, or irritation such as inflammation of the pleural surface may provoke the shoulder pain [5, 7, 8]. The brain then misconstrues this as pain from the somatic shoulder area. That effective relief of shoulder pain after thoracotomy could be achieved by infiltrating local anesthetics around the phrenic nerve [5] confirms the role of referred pain via the phrenic nerve. Interscalene brachial plexus block has also been used to abolish ipsilateral shoulder pain after thoracotomy [9, 10], possibly as a result of concurrent phrenic nerve blockade. However, a potential problem with interscalene brachial plexus and phrenic nerve blocks is diaphragmatic dysfunction, and the associated risk of respiratory depression [5, 11]. In addition, complications such as pneumothorax, Horner’s syndrome and the systemic toxicity of local anesthetics must be kept in mind. Pregabalin, a derivative of c-aminobutyric acid (GABA), is a drug that exerts an analgesic effect by binding to Ca2? channels in nerve presynapses and suppressing release of neural transmitters [12]. Pregabalin has anticonvulsant, anti-hyperalgesic and anxiolytic properties similar to gabapentin, but it has a more favorable pharmacokinetic profile, including dose-independent absorption [13, 14]. There have been several reports describing the efficacy of pregabalin for treating neuropathic pain [15– 17]. In addition, in a recent meta-analysis that considered the amount of analgesic drug administered during the postoperative period and the postoperative pain at rest and during movement, perioperative pregabalin reduced opioid consumption and opioid-related adverse effects [18]. Multimodal analgesia [19], achieved through use of a combination of drugs that differ in their mechanism of action, is the standard practice for postoperative pain, and has shown significant benefits over opioids alone. These include better pain control, reduced opioid consumption, fewer opioid-related side effects and an earlier return to the activities of daily living [20, 21]. We therefore, investigated the analgesic effect of pregabalin in combination with non-steroidal anti-inflammatory drugs (NSAIDs) in comparison with NSAIDs alone for shoulder pain after thoracotomy. The aim of this comparative trail was to test whether the addition of pregabalin to the treatment of shoulder pain in
123
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patients who had undergone thoracic surgery for lung cancer would have a significant impact on the visual analog scale (VAS) scores.
Methods Patients This study was approved by the Institutional Review Boards at Akita University School of Medicine and Akita University Hospital. The study was a non-randomized, single-center prospective study. After obtaining written informed consent, 20 patients diagnosed with lung cancer were enrolled in the control group between May 2012 and December 2012, and 20 patients were enrolled in the pregabalin group between January 2013 and July 2013 consecutively. None of the patients received preoperative chemotherapy or radiotherapy. The patient’s characteristics are summarized in Table 1. Patients were excluded if they had preexisting shoulder pain, or had an ASA physical status of more than III. Methods All patients had standard pre- and intraoperative care, including noninvasive monitoring of blood pressure, Table 1 Patients’ characteristics Control group (n = 20)
Pregabalin group (n = 20)
p value
0.343
Age (year)
71 ± 10
69 ± 8
Gender (M/F)
13/7
9/11
Type of surgery
0.204 0.507
Lobectomy
12
14
Segmentectomy
8
6
Rib fracture (%)
30
25
0.727
Node dissection 2a (%)
75
90
0.139
Total skin incision length (cm)
25.3 ± 7.7
22.3 ± 7.8
0.076
Surgery duration (min)
200 ± 46
188 ± 47
0.756
Postoperative epidural anesthesia duration (days)
5.0 ± 2.0
4.6 ± 0.9
0.555
Intra-operative fentanyl citrate
109.2 ± 85.1
101.9 ± 100.4
0.372
IA
13
12
IB
4
5
IIA-IV
3
3
Pathological Stage
0.480
Rib fracture was included accidently fracture because of rib spreader
Gen Thorac Cardiovasc Surg (2015) 63:99–104
electrocardiography and pulse oximetry, and establishment of intravenous access. A thoracic epidural catheter (T5–T8) was placed before the induction of general anesthesia. The paramedian approach was used in all patients, and the epidural space was identified using the loss-of-resistance technique, after which the epidural catheter was inserted. A test dose of 3 mL of 1.5 % lidocaine with epinephrine 1:2,00,000 was administered via the epidural catheter and was followed first by a bolus dose of 1.5 % lidocaine and then by a continuous infusion of 4 mL/h of 0.2 % levobupivacaine with fentanyl 0.002 mg/mL. In both groups, general anesthesia was induced using propofol 1.5–2 mg/ kg and remifentanil 0.2–0.4 lg/kg/min. Tracheal intubation was facilitated by administration of rocuronium bromide 1 mg/kg. A left-sided double-lumen endobronchial tube (Mallinckrodt’s Broncho-Cath 32–37 Fr, Mallinckrodt Medical Ltd, Athlone, Ireland) was then inserted, and a fiberoptic bronchoscope was used to confirm the proper position of the tube. Anesthesia was maintained with 1–2 % sevoflurane and oxygen in air. All patients were placed in the standard lateral decubitus position. Padded rolls were placed under the dependent axilla, and the arms were flexed and supported by a soft-surface pillow. Care was taken to avoid excessive strain on the shoulder joint by ensuring that there was \ 90° of flexion of the upper arm. These lung cancer patients were treated with segmentectomy or lobectomy plus systematic nodal dissection. A standard surgical technique with respect to rib retraction and chest tube placement was used. Patients in the pregabalin group received pregabalin 150 mg po (divided into 2 oral applications every day) POD 1 followed by NSAIDs (loxoprofen sodium 180 mg/ day) po 2 h later. Patients in the control group received only NSAIDs po at exactly the same times after surgery (control group). Shoulder pain was assessed 30 min after surgery, 4 h after surgery (before postoperative analgesia with pregabalin and/or NSAIDs), 12 h after surgery (POD 1, after pregabalin po and before NSAIDs in the pregabalin group), and on POD 2, POD 3 and POD 7. Pain severity was measured using a 100-mm VAS, where 0 represented no pain and 100 represented the worst pain imaginable. Postoperative patients unable to understand the VAS scoring system, despite preoperative coaching, were also excluded from the study. A patient-controlled epidural analgesia (PCEA) bolus, a diclofenac sodium suppository (25 mg/body) or intramuscular pentazocine hydrochloride (15 mg/body) was administered as rescue medication if patients complained of severe wound or shoulder pain despite the oral administration of pregabalin and/or NSAIDs. The patients in both groups were allowed to change to other NSAIDS, and to add analgesic adjuvant drugs (e.g., tramadol hydrochloride/
101
acetaminophen combination tablet) after POD 4. The time and dose of the rescue medication were recorded. Statistics Group data were expressed as mean ± standard deviation. Continuous data were compared using the Wilcoxon signed ranks test, and categorical data were compared using the Chi squared test with continuity correction or Fisher’s exact test when applicable. Differences between the measured VAS scores in the pregabalin and control groups were examined using Welch’s t test. All statistical analyses were performed using JMP IN 8.0.2 (SAS Institute, Cary, NC, USA). Values of p \ 0.05 were considered significant.
Results Following radical pulmonary resection for lung cancer, pregabalin was administered to 20 of the patients recruited for this study. 16 of 20 patients in the control group had shoulder pain immediately after surgery, and 11 patients had VAS score of shoulder pain [50 mm before treatment. In contrast, 14 of 20 patients in the pregabalin group had it, and 11 patients had VAS score [50 mm, similarly. Rescue medication (time) was not significantly different between groups (control: 11 ± 10 vs. pregabalin: 9 ± 9;
Fig. 1 Visual analog scale scores for postoperative shoulder pain experienced in the pregabalin and control groups. VAS shoulder pain scores indicated that the pregabalin group (NSAIDs and pregabalin po) experienced significantly less pain on postoperative day 2 than the control group (only NSAIDs po). Patients in the pregabalin group received only pregabalin po without NSAIDs po when measuring VAS score on POD 1, and those patients received multimodal analgesia in combination with NSAIDs for the first time before POD 2. *p \ 0.05. NSAIDs non-steroidal anti-inflammatory drugs, VAS visual analog scale
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102
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Table 2 Frequency of adverse events Side effect
Control group
Pregabalin group
Dizziness
0
0
Somnolence
0
3
Ataxia
0
0
Headache
0
0
Peripheral edema
0
0
p = 0.524). In addition, PCEA bolus (control: 10.6 ± 9.6 vs. pregabalin: 6.6 ± 6.3; p = 0.148) and other rescue (control: 1.5 ± 1.7 vs. pregabalin: 3.4 ± 5.2; p = 0.396) were not significantly different between groups. This treatment relieved the patient’s shoulder pain on POD 2 after their surgery when they received pregabalin in combination with NSAIDs (Fig. 1). Moreover, their VAS scores indicated the pregabalin group experienced significantly less shoulder pain on POD 2 than the control group (pregabalin: 11.8 ± 14.4 vs. control: 27.9 ± 28.1; p = 0.030). No differences were observed between the two groups on POD 3 or on POD 7, when the patients left the hospital. There were significant differences on only POD 2 between 16 patients with shoulder pain immediately after surgery in the control group and 14 patients with it in the pregabalin group (pregabalin: 16.0 ± 15.2 vs. control: 34.1 ± 27.9; p = 0.035). Three of the pregabalin-treated patients showed mild somnolence, and their dose of pregabalin was reduced to 75 mg divided into an oral application at night (Table 2). These were the only adverse events in patients from either group, as evidenced by their physical examinations, laboratory data, arterial blood gasses and chest X-rays.
Discussion The results of this pilot study indicate that pregabalin effectively relieves the shoulder pain associated with thoracotomy for pulmonary resection in patients with lung cancer. A significant beneficial effect was seen for POD 2 after surgery, and there were no major adverse events associated with using pregabalin po. This is the first study evaluating the efficacy of postoperative pregabalin for the attenuation of postoperative shoulder pain following thoracotomy in patients with lung cancer. Burgess et al. [1] was the first group to describe and better characterize prospective ipsilateral shoulder pain following thoracic surgery. They recommended the postoperative use of ketorolac, and suggested that transection of a major bronchus was the mechanism involved in this type of pain. Barak et al. [2] showed that intrarectal indomethacin reduced the intensity of the shoulder pain,
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which implied that inflammation plays an active role in the process. However, the complications associated with NSAIDs, including platelet inhibition, gastrointestinal bleeding and potential renal toxicity, render these drugs questionable for routine use. It is also being debated whether NSAIDs should be used in dehydrated patients, which includes those undergoing thoracic surgery for lung cancer. Another option for the management of post-thoracotomy pain is the use of opioids and suprascapular nerve block [2, 6, 22]. However, opioids are respiratory depressants and should be given with caution to patients following lobectomy or segmentectomy, which diminish pulmonary reserve, especially in patients who suffer from chronic obstructive pulmonary disease. And although it is a safe and reliable technique, suprascapular nerve block using 0.5 % bupivacaine is not effective for ipsilateral shoulder pain occurring after thoracotomy [6]. Thus, a safe and effective solution for the management of post-thoracotomy shoulder pain is still lacking. We suggest that there is a need for pharmacological treatment options that could be administered as multimodal analgesia to relieve postoperative incisional pain and shoulder pain. The widespread interest in two anticonvulsants, gabapentin and pregabalin, stems from their clinical versatility and has stimulated over 1,500 related publications in just the 5 years up to 2012 [23]. Gabapentin, which is a synthetic GABA analog originally used for the adjunctive treatment of seizure disorders, has also been used to treat chronic neuropathic pain, mainly in patients with either diabetic neuropathy or postherpetic neuralgia. However, Huot et al. [24] reported that gabapentin at a dose of 1,200 mg was no better than placebo for reducing the incidence or severity of shoulder pain after thoracotomy in patients receiving thoracic epidural analgesia. On the other hand, pregabalin is considered to be more potent than gabapentin. Two reasons for the lower dosage of pregabalin are its much higher bioavailability (90 % of pregabalin vs. 33–66 % of gabapentin) and its rapid absorption (peak blood levels: 1 h). In addition, plasma concentrations of pregabalin increase linearly with increasing dose [25]. In the present non-randomized preliminary study, pregabalin provided significant relief of postoperative shoulder pain during earlier POD after thoracotomy. The frequency and severity of adverse events in pregabalin-treated patients were similar to those reported in neuropathic studies and in a meta-analysis and review of surgical pain [18, 26–28]. The most commonly reported adverse events are somnolence, dizziness, ataxia, headache and peripheral edema, all of which appear to be doserelated and are generally mild to moderate. In three of the pregabalin-treated patients in the present study, the dose of pregabalin was reduced to 75 mg due to mild somnolence,
Gen Thorac Cardiovasc Surg (2015) 63:99–104
but there were no major complications. Thus, pregabalin appears to reduce the intensity of shoulder pain after thoracotomy without increasing the frequency of severe adverse events. The limitations of our study are the small number of patients in the two groups and the study’s non-randomized design. It would have been difficult, if not impossible, to perform a randomized study of the uncertain effects of pregabalin on shoulder pain after thoracotomy, as this is the first evaluation of the efficacy of postoperative pregabalin for the prevention and attenuation of shoulder pain after thoracotomy in patients with lung cancer. Further investigation will be needed to more precisely define the role of pregabalin as a component of multimodal analgesia or a preanesthetic medication. Secondary, the patients in the pregabalin group had significantly less shoulder pain on only POD 2 than those in the control group. When measuring VAS score on POD 1, patients in the pregabalin group received only pregabalin po without NSAIDs po. Another limitation of our study is that water intake started on POD 1 according to clinical pathway in our hospital. Moreover, the shoulder pain might be improved spontaneously in both groups after POD 3. We therefore recommend multimodal analgesia of pregabalin in combination with NSAIDs at the early postoperative period. And we suggest administration of pregabalin as pre-anesthetics is the best schedule for preventing the shoulder pain after thoracic surgery.
Conclusions In sum, post-thoracotomy ipsilateral shoulder pain remains a significant problem, despite effective epidural analgesia. Postoperative administration of pregabalin significantly reduces shoulder pain during earlier POD after thoracic surgery when received multimodal analgesia. The efficacy of postoperative pregabalin for use after painful procedures and for the prevention of the shoulder pain should be investigated in future studies. In addition, future doubleblind randomized studies should explore the effects of using combinations of various anti-hyperalgesic and analgesic drugs with a low potential of adverse effects as protective premedications against shoulder pain after thoracotomy. Acknowledgments The authors are grateful to Prof. Hiroshi Nanjo (Department of Pathology, Akita University Graduate School of Medicine) and Prof. Akiteru Goto (Department of Cellular and Organ Pathology, Akita University Graduate School of Medicine) for suggesting pathological diagnoses. And we thank Prof. Katsuyuki Murata (Department of Environmental Health Sciences, Akita University Graduate School of Medicine) for suggesting statistics.
103 Conflict of interest flict of interest.
Yukako Imai and his co-authors have no con-
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