Indian Journal of Anaesthesia  
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Year : 2008  |  Volume : 52  |  Issue : 4  |  Page : 448 Table of Contents     

Epidural Naloxone to Prevent Buprenorphine Induced PONV

1 Senior Consultant and Head, Department of Anaesthesia, Tata Motors Hospital, Jamshedpur-83100, India
2 Senior Cosultant, Department of Anaesthesia, Tata Motors Hospital, Jamshedpur-83100, India
3 Consultant, Department of Anaesthesia, Tata Motors Hospital, Jamshedpur-83100, India
4 DNB student, Department of Anaesthesia, Tata Motors Hospital, Jamshedpur-83100, India

Date of Acceptance27-Apr-2008
Date of Web Publication19-Mar-2010

Correspondence Address:
Ashok Jadon
44, Beldih Lake Flats, Dhatkidih, Jamshedpur-831001, Jharkhand
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Source of Support: None, Conflict of Interest: None

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Epidural infusion of local analgesic and opioid are commonly used for postoperative pain relief. This combina­tion gives excellent anlgesia but nausea and vomiting remains a major concern. Low dose epidural naloxone prevents PONV induced by spinal opioids like morphine, fentanyl and sufentanil. However, it is not known that epidural naloxone administration prevents PONV induced by epidural buprenorphine. We have reported three cases of major abdominal operation in which lowdose epidural infusion of naloxone releived the symptom of buprenorphine induced severe PONV and improved the quality of analgesia.

Keywords: Buprenorphine, Epidural opioid, Naloxone, PONV

How to cite this article:
Jadon A, Parida S S, Chakroborty S, Panda A. Epidural Naloxone to Prevent Buprenorphine Induced PONV. Indian J Anaesth 2008;52:448

How to cite this URL:
Jadon A, Parida S S, Chakroborty S, Panda A. Epidural Naloxone to Prevent Buprenorphine Induced PONV. Indian J Anaesth [serial online] 2008 [cited 2020 Jul 14];52:448. Available from:

   Introduction Top

Buprenorphine is a popular choice for epidural analgesia because it gives longer duration of pain re­lief with comparatively less side effects [1],[2] . We rou­tinely use buprenorphine and bupivacaine mixture ei­ther bolus or continuous infusion by syringe pump for postoperative analgesia in major gynecological sur­gery. This mixture gives an excellent quality and dura­tion of analgesia (6-10 hrs.) for each bolus, however large number of patients (30-40%) complain nausea and vomiting particularly on repeated bolus or on con­tinuous infusion. Epidural naloxone has been used to prevent PONV induced by epidural opioids like mor­phine [3] , and sufentanil [4] . We have investigated the ef­fect of low dose epidural infusion of naloxone on buprenorphine induced PONV in hysterectomy pa­tients.

Case-1: A 38-yr-old ASA- I female wt 64 Kg, had hysterectomy operation under combined spinal epidural anaesthesia and received bupivacaine and buprenorphine mixture for postoperative pain relief. Needle through needle technique (CSE Cure, Portex Combined Spinal/Epidural mini pack 27G/18G) was used to give anaesthesia. Epidural needle placed with loss of resistance to air technique at L3/L4 space and subarachnoid block was given with 0.5% heavy bupivacaine 4 ml by 27G whitacre pencil point needle then epidural catheter 18G was inserted 3-4 cm ceph­alad and flushed with 1 ml saline after negative aspira­tion for blood and CSF. No intra-operative top-up was required. In postoperative ward, patient started com­plaining of pain VAS score was 6-7/10, 3 ml of 1% lidocaine with adrenaline was given epidurally as test dose and after ten minutes, five ml mixture of 0.125% bupivacaine + 150 µg buprenorphine was given. After 30 minutes (epidural was effective VAS=4) infusion of 0.125% bupivacaine + buprenorphine -1 was started with syringe pump at 4 -1 ondansetron 4 mg IV for vomiting, and diclofenac 75 mg IM or 5 ml bolus of infusion mixture for pain ( VAS >3) was ad­vised as rescue analgesic on demand basis (decided by observer anaesthetist). Two hourly Visual Analog Score was done for pain (scale 0-10) and for vomiting (scale 0-5) for 24 hrs, then 4 hrly for 48 hrs. If patient found sleeping Zero score was given for pain and PONV. However, if complained of pain or PONV occurred in between it was included in near by time record. After one hour of epidural injection patient started severe nausea and repeated vomiting (4 times in one hr, PONV score=5.), complain of uneasiness and malaise. Injection ondansetron 4mg , was given and after 20 minutes when vomiting did not stop metoclopramide 10 mg + dexamethasone 8 mg was given. After 2 hrs of treatment vomiting stopped but severe nausea ( PONV score=2) and uneasiness per­sisted. After eight hours of first epidural injection pa­tient started complaining of pain( VAS=8-9/10). This time we gave 5 ml epidural mixture of 0.125% bupivacaine+ 25 mcg buprenorphine+ 16.5 mcg nalox­one ( 30 ml 0.25% bupivacaine+ 300 mcg buprenorphine+ 200 mcg naloxone+ 28 ml saline=60 ml solution) and infusion of same mixture was started at 4 -1 (effective dose of -1 .hr -1 , and naloxone was observed for next 36 hours and no epi­sode of PONV occurred. Patient reported better pain relief and physical comfort this time. Pain score remained 0-2 during this infusion regimen.

Case-2: A 41 yr old, 62 kg female, with the his­tory of fibroid uterus scheduled for hysterectomy. She had two previous operations and reported excessive PONV lasted for >36 hrs postoperatively even with antiemetic prophylaxis and treatment , in both the op­erations. Hysterectomy was done under combined spi­nal epidural technique (needle through needle, CSE Cure, Portex), and postoperative analgesia was pro­vided as per protocol used in previous case. However, this time 60 ml 0.125% bupivacaine solution contain­ing (Naloxone 200 mcg + 300 mcg buprenorphine) was started from beginning at the rate of 4 -1 (the dose of naloxone = -1 .hr -1 , and buprenorphine = -1 .hr -1 ). Visual analog score was done. Patient had nausea (PONV score= 1), just after taking biscuits and tea 6 hrs after operation, otherwise she never had nausea or vomiting in 48 hrs of observation period (PONV score remain=0). Pain relief was ex­cellent as score was 0-2). She was highly satisfied with present pain relief and quality of comfort.

Case-3: A 37 yr and 59 kg , ASA- II patient undergone right ovarian cystectomy + abdominal hys­terectomy under epidural analgesia. Epidural catheter(18G , Perifix 400 mini set, B/Braun) ) was inserted through L3/L4 space directed up-wards 4 cm. Anaesthesia was provided by 16ml ( 1:1 mixture of 2% lidocaine with adrenaline and 0.5% bupivacaine) after 3ml test dose of 1% lidocaine with adrenaline. During skin closure when patient complained of dis­comfort, 4 ml of similar solution + 150 microgram buprenorphine was given through epidural catheter. Postoperative monitoring for PONV and pain was done as per protocol. After 2 hours of operation patient com­plained of severe nausea and uneasiness (PONV score=3). She received ondansetron 4 mg IV, pain score was 5-7 on the scale of 10. She vomited once, nausea and discomfort (uneasiness& giddiness) was increas­ing (PONV score4). Infusion of naloxone 4 -1 ( 200 mcg in 50 ml normal saline) was started at 4­1 ( -1 .hr -1 ). After 30 minutes the intensity of nausea was decreased (PONV score= 1) and after 1 hr patient was comfortable and free from nausea( PONV score=0). Pain relief was also better (VAS 0/ 10). This infusion was continued for 6 hrs, then bupivacaine and buprenorphine were mixed in same syringe for postoperative pain relief to get concentra­tion of 0.125% bupivacaine and dose of buprenorphine -1 .hr -1 and naloxone 0.20 -1 .hr -1 . Rest of the postoperative period was uneventful pain score remain 0-2/10 and patient was highly satisfied with pain relief.

   Discussion Top

Epidural buprenorphine is an effective analgesic but PONV is very common undesirable side effect [5] . Buprenorphine and other opioid drugs cause PONV by action on MOR (µ opioid receptor) present in the brain and gastro intestinal tract [6] . Buprenorphine is a semi-synthetic opioid with agonistic activity at the MOP-receptor and antagonistic properties at the KOP­receptor. Human studies show that buprenorphine be­havior is typical of MOP-receptor agonists, with re­spect to its intended effect (potent and long-lasting an­algesia) and side-effects (e.g. it causes sedation, nau­sea, delayed gastric emptying ) but a partial agonist at MOP receptors involved in respiratory depression. Buprenorphine's behavior may be due to difference in the agonist/ MOR/ G-protein/l3-arrestin complex in pain and respiratory neurons. [7]

Naloxone is an opiate receptor antagonist has been used through intravenous and epidural route to counter opioid induced side effects like itching, nausea, vomit­ing, decreased intestinal motility and respiratory depres­sion. By titration of naloxone doses it is possible that, only side effects (PONV, itching, respiratory depres­sion etc.) are controlled and opioid analgesia is retained [3],[4],[8] .

The possible mechanism include, (a) low dose naloxone may enhance release of endogenous opioid peptides by blocking presyneptic autoinhibition of encephalin release [9] and, (b) low dose naloxone directly and competetively antagonize the Gs protein-coupled excitatory opioid receptor that are responsible for the hyperalgesia occasionally reported with opioid admin­istration without attenuating inhibitory Gi/Go-coupled opioid receptors mediating analgesia [10] . Whether simi­lar mechanism also active with co-administration of naloxone and buprenorphine is not documented how­ever, experimental studies have shown the efficacy of intrathecal naloxone to counteract effects of bupren­orphine administered intrathecally [11] . We used infusion of naloxone after initial bolus instead of only bolus be­cause it is better to infuse naloxone continuously as it has half life of 55 minutes and intermittent administra­tion will result in fluctuation of concentration [12] . There was no previous guideline available for epidural dose of naloxone to prevent PONV with buprenorphine. We have used an average dose of 0.20-0.27, considering that, this will be low dose as similar dose has been used to prevent sufentanil induced PONV [4] . Regarding safety of naloxone for spinal use, various experimental and clinical studies have shown that nalox­one not only safe for spinal use rather it is neuroprotective [13] .

So far clinically reduction in nausea, vomiting and analgesia enhancing effect with low dose naloxone have been noticed only with pure mu agonist like morphine, fentanyl and sufentanil. In present report, we have ob­served that similar effects were seen when naloxone interacted with partial mu agonist buprenorphine, as all three patients responded in similar and predicted man­ner. Symptoms of PONV were controlled and quality of analgesia improved.

Pharmacology of buprenorphine is very complex and still poorly understood. This case report highlights the possibilities that, epidural administration of nalox­one may help in management of epidural buprenorphine induced PONV and may enhance analgesic effect of epidurally administerd buprenorphine. However to prove this hypothesis, a large RCT along with receptor binding analysis studies are required.

We noticed improvement in pain score with relief of nausea and vomiting when low dose naloxone used epidurally to control buprenorphine-induced nausea and vomiting. However, with only three cases observed, further detail study is required to reach any conclusion.

   References Top

1.Hakim Abdul, Hashia AM., Shabir A Akhtar Rafiqa. Epi­dural morphine and buprenorphine for post operative analgesia-A comparative study. J Anesth Clin Pharma­cology 2007; 23: 155-158.  Back to cited text no. 1      
2.Cahill J, Murphy D, O'Brien D, Mulhall J and Fitzpatrick G. Epidural buprenorphine for pain relief after major ab­dominal surgery. Anaesthesia 1983; 38:760-764.  Back to cited text no. 2      
3.Choi JH, Lee J, Choi JH, Bishop MJ. Epidural naloxone reduces pruritus and nausea without affecting analge­sia by epidural morphine in bupivacaine. Can J Anesth 2000; 47: 33-7.  Back to cited text no. 3  [PUBMED]    
4.Kim MK, Nam SB., Cho MJ., and Shin YS. Epidural naloxone reduces postoperative nausea and vomiting in patients receiving epidural sufentanil for postopera­tive analgesia. Br J Anaesth 2007; 99: 270 - 275.  Back to cited text no. 4      
5.Capogna G, Celleno D, Tagariello V, Loffreda-Mancinelli C. Intrathecal buprenorphine for postoperative analge­sia in the elderly patient. Anaesthesia 1988;43:128-130.  Back to cited text no. 5  [PUBMED]    
6.Cowan A. Update of the general pharmacology of buprenorphine. In Cowan A and Lewis JW (Eds.). Buprenorphine, Combating Drug Abuse with a Unique Opioid 1995.New York Wiley-Liss, Inc. pp. 31-47  Back to cited text no. 6      
7.Dahan A, Yassen A, Romberg R, et al. Buprenorphine induces ceiling in respiratory depression but not in an­algesia. British Journal of Anaesthesia 2006;96:627-632  Back to cited text no. 7      
8.Kim ES, Lee J, Choi JH. Optimal dose range of epidural naloxone to reduce nausea in patients receiving epidu­ral morphine. Can J Anaesth 2004;51:1048-9.  Back to cited text no. 8  [PUBMED]    
9.Ueda H, Fukushima N, Kitao T, Ge M, Takagi H. Low doses of naloxone produces analgesia in the mouse brain by blocking presyneptic autoinhibition of encephalin release. Neurosci Lett 1986; 65: 247-52.  Back to cited text no. 9  [PUBMED]    
10.Crain SM, Shen KF. Antagonist of excitatory opioid re­ceptor functions enhance morphine's analgesic potency and attenuate opioid tolerance/dependence liability. Pain 2000;84:121-31.  Back to cited text no. 10  [PUBMED]  [FULLTEXT]  
11.Tejwani GA, Rattan AK. The role of spinal opioid recep­tors in antinociceptive effects produced by intrathecal administration of hydromorphone and buprenorphine in the rat. Anesth Analg 2002; 94:1542-6.  Back to cited text no. 11  [PUBMED]  [FULLTEXT]  
12.Van Dorp E, Yassen A, Sarton E, Romberg R, Olofsen E, Teppema L, et al. Naloxone reversal of buprenorphine­induced respiratory depression. Anesthesiology 2006;105:51-7.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]  
13.Cole DJ, Drummond JC, Shapiro HM, et al. The effect of fentanyl anesthesia and intratheacl naloxone on neuro­logic outcome following spinal cord injury in the rat. Anesthesiology 1989; 71: 426-30.  Back to cited text no. 13  [PUBMED]  [FULLTEXT]  


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