|Year : 2019 | Volume
| Issue : 3 | Page : 184-187
Analgesic efficacy and safety of oxycodone as an adjuvant epidural analgesia for patients undergoing laparotomy gynecology
Tjokorda Gde Agung Senapathi, I Made Gede Widnyana, I Gusti Agung Gede Utara Hartawan, Christopher Ryalino, Cokorda Istri Arintha Devi
Department of Anesthesiology and Intensive Care, Faculty of Medicine, Udayana University, Denpasar, Bali, Indonesia
|Date of Submission||02-Dec-2019|
|Date of Acceptance||02-Dec-2019|
|Date of Web Publication||23-Jan-2020|
Dr. Christopher Ryalino
Department of Anesthesiology and Intensive Care, Faculty of Medicine, Udayana University, Jl. PB Sudirman, Denpasar 80232, Bali
Source of Support: None, Conflict of Interest: None
Postoperative pain, when poorly controlled, will cause chronic pain and prolong the healing process. The use of an epidural catheter is a safe and effective method for pain relief in the intraoperative and postoperative period. Opioid as an adjuvant can increase the potency and duration of epidural analgesia. Morphine has been used as an adjuvant in epidural analgesia, but with known side effects such as nausea, vomiting, and pruritus. Oxycodone is one of the opioids which can be given through epidural route as an adjuvant with fewer side effects than morphine. In this case series, we describe six patients with American Society of Anesthesiologists physical status I–II who underwent laparotomy gynecological surgery. All patients were managed by combined general and epidural anesthesia. The regimen for epidural anesthesia is bupivacaine with oxycodone as adjuvant. In this study, we described the hemodynamic profile, quality of analgesia, side effects, and anti-inflammatory effect of oxycodone as an adjuvant in epidural analgesia.
Keywords: Adjuvant, epidural, laparotomy, oxycodone
|How to cite this article:|
Agung Senapathi TG, Gede Widnyana I M, Utara Hartawan I G, Ryalino C, Arintha Devi CI. Analgesic efficacy and safety of oxycodone as an adjuvant epidural analgesia for patients undergoing laparotomy gynecology. Bali J Anaesthesiol 2019;3:184-7
|How to cite this URL:|
Agung Senapathi TG, Gede Widnyana I M, Utara Hartawan I G, Ryalino C, Arintha Devi CI. Analgesic efficacy and safety of oxycodone as an adjuvant epidural analgesia for patients undergoing laparotomy gynecology. Bali J Anaesthesiol [serial online] 2019 [cited 2020 Mar 29];3:184-7. Available from: http://www.bjoaonline.com/text.asp?2019/3/3/184/276622
| Introduction|| |
Inadequate postoperative acute pain management will cause complications such as chronic pain. There are some techniques for acute pain relief in gynecological surgery. Systemic opiates such as morphine have proved as one of the best acute pain relief medications, but still, they have side effects such as nausea, drowsiness, itching, and ileus, which disturb the healing process. Epidural anesthesia has become a safe and effective method for postoperative pain management because of the superior analgesic and physiologic benefits it provides, especially in the majority of cases of abdominal surgery.
Opioid as an adjuvant can increase the potency and duration of epidural analgesia. It also decreases the needed dosage of local anesthesia up to 19%–31%, which will reduce the side effect of local anesthesia., Opioid has a dose-sparing effect for local anesthetic., Morphine has been used as an adjuvant in epidural analgesia. Although it provides excellent analgesic effect, side effects such as nausea, vomiting, and pruritus are unavoidably high and are unable to treat by conventional medications, such as antihistamines. This happens in 30%–65% of morphine use.
Oxycodone is one of the opioids which can be given through epidural route as an adjuvant with less side effects than morphine. Oxycodone is a semi-synthetic drug used since 1917, has structure and lipid solubility similar to morphine, and achieves analgesic effect by binding to μ receptor., By binding also with κ receptor, oxycodone produces an analgesic effect for visceral pain without euphoria, prolonged gastrointestinal motility, and respiratory depression. Some studies have reported that oxycodone also releases histamine less than that of other opioids.
| Case Report|| |
Six patients in the age ranged of 16–65 years with American Society of Anesthesiologists physical status I–II were scheduled for elective laparotomy gynecology in Sanglah General Hospital with combined general and epidural anesthesia technique. We withdrew blood samples for complete blood count (CBC), C-reactive protein (CRP), and blood sugar from all patients.
All patients received premedication with 2-mg midazolam, 10-mg dexamethasone, and 10-mg diphenhydramine. Patients were then placed in left lateral position and got prepared to have epidural insertion. L2–L3 interspace was identified, and epidural catheter insertion was made with loss of resistance technique. Correct catheter placement was confirmed with lidocaine 1.5% and epinephrine 1:200,000 to ensure that the catheter was inserted in epidural space. Then, the patients were placed back to supine position for general anesthesia. Each patient received 3 μg/kg fentanyl and 2 mg/kg propofol. To facilitate intubation, we used 0.6 mg/kg atracurium. Maintenance was provided by air: oxygen mixture, isoflurane, and atracurium.
Bupivacaine 0.25% and 2-mg oxycodone (total volume 15 ml) were injected through the catheter. Hemodynamics was recorded every 15 min after epidural injection [Table 1]. No additional vasopressor was given. Ondansetron 0.1 mg/kg was administered prior to completion of the surgery, neuromuscular blockade was reversed, and the patient was extubated.
For postoperative analgesia, bupivacaine 0.125% + oxycodone 2 mg (total volume 15 ml) were administrated per epidural catheter at the end of surgery and every 10 h afterward. Paracetamol oral in 500 mg dose was also prescribed for every 6 h.
The mean duration of postoperative analgesia equaled 7 h and 50 min without any adverse effects such as nausea, vomiting, and pruritus. The adverse effects were recorded every 6 h in the first 12 h and every 12 h for the rest 24 h. No patient was reported to develop any adverse effect. When VAS arises above 30 mm, 30-mg ketorolac was administered. Most patients received ketorolac at 7 h postoperatively; only two patients received ketorolac at 9 h. The blood sample for CBC, CRP, and blood sugar was drawn from all patients in 24 h after surgery, and comparison with basal value was made and is shown in [Table 1].
| Discussion|| |
Oxycodone is derived from the opioid alkaloid thebaine, which is a full-opioid agonist that has two planar rings, two aliphatic rings, and four chiral centers, and also its molecular weight is 351.83 g/mol. It is hygroscopic, is soluble in free water, and is slightly soluble in ethanol. Oxycodone is a semi-synthetic opioid with an agonist activity on mu (μ), kappa (κ), and delta (δ) receptors, which are known as opioid receptors. The affinity of oxycodone for the μ-opioid receptor is 18±4 nM compared to 677±326 nM for the κ-opioid receptor. The μ-opioid receptor binding affinity of oxycodone is lesser than that of morphine or methadone. Oxycodone binds to opioid receptor, which stimulates the exchange of guanosine-5′-triphosphate to guanosine-5′-diphosphate on the G-protein complex. This stimulation inhibits adenylate cyclase and prevents cyclic adenosine-monophosphate production, which results in the inhibition of the release of nociceptive neurotransmitters, substance P, γ-aminobutyric acid, dopamine, acetylcholine, and noradrenaline.
Opioids are highly effective in spinal analgesia. Morphine and sufentanil are two opioids which are approved for intradural use. Fentanyl is not formally approved for intradural administration, as both morphine and sufentanil provide more long-lasting analgesia than the lipophilic fentanyl. Oxycodone is another hydrophilic opioid., No studies have been conducted on oxycodone's usage as an adjuvant to epidural analgesia in patients undergoing laparotomy.
Currently, there are only a few published studies regarding oxycodone administration through the spinal and epidural routes; oxycodone was used as a single epidural opioid continuous regimen. Different analgesic effects were observed. Backlund et al. proved that in patients post abdominal surgery, the epidural effective dose of oxycodone was ten times greater than that of morphine. Oxycodone was used at a dose of 0.15 mg/kg in bolus, and subsequently as a continuous infusion of 0.03 mg/kg/h.
Yanagidate and Dohi  indicated that by doubling the dose of oxycodone via epidural catheter provides similar analgesia as morphine in patients underwent gynecological surgery. The authors used a bolus of 2 mg of morphine and 4 mg of oxycodone administered through the epidural catheter and subsequently maintained with continuous infusion of 6 and 12 mg daily for 3 days, respectively.
In our serial case report, it was found that oxycodone can prolong the effectiveness of local epidural analgesia for approximately 8 h. Kokki et al. indicated that epidural oxycodone offers highly effective and safe administration route for postoperative pain relief. The study showed that patients receiving an epidural injection along with oxycodone require less analgesia rescue and have lower pain scores than those receiving oxycodone intravenously. The concentration of oxycodone and its metabolites in serum and cerebrospinal fluid after the administration of oxycodone by both intravenous (IV) and epidural routes at a dose of 0.1 mg/kg of body weight was compared. It was found that neuraxial administration is more likely to provide effective analgesia with a lower dose of oxycodone than the dose of IV administration.
Studies regarding the safest drugs in central blockades, both local anesthetics and the so-called adjuvants that would guarantee for an extended period of analgesia, have been ongoing in decades. Among the most commonly used are opioids, especially morphine, which may result in pruritus. A study showed that a significantly lower percentage of patients treated with epidural oxycodone experienced pruritus and nausea than those treated with epidural morphine.
In this serial case report, no patient developed adverse events such as nausea, vomiting, or pruritus. Some side effects, such as pruritus and nausea, are believed to be caused through μ-receptor opioid stimulation on the supraspinal level. Although oxycodone had effects on both μ- and κ-opioid receptors, the affinity of oxycodone on the mu-opioid receptor was reported to be one-tenth that of morphine. This may be due to the fewer side effects and less analgesic effect when compared with the same dose of epidural morphine.
Morphine, hydromorphone, hydrocodone, and meperidine lead to histamine release and, as a result, can cause significant decreases in systemic vascular resistance and blood pressure, while oxycodone does not have these side effects. This is because oxycodone produces only less histamine release compared to other opioids. In this serial case report, the hemodynamics of all patients remained stable compared to the basal value.
Injury due to surgical trauma and infection will induce an acute inflammatory reaction with excessive mediator release along with it. This cumulative homeostatic process is known as inflammation, and the next set of responses caused is known as the acute-phase response. Activated macrophages will release cytokines and initiate the accumulation of inflammatory cells. CRP is an acute inflammatory protein that increases up to 1.000-fold in infection or inflammation sites. CRP is the downstream mediator of the acute-phase response following an inflammatory event and is primarily synthesized by interleukin-6-dependent hepatic biosynthesis principally.
There are many factors which can alter baseline CRP levels, including age, gender, smoking status, weight, lipid levels, and blood pressure. Stress response due to major surgery can increase CRP level. The blockade by regional anesthesia with local anesthetics has a direct influence on the endocrinal and metabolic responses. The basic mechanism of a neural blockade on stress response to surgery is the total prevention to cut nociceptive signals from the surgical area reaching the central nervous system. This case series showed increased stress response including CRP, blood glucose, and neutrophil count compared to the basal value. Further studies to compare the immunosuppressive effect between opioids are needed.
| Conclusion|| |
Oxycodone should be considered an adjuvant to epidural analgesia and as an alternative to morphine due to better satisfactory results and fewer side effects. Further studies with a larger number of patients are required in future to support this finding.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Macrae WA. Chronic post-surgical pain: 10 years on. Br J Anaesth 2008;101:77-86.
Nelson G, Altman AD, Nick A, Meyer LA, Ramirez PT, Achtari C, et al
. Guidelines for postoperative care in gynecologic/oncology surgery: Enhanced Recovery After Surgery (ERAS®) Society recommendations-Part II. Gynecol Oncol 2016;140:323-32.
Wu CL, Cohen SR, Richman JM, Rowlingson AJ, Courpas GE, Cheung K, et al
. Efficacy of postoperative patient-controlled and continuous infusion epidural analgesia versus intravenous patient-controlled analgesia with opioids: A meta-analysis. Anesthesiology 2005;103:1079-88.
Lysak SZ, Eisenach JC, Dobson CE 2nd
. Patient-controlled epidural analgesia during labor: A comparison of three solutions with a continuous infusion control. Anesthesiology 1990;72:44-9.
Boulier V, Gomis P, Lautner C, Visseaux H, Palot M, Malinovsky JM. Minimum local analgesic concentrations of ropivacaine and levobupivacaine with sufentanil for epidural analgesia in labour. Int J Obstet Anesth 2009;18:226-30.
Chaney MA. Side effects of intrathecal and epidural opioids. Can J Anaesth 1995;42:891-903.
Kalso E. Oxycodone. J pain symptom manage 2005;29 Suppl 5:S47-56.
Cui JH, Jiang WW, Liao YJ, Wang QH, Xu M, Li Y. Effects of oxycodone on immune function in patients undergoing radical resection of rectal cancer under general anesthesia. Medicine (Baltimore) 2017;96:e7519.
Kinnunen M, Piirainen P, Kokki H, Lammi P, Kokki M. Updated clinical pharmacokinetics and pharmacodynamics of oxycodone. Clin Pharmacokinet 2019;58:705-25.
Backlund M, Lindgren L, Kajimoto Y, Rosenberg PH. Comparison of epidural morphine and oxycodone for pain after abdominal surgery. J Clin Anesth 1997;9:30-5.
Yanagidate F, Dohi S. Epidural oxycodone or morphine following gynaecological surgery. Br J Anaesth 2004;93:362-7.
Kokki M, Välitalo P, Kuusisto M, Ranta VP, Raatikainen K, Hautajärvi H, et al
. Central nervous system penetration of oxycodone after intravenous and epidural administration. Br J Anaesth 2014;112:133-40.
Mugabure Bujedo B. A clinical approach to neuraxial morphine for the treatment of postoperative pain. Pain Res Treat 2012;2012:612145.
Chen A, Ashburn MA. Cardiac effects of opioid therapy. Pain Med 2015;16 Suppl 1:S27-31.
Singh M. Stress response and anaesthesia: Altering the peri and post-operative management. Indian J Anaesth 2003;47:427-34. [Full text]
Sproston NR, Ashworth JJ. Role of C-reactive protein at sites of inflammation and infection. Front Immunol 2018;9:754.