|Year : 2018 | Volume
| Issue : 3 | Page : 220-225
Potential analgesia of lumbar intrathecal fentanyl in breast cancer surgery
Alaa El-Din Mazy Abdou Mazy, Hossam I El-Said Saber
Department of Anesthesia and Surgical Intensive Care, Faculty of Medicine, Mansoura University, Mansoura, Egypt
|Date of Submission||11-Jul-2017|
|Date of Acceptance||22-Jan-2018|
|Date of Web Publication||31-Aug-2018|
Alaa El-Din Mazy Abdou Mazy
Associate Professor of Anesthesia and Surgical Intensive Care, Oncology Center, Mansoura University, Mansoura, postal code 35516
Source of Support: None, Conflict of Interest: None
Background Various regional anesthetic techniques are used during mastectomy for reduction of pain and side effects. The intrathecal (IT) route for drug administration is interesting despite the poorly understood and complex nature of cerebrospinal fluid kinetics and IT drug pharmacokinetics. Lumbar IT opioids are used for analgesia during thoracic and cardiac surgeries, but not for breast surgeries. IT fentanyl (F) is evaluated in this study for mastectomy analgesia.
Patients and methods Forty-four patients were divided into two equal groups: one group was given general anesthesia only and the other group given lumbar IT 20 mg bupivacaine plus F 25 microgram (mcg) in lateral position followed by general anesthesia.
Results In the IT group, analgesia manifested as delayed request for postoperative analgesia 5 h postinjection; 50% reduction in intraoperative and 24 h postoperative analgesic requirements; low visual analog pain scale, and high range of arm movement in the first 3 h postoperatively. But there was associated intraoperative hypotension and postoperative pruritus.
Conclusion Lumbar IT F potentiates analgesia in mastectomy surgery.
Keywords: analgesia, bupivacaine, fentanyl, intrathecal, kinetics, mastectomy, pain measurement
|How to cite this article:|
Abdou Mazy AE, El-Said Saber HI. Potential analgesia of lumbar intrathecal fentanyl in breast cancer surgery. Res Opin Anesth Intensive Care 2018;5:220-5
|How to cite this URL:|
Abdou Mazy AE, El-Said Saber HI. Potential analgesia of lumbar intrathecal fentanyl in breast cancer surgery. Res Opin Anesth Intensive Care [serial online] 2018 [cited 2019 Apr 24];5:220-5. Available from: http://www.roaic.eg.net/text.asp?2018/5/3/220/240273
| Introduction|| |
Regional analgesia is uniquely imperative in mastectomy surgery to reduce acute as well as chronic pain . Several techniques are used such as paravertebral blocks , thoracic epidural , intercostal nerve blocks , intrapleural , wound infiltration , pectoral nerve 1 and II blocks , and serratus plane block . However, there may be associated disadvantages such as the failure rate, complications such as pneumothorax and a total spinal block in addition to the required specific skills, instruments, and time . Really, spinal anesthesia is one of the most reliable regional techniques, it is relatively simple with low cost, and high success rate . Recently, drug administration through the intrathecal (IT) route is getting interest .
The aim of this study is to test the visibility of providing analgesia during mastectomy surgery using fentanyl (F) as an adjuvant to bupivacaine (B) through the lumbar IT route. This approach is already applied in thoracic  and cardiac surgeries , but not in breast surgery. The applied doses of B in cardiac surgery may range from 23 to 45 mg and morphine from 0.3 to 4 mg . Essentially, a modification using a lower dose of B and replacing morphine with F may be suitable for breast surgeries.
Morphine may be the best but not the ideal opioid for IT administration in all situations . Unfortunately, lumbar IT F has lower rostral spread than morphine . However Swenson et al. , have reported a remarkable rapid and distant spread of IT extremely lipophilic sufentanil in cerebrospinal fluid (CSF). Interestingly, there is a gross similarity between F and morphine in initial distribution in the first hour after lumbar IT injection. Remarkably, F concentrations remain constant in CSF from 30 to 120 min at the upper detection site . Nevertheless, F has a fast onset of analgesia , early not late respiratory depression, and enhanced sensory block .
In theory, lumbar IT opioids may reach cisternal CSF through, mixing with the CSF and rostral bulk movement of CSF, vascular uptake to the systemic circulation, epidural venous uptake by Batson’s plexus that is a valve less system communicating spinal and neck veins and sagittal sinus . Interestingly, IT drug distribution occurs in all directions along the CSF spaces as a result of complex CSF movement . IT drug transport occurs through a convective movement of small bulk flow superimposed on CSF pulsatile flow ; conversely, the CSF also described as a ‘poorly mixed compartment’ .
Lipid soluble opioids resemble local anesthetics in pKa and molecular weight. The pKa of F is (8.4). At physiological pH (7.4), the percent of unionized F is 9% , where the tertiary amine groups of opioids are ionized rendering them water soluble .
| Patients and methods|| |
This single, blinded, prospective randomized study was performed after approval from the Institutional Research Board. A preliminary study including 10 patients was done that provided a mean value of visual analog pain scale (VAS) at 3 h postoperatively at 3.7±0.8 for the control (C) group, while IT group value was 2.8±0.9 accordingly. The calculated sample size with G power program was 42 patients, with an α error of 0.05, and a power of 95%. For a possible loss of data, sample size included 44 patients.
This study included female patients aged between 18 and 65 years, American Society of Anesthesiologists physical status grade 1 or II, with breast cancer scheduled for elective unilateral modified radical mastectomy.
Patients were randomly allocated using the sealed envelopes method into two groups each of 22 patients:
- The control group: they received only general anesthesia. An adhesive tab was attached at the lumbar site for assessor blinding.
- The IT group: they received IT block followed by general anesthesia.
Exclusion criteria were: patient refusal, inability to comprehend pain scale, localized or systemic sepsis, low platelets count (<100 000 platelets/ml), coagulopathy, deformity, or surgery interfering with the spinal technique.
All patients were subjected to clinical examination, evaluation of laboratory investigations, and ECG. Preoperatively an informed consent was taken. Oral diazepam (0.1 mg/kg) was given the night before surgery. Volume loading was done using Ringer’s acetate 10 ml/kg before patient’s shift to the theater. Patients were trained for VAS.
In the operating theater, the standard monitoring was applied. Basal heart rate (HR), mean blood pressure (MAP), and oxygen saturation (SaO2) data were registered.
In the IT group, using a 25 G spinal needle, a dose of 20 mg of 0.5% hyperbaric bupivacaine (B) with 25 mg F were injected into the IT space at the L2–L3 or L3–L4 vertebral level, while the patient in the lateral position with the side to be operated downwards. The technique is canceled after three failed trails. Patients were kept in lateral position for 10 min after injection, with the Trendelenburg position of less than 5° as recommended for cardiac surgery , then turned supine with a bellow under the head for epsilateral (operative side) upper sensory block level assessment after 15 min by pinprick. Determination of dermatomal block level was according to Lee et al. .
Hemodynamic stabilization was achieved using 5 mg aliquots of intravenous ephedrine if the MAP was less than 60 mmHg or systolic BP was less than 90 mmHg. If atropine 0.5 mg if HR was lower than 60 beats/min, then general anesthesia was induced.
In both groups, general anesthesia was induced using sleeping dose of propofol, F at 1 mcg/kg, and atracurium 0.5 mg/kg. Anesthesia was maintained with isoflurane 1%. F 25 mcg boluses were added if HR or MAP increased above 20% of the basal values. The total required doses of analgesics were recorded. Intraoperative hemodynamics were recorded during the intubation stress response at 1, 2, and 5 min, then at 30, 60 min, and before extubation.
HR, MAP, VAS, and the range of ipsilateral arm movement (coronal abduction movement using arthrodial protractor) were recorded at 0.5, 1, 3, 6, 9, 12, and 24 h postoperatively. SaO2 was recorded at 0.5 and 1 h postoperatively. Rescue analgesia was administered using ketorolac tromethamine (Ketolac; Amriya Pharmaceutical Industries, Alexandria, Egypt), ampoules 30 mg diluted in 10 ml, intravenous, morphine 3 mg if VAS of at least 3. The time to first request for analgesia starting from IT injection time and total doses were recorded. Complications as hypotension, bradycardia, pruritus, nausea, and vomiting and postdural puncture headache were assessed.
Data were analyzed using statistical package for the social sciences (SPSS) version 16.0 (SPSS, Inc., Chicago, IL, USA). Data were tested for normality by the Kolmogorov–Smirnov test. Normally distributed data were presented as mean±SD using t-test. For nonparametric data, the Mann–Whitney U-test was used. Qualitative data were presented as number and percent. Comparison between groups was done by χ2-test. P value of less than 0.05 is considered statistically significant.
| Results|| |
This study included 52 patients. Eight patients were excluded: six of them refused spinal anesthesia preoperatively during the night visit and two patients were excluded in the theater due to difficult IT access after three trails ([Figure 1]). Both groups were comparable in demographic data ([Table 1]).
|Table 1 Patient characteristics and duration (min) in the studied groups|
Click here to view
Data revealed considerable intraoperative and postoperative analgesia in the IT group. That was evident through delayed time to first rescue analgesia about 5 h in the IT group (308 min, [Table 2]), in addition to about 50% reduction of intraoperative F and ketorolac requirements during 24 h postoperatively ([Table 2]). Also, VAS showed lower values in the IT group during the first 3 h postoperatively ([Figure 2]). In the same time, there was a concomitant higher range of arm movement in the IT group ([Figure 3]). No more significant differences in both items after 6 h postoperatively.
|Figure 2 Postoperative VAS (scale 0–10), in the study groups. ★Significant difference between IT and C groups (P=0.001). C, control; IT, intrathecal; VAS, visual analog pain scale.|
Click here to view
|Figure 3 Postoperative range of movement in degrees in C and IT groups. ★Significant difference between IT and C groups (P=0.001). C, control; IT, intrathecal.|
Click here to view
The upper sensory nerve blockade reached to T2 level or higher in 95% of patients during the first 15 min after IT injection ([Table 3]).
There was no significant difference in SaO2 perioperatively. The mean SaO2 was not less than 97% after spinal injection till 1 h, postoperatively. The HR results showed no significant perioperative differences between the two groups. The basal HR was slightly higher in the IT group (99 vs. 92 beats/min, P˃0.05) that may reflect stress due to spinal injection. HR was around 80 beats/min intraoperatively, while it was around 85 beats/min, postoperatively.
MBP was significantly lower following spinal injection, at 1, 2, and 5 min postintubation and intraoperatively till the end of operations ([Figure 4]).
|Figure 4 Mean perioperative blood pressure (mmHg) [before tube=15 min after spinal injection (P=0.005); tube=1, 2, 5 min after intubation (P=0.001); surgery=intraoperative (P=0.001), at end OR (P=0.013); and no difference postoperatively]. ★Significant difference between the two groups (P≤0.05).|
Click here to view
Hypotension and pruritus were significantly higher in the IT group, while vomiting was not ([Table 4]). Six (21%) patients required ephedrine in comparison to two (8%) patients in the C group who required ephedrine after induction of general anesthesia ([Table 4]). There was no postdural puncture headache.
| Discussion|| |
This study reveals superior intraoperative and postoperative analgesia beside depressed hypertensive stress response in IT compared with the C group. In the IT group, the first request for postoperative analgesia is delayed by about 5 h, VAS was significantly lower and the range of arm movement was concomitantly higher in the first 3 h postoperatively.
Generally, IT F provides postoperative analgesia for 2–4 h . However, Ouerghi et al. , have shown limited analgesia to 120 min in thoracotomy patients using IT lumbar F (25 mcg). Sudarshan et al.  using larger dose F (50 mcg) at the L2–L3 level, showed a median duration of analgesia 4 h (range: 2–14 h)in thoracotomy patients.
Helmi et al. , using a similar dose of B (20 mg) reported a duration of sensory and motor block at about 3 h. In this study, analgesia was extended to 5 h, which may be explained by the enhanced effect of B–F combination . The visibility of F action can be elucidated through measuring CSF concentration of F at the cervical level which is a limitation of this study. Another limitation is the absence of control group medicated by B alone.
Cephalad spread of F is initially through mixing with CSF under the influence of the physical forces. Later on, its concentration is determined mainly by the distance from the injection site .
In this study, analgesia was associated with sensory nerve block at the T2 level or above in 95% of patients. This high block level is explained by using 20 mg hyperbaric B, in addition to IT injection in lateral position that enhances cephalad spread . This high blockade was a prerequisite to correlate with the sensory innervation of the breast that is mediated by the lower cervical and upper six thoracic levels .
Compared with paravertebral block, Das et al. , found that the time to first request for analgesia was 5 h using multilevel B during mastectomy. Boughey et al. , reported also a duration of analgesia about 6 h using multilevel ropivacaine, while Moller et al. , showed a shorter duration of analgesia (120 min) after multilevel ropivacaine. A meta-analysis showed no improvement of analgesia after thoracotomy . Therefore, analgesia provided in this study was not inferior to paravertebral block analgesia, while retrieving the advantage of lower doses of B and F, one injection rather than multiple ones, rapid onset, avoiding pneumothorax, no failure rate besides easy performance in a shorter time.
The present study showed no early or late respiratory depression. Varassi et al.  reported the very little risk of respiratory depression using IT 25 mcg F even in elderly men. Moreover, Sudarshan et al.  reported improved lung function after thoracotomy using IT F 50 mcg.
In this study, MBP was significantly decreased after IT injection; the number of patients requiring ephedrine was significantly higher (27 vs. 9%) in IT compared with C groups. Singh et al. , showed increased hypotensive episodes of about three-fold when F was added to IT B (43 vs. 14%).
The lateral position assumed in the IT group may contribute to high blockade level and consequently hypotension . While the possibility of hemispinal effect may ameliorate hypotension, the sensory level assessment at the surgical side only represents a limitation. The high dermatomal block achieved in our cases assumes cardiac sympathectomy. That may explain the depression of hypertensive stress response in the IT group. During cardiac surgery, 23–30 mg of hyperbaric IT B with morphine 0.5–1.0 mg induced cardiac sympathectomy associated with minimal hemodynamic response to surgery, improved left ventricular wall motion with beneficial effects on β-adrenergic function and stress hormones .
In this study, vomiting was not different between C and IT groups (50 vs. 41%). Similar results obtained by Mason et al., following thoracotomy . IT F may actually protect against nausea and vomiting .
Pruritus is a frequent complication of IT F. In this study, pruritus occurred in 41% of patients in the IT group. However, adding B to F reduces the frequency of pruritus (36.4 vs. 95%) .
| Conclusion|| |
Lumbar IT F potentiates analgesia in mastectomy surgery.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Bolin ED, Harvey NR, Wilson SH. Regional anesthesia for breast surgery: techniques and benefits. Curr Anesthesiol Rep 2015; 5:217–224.
Schnabel A, Reichl S, Pogatzki-Zahn E, Kranke P, Zahn P. Efficacy and safety of paravertebral blocks for breast surgery: a quantitative systematic review of randomised controlled trials. Br J Anaesth 2010; 27:824–25.
Lynch EP, Welch KJ, Carabuena JM, Eberlein TJ. Thoracic epidural anesthesia improves outcome after breast surgery. Ann Surg 1995; 222:663–669.
Atanassoff PG, Alon E, Weiss BM. Intercostal nerve block for lumpectomy: superior postoperative pain relief with bupivacaine. J Clin Anesthesia 1994; 6:47–51.
O’Donoghue JM, Bahia H, Bunsell RP, Regan PJ. Intrapleural bupivicaine in latissimus dorsi breast reconstruction. Ann Plastic Surg 2008; 61:252–255.
Bansal P, Saxena KN, Taneja B, Sareen B. A comparative randomized study of paravertebral block versus wound infiltration of bupivacaine in modified radical mastectomy. J Anaesthesiol Clin Pharmacol 2012; 28:76–80.
] [Full text]
Blanco R, Fajardo M, Maldonado TP. Ultrasound description of Pecs II (modified Pecs I): a novel approach to breast surgery. Rev Esp Anestesiol Reanim 2012; 59:470–475.
Blanco R, Parras T, McDonnell J, Prats‐Galino A. Serratus plane block: a novel ultrasound‐guided thoracic wall nerve block. Anaesthesia 2013; 68:1107–1113.
Ruppen W, Steiner L, Drewe J, Hauenstein L, Brugger S, Seeberger M. Bupivacaine concentrations in the lumbar cerebrospinal fluid of patients during spinal anaesthesia. Br J Anaesthesia 2009; 102:832–838.
Calias P, Banks WA, Begley D, Scarpa M, Dickson P. Intrathecal delivery of protein therapeutics to the brain: a critical reassessment. Pharmacol Ther 2014; 144:114–122.
Ouerghi S, Fnaeich F, Frikha N, Mestiri T, Merghli A, Mebazaa M et al.
The effect of adding intrathecal magnesium sulphate to morphine-fentanyl spinal analgesia after thoracic surgery. A prospective, double-blind, placebo-controlled research study. Ann Fr Anesth Reanim 2011; 30:25–30.
Hammer GB, Wolf AR. The use of regional anesthesia in combination with general anesthesia for cardiac surgery in children. Tech Reg Anesth Pain Manag 2008; 12:64–71.
Lee TW, Jacobsohn E. Spinal anesthesia in cardiac surgery. Tech Reg Anesth Pain Manag 2008; 12:54–56.
Bernards CM. Recent insights into the pharmacokinetics of spinal opioids and the relevance to opioid selection. Curr Opin Anesthesiol 2004; 17:441–447.
Ummenhofer WC, Arends RH, Shen DD, Bernards CM. Comparative spinal distribution and clearance kinetics of intrathecally administered morphine, fentanyl, alfentanil, and sufentanil. Anesthesiology 2000; 92:739–753.
Swenson JD, Owen J, Lamoreaux W, Viscomi C, McJames S, Cluff M. The effect of distance from injection site to the brainstem using spinal sufentanil. Reg Anesth Pain Med 2001; 26:306–309.
Eisenach JC, Hood DD, Curry R, Shafer SL. Cephalad movement of morphine and fentanyl in humans after intrathecal injection. Anesthesiology 2003; 99:166–173.
Payne R. CSF distribution of opioids in animals and man. Acta Anaesthesiol Scand 1987; 31:38–46.
Singh H, Yang J, Thornton K, Giesecke AH. Intrathecal fentanyl prolongs sensory bupivacaine spinal block. Can J Anaesth 1995; 42:987–991.
Payne R, Inturrist CE. CSF distribution of morphine, methadone and sucrose after intrathecal injection. Life Sci 1985; 37:1137–1144.
Orešković D, Klarica M. A new look at cerebrospinal fluid movement. Fluids Barriers CNS 2014; 11:16–19.
Linninger AA, Tangen K, Hsu CY, Frim D. Cerebrospinal fluid mechanics and its coupling to cerebrovascular dynamics. Annu Rev Fluid Mech 2016; 48:219–257.
Chrubasik J, Chrubasik S, Mather L. Determinants of opioid activity. In: Joachim Chrubasik SC, Mather L, editors. Postoperative epidural opioids. Berlin Heidelberg, Germany: Springer 1993. pp. 9–23.
Bernards CM. Understanding the physiology and pharmacology of epidural and intrathecal opioids. Best Pract Res Clin Anaesthesiol 2002; 16:489–505.
Lee M, McPhee R, Stringer M. An evidence‐based approach to human dermatomes. Clinical Anatomy 2008; 21:363–373.
Hamber EA, Viscomi CM. Intrathecal lipophilic opioids as adjuncts to surgical spinal anesthesia. Reg Anesth Pain Med 1999; 24:255–263.
Sudarshan G, Browne B, Matthews J, Conacher I. Intrathecal fentanyl for post-thoracotomy pain. Br J Anaesthesia 1995; 75:19–22.
Helmi M, Uyun Y, Suwondo BS, Widodo U. Comparison of intrathecal use of isobaric and hyperbaric bupivacaine during lower abdomen surgery. J Anesthesiol 2014; 2014:4.
Asokumar B, Newman LM, McCarthy RJ, Ivankovich AD, Tuman KJ. Intrathecal bupivacaine reduces pruritus and prolongs duration of fentanyl analgesia during labor: a prospective, randomized controlled trial. Anesth Analg 1998; 87:1309–1315.
Nair G, Abrishami A, Lermitte J, Chung F. Systematic review of spinal anaesthesia using bupivacaine for ambulatory knee arthroscopy. Br J Anaesthesia 2009; 102:307–315.
Sarhadi N, Shaw-Dunn J, Soutar D. Nerve supply of the breast with special reference to the nipple and areola: Sir Astley Cooper revisited. Clin Anat 1997; 10:283–288.
Das S, Bhattacharya P, Mandal MC, Mukhopadhyay S, Basu SR, Mandol BK. Multiple-injection thoracic paravertebral block as an alternative to general anaesthesia for elective breast surgeries: a randomised controlled trial. Indian J Anaesthesia 2012; 56:27–33.
Boughey JC, Goravanchi F, Parris RN, Kee SS, Kowalski AM, Frenzel JC et al.
Prospective randomized trial of paravertebral block for patients undergoing breast cancer surgery. Am J Surg 2009; 198:720–725.
Moller JF, Nikolajsen L, Rodt SA, Ronning H, Carlsson PS. Thoracic paravertebral block for breast cancer surgery: a randomized double-blind study. Anesth Analg 2007; 105:1848–1851.
Kotze A, Scally A, Howell S. Efficacy and safety of different techniques of paravertebral block for analgesia after thoracotomy: a systematic review and metaregression. Br J Anaesthesia 2009; 103:626–636.
Varrassi G, Celleno D, Capogna G, Costantino P, Emanuelli M, Sebastiani M et al.
Ventilatory effects of subarachnoid fentanyl in the elderly. Anaesthesia 1992; 47:558–562.
Adkisson G, Waters J, Burger G. Fentanyl added to lidocaine results in higher spinal anesthetic levels. Anesth Analg 1993; 76:S2.
Mason N, Gondret R, Junca A, Bonnet F. Intrathecal sufentanil and morphine for post‐thoracotomy pain relief. Br J Anaesthesia 2001; 86:236–240.
Palmer CM, Voulgaropoulos D, Alves D. Subarachnoid fentanyl augments lidocaine spinal anesthesia for cesarean delivery. Reg Anesth Pain Med 1995; 20:389–394.
[Figure 1], [Figure 2], [Figure 3], [Figure 4]
[Table 1], [Table 2], [Table 3], [Table 4]