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Year : 2022  |  Volume : 6  |  Issue : 3  |  Page : 127-132

Comparison of oxycodone with morphine as adjuvant epidural analgesia and its side effects: A systematic review

Department of Anesthesiology and Intensive Care, Faculty of Medicine, University of Udayana, Bali, Indonesia

Date of Submission15-Mar-2022
Date of Decision09-May-2022
Date of Acceptance11-Apr-2022
Date of Web Publication30-May-2022

Correspondence Address:
Christopher Ryalino
Department of Anesthesiology and Intensive Care, Faculty of Medicine, University of Udayana, Jl. PB Sudirman, Denpasar 80232, Bali,
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bjoa.bjoa_83_22

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Despite morphine’s ability to deliver effective analgesia, its use as an epidural adjuvant is limited by adverse effects such as nausea, vomiting, and pruritus, which are typically intractable with conventional antihistamines. Another negative effect that we are particularly concerned about is respiratory depression. This systematic review aimed to summarize the evidence based on randomized controlled trials (RCTs) comparing epidural analgesic adjuvants between oxycodone and morphine. We searched the Cochrane Library, PubMed, and EMBASE databases from 1990 until 2021 to find RCTs published in English language, which have investigated pain score and side effects such nausea and vomiting. Three RCTs were included in the final analysis. All of them employed similar argument that epidural analgesic with oxycodone has good analgesic effects at higher dose than morphine. Oxycodone provides analgesic properties equivalent to morphine, but with less nausea and vomiting. We found that epidural analgesic with oxycodone has comparable analgesic effect to morphine, as well as lower side effects on nausea and vomiting at twice morphine doses. Future study is needed to compare epidural oxycodone with morphine in terms of analgesia and adverse effects.

Keywords: Morphine, nausea, oxycodone, pain, pruritus

How to cite this article:
Senapathi TG, Sanjaya DN, Pradhana AP, Ryalino C, Sutawan IB. Comparison of oxycodone with morphine as adjuvant epidural analgesia and its side effects: A systematic review. Bali J Anaesthesiol 2022;6:127-32

How to cite this URL:
Senapathi TG, Sanjaya DN, Pradhana AP, Ryalino C, Sutawan IB. Comparison of oxycodone with morphine as adjuvant epidural analgesia and its side effects: A systematic review. Bali J Anaesthesiol [serial online] 2022 [cited 2023 Mar 22];6:127-32. Available from: https://www.bjoaonline.com/text.asp?2022/6/3/127/346243

  Introduction Top

Epidural anesthesia has long been recognized as one of the modalities in the field of anesthesiology that can provide adequate analgesics with minimal doses. Administration of opioid through epidural route could produce an adequate postoperative analgesia and has been used for over three decades worldwide.[1],[2] Hence, epidural opioid is commonly used for postoperative analgesia, especially in moderate or severe surgery.[1]

Morphine is a type of opioid that has been commonly used as an adjuvant in epidural analgesia. Although can provide a good analgesia, the use of morphine as an epidural adjuvant is limited by side effects such as nausea, vomiting, and pruritus, which often cannot be removed with conventional antihistamines. Another side effect that we concern the most is their respiratory depression effect.[2],[3] Oxycodone is a semisynthetic opioid that has pharmacokinetics similar to morphine but with minimal side effects. Administration of oxycodone can be done using various routes including oral, rectal, intravenous, or epidural. Intravenous oxycodone and morphine have been reported to have the same potency as postoperative analgesia.[4] The previous study stated that administration of oxycodone epidurally had greater efficacy than oral, rectal, or intravenous route.[5] Thus, the purpose of this review is to compare oxycodone with morphine as adjuvant in epidural analgesia and its side effects.

  Materials and Methods Top

We search for literatures that compare the analgetic effect of epidural morphine and epidural oxycodone in various surgeries. We only include the randomized controlled trial (RCT) and exclude studies that compared the analgetic effect of oxycodone and morphine through other routes (i.e., intravenous, intrathecal, orally, or rectally). The review process was based on the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement standards [Figure 1].
Figure 1: PRISMA flow diagram

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Various databases including the Cochrane Library, PubMed, and ClinicalTrials.gov were searched with the following terms: (((adult) ((epidural) AND (morphine) AND (oxycodone)) (pain) (pruritus))) conducted from January 1990 until February 2022 to identify potentially eligible studies. Any RCT reports epidural analgesia comparing oxycodone and morphine as adjuvant and its side effect. We searched adult human subjects with no restriction regarding country, age, race, gender, language, and publication year. Exclusion criteria are studies that duplicate or overlapping, unavailable full text/abstract only and review, conference paper, preceding, editorial, letter, books, systematic review, and non-RCT study. This search strategy was according to the recommendation by the Cochrane Collaboration. Disagreements within the selection of studies were discussed by the two authors or prosecuted by a third reviewer.

Two reviewers screened the literatures found based on the inclusion and exclusion criteria, independently. Each study title and abstract were reviewed. It was submitted to a third reviewer if there was conflict appraisal. The data extracted from the studies included characteristics of the included studies, such as author, region, publication year, sample size, primary and secondary outcomes, as well as baseline characteristics of the included patients. The methodological quality of the included RCTs was evaluated according to the RCT evaluation criteria recommended by the Cochrane Handbook 5.1.0. There are five main aspects to be assessed, including randomization, concealment, blinding, selective reporting, and other source biases. The third reviewer resolves methodological quality disagreements. The quality of RCT included in this study was assessed using the ROB-2 tool [Figure 2].
Figure 2: Risk of bias assessment tool

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  Results Top

After preliminary search, a total of 27 articles were obtained. Seven articles were duplicates. The remaining 20 articles were screened for title, abstract, and full text. A total of three eligible RCTs were found and included in this review. A total of 208 patients were included in this study, but only 197 patients were studied for epidural comparison, including 86 patients with epidural morphine and 111 patients with epidural oxycodone.

All three journals investigated post-operative pain. Backlund et al.[6] used a scale of 0 (no pain) to 3 (maximum pain) and evaluated the scale hourly up to 3 h after surgery and every 3 h until the end of study infusion on the ward. Yanagidate and Dohi[7] used VAS (visual analog scale) every 3 h for 6 h and the day after. Sng et al.[4] used the numerical rating scale every 2, 4, 8, 12, and 24 h after surgery. All three RCTs reported that pain score was significantly higher in the oxycodone group compared with the morphine group at the same dose. Two RCTs compared morphine with higher dose with oxycodone that resulted in similar analgesia properties.[2],[3] Rescue analgesic requirements were significantly higher when an equivalent dose of opioids was given. A study showed that if the oxycodone dose is increased to twice the equivalent morphine dose, it had equal analgesic effect without significant difference in rescue analgesic requirements [Table 1].
Table 1: Comparison of oxycodone with morphine as adjuvant regarding epidural analgesia and its undesirable effect.

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The incidence of nausea and vomiting was lower in the oxycodone group when compared with the morphine group when the dose given was 1:1 and 1:2 morphine-equivalent, but one RCT found that when given 1:10 the incidence of nausea and vomiting was equal. All studies reported that standard treatment was sufficient to alleviate nausea and vomiting. When given at the same dose or twice of morphine-equivalent dose, oxycodone produced less pruritus. However, all studies reported that standard treatment was satisfactory to ease the pruritus.

  Discussion Top

Epidural opioid had been approved by the United States Food and Drugs Administrations (FDA) since 1984 and was commonly used worldwide. Morphine is one of the most commonly used opioids in epidural routes for management of moderate or severe pain.[2] Administration of morphine through epidural routes will cause morphine to be distributed in cerebrospinal fluid (CSF), activating the mu-opioid receptors throughout the central nervous system (i.e., cerebellum, nucleus accumbens, caudate nucleus of the brain, putamen, cerebral cortex, substantia nigra, and spinal cord). After binding to the mu-opioid receptor, opioid activates the transduction pathway that decreases the adenylyl cyclase. Further, this will cause an increase in potassium efflux, decrease in calcium influx, and reduction of intracellular cAMP. Neurons will become hyperpolarized, and no neurotransmitters will be released from the neurons. Thus, the ascending pain pathway in neurons will be inhibited.[3],[8]

Oxycodone is a semisynthetic opioid agonist that is gaining its popularity for acute and chronic pain management. Like morphine, oxycodone is also a hydrophilic opioid. Oxycodone is reported to have physiochemical properties similar to those of morphine, with faster onset but shorter duration of analgesia than morphine. Oxycodone, fentanyl, and morphine were full agonists for antinociception and for respiratory depression; morphine and fentanyl are also full agonists but partial in oxycodone.[9] Similar to morphine, oxycodone also acts on mu-opioid receptor.[10],[11],[12] Oxycodone had low affinity to the kappa- and delta-opioid receptor, so it almost exclusively binds to the mu-opioid receptor. Activation of mu-opioid receptor in periaqueductal gray, rostral ventral medulla, and nucleus raphe magnus by oxycodone will also cause inhibition of pain transmission.[10] Studies reported that epidural route of oxycodone is highly effective for post-operative analgesia. Piirainen et al.[13] found that oxycodone at 0.1 mg/kg has better pain relief than lower rescue doses that support the superiority of epidural oxycodone compared with the intravenous route. After epidural administration, 60% of oxycodone is absorbed into CSF and 40% to systemic circulation, with CSF concentration 100–300-fold than intravenous administration.[14],[15]

When compared with the morphine, there were conflicting results regarding the efficacy of analgetic effects and side effects of oxycodone.[13],[16] The analgesic duration of oxycodone was 7–10 h after epidural administration. At 1:10 of morphine-to-oxycodone ratio, the analgesic effect was comparable. However, this is followed also by undesirable effect.[6] When given at the same dose, oxycodone has inferior analgesic effect.[4] Oxycodone has a potency lower than morphine in activating mu opioid receptors. This explains why oxycodone requires higher doses to produce the same analgesic effect as morphine.[10],[11] Two RCTs included in this review reported that pain scores were significantly higher in the epidural oxycodone group than in the epidural morphine group.[4],[7] Only RCTs conducted by Backlund et al.[6] reported that analgesic effects of the epidural oxycodone group and epidural morphine group were similar. However, Backlund et al. did not use the same dose where the oxycodone dose was 10-fold higher than the morphine dose (oxycodone 0.15 mg/kg vs. morphine 0.015 mg/kg). Other studies also report that oxycodone needs twice the dose of morphine to have comparable analgesic effect in various routes, but with fewer undesirable effects.[14],[15],[16],[17] Although oxycodone is comparable to morphine in rescue analgesic requirements in previous studies, this claim should be proven in future trials.

Pruritus, nausea, vomiting, urinary retention, and respiratory depression are some of the known side effects related to opioid use.[1],[2],[18],[19] Administration of opioid through epidural routes had lower incidence of hypotension and lower effect on heart rate than intravenous opioid. Lipophilic opioid (i.e., fentanyl) is absorbed rapidly in the epidural venous plexus and may cause immediate respiratory depression due to the rapid distribution to the brain and respiratory centers in brainstem. Both oxycodone and morphine are hydrophilic opioids that have slower rostral distribution and thus may cause delayed respiratory depression.[1],[2],[20] Nausea and vomiting occur due to interaction of opioids with the opioid receptor in the area postrema and chemotactic trigger zone of medulla oblongata. Meanwhile, the mechanism of pruritus in the administration of opioids is unclear. The symptoms of opioid-associated pruritus usually start in the trunk, nose, and around the eyes. The opioid-associated pruritus due to administration of lipophilic opioids usually had a rapid onset. In contrast, opioid-associated pruritus due to administration of hydrophilic opioids (including oxycodone and morphine) had a delayed onset, but had a longer duration and more resistant to antipruritic treatment. Several proposed theories regarding the opioid-associated pruritus are the activation of “itch center” in the central nervous system, increased activity of the dorsal horn, and wrong modulation of central serotonergic pathway in the central nervous system.[21],[22] Another theory is that pruritus is a result of central and peripheral sensitization.[21] Constipation may also found as side effects of opioid administration. Constipation may occur due to activation of mu-opioid receptor in myenteric plexus, which results in the reduction of gastric emptying and peristaltic movement.[8],[23] Opioids may also cause urinary retention by inhibiting the sympathetic nerves, thus resulting in the reduction of bladder fullness sensation.[24]

Oxycodone has side effects similar to those of usual opioids, with constipation, nausea, vomiting, pruritus, and drowsiness being the most common side effects reported in oxycodone use.[11],[25] None of the three RCTs included in this review reported the incidence of urinary retention. Only one RCT reported mild respiratory depression (respiratory rate <8 times/min) in both epidural morphine and epidural oxycodone groups. The two RCTs included in this study agreed that the incidence of nausea, vomiting, and pruritus was lower in the epidural oxycodone group than in the epidural morphine group with the same dose.[4],[7] However, Backlund et al.[6] reported that the incidence of nausea and vomiting was equal when oxycodone was given at higher dose. When given per intrathecal or epidural route, the side effects of opioid will be profoundly affected by their agent’s pharmacokinetic behavior. This might be an explanation from faster onset and lower side effects from oxycodone when compared with morphine.

  Conclusion Top

Epidural oxycodone has lower analgesic effects than morphine in the same dose. Higher doses of epidural oxycodone may provide similar analgesic effects with lower side effects on nausea and vomiting. However, there were limited trials comparing neuraxial oxycodone with morphine. With its potential benefit, future research needed to establish the benefit of neuraxial oxycodone in daily anesthesia practice.

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Conflicts of interest

There are no conflicts of interest.

  References Top

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Meng ZT, Cui F, Li XY, Wang DX. Epidural morphine improves postoperative analgesia in patients after total knee arthroplasty: A randomized controlled trial. PLoS One 2019;14:e0219116.  Back to cited text no. 3
Sng BL, Kwok SC, Mathur D, Ithnin F, Newton-Dunn C, Assam PN, et al. Comparison of epidural oxycodone and epidural morphine for post-caesarean section analgesia: A randomised controlled trial. Indian J Anaesth 2016;60:187-93.  Back to cited text no. 4
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Piirainen P, Kokki H, Anderson B, Hannam J, Hautajärvi H, Ranta VP, et al. Analgesic efficacy and pharmacokinetics of epidural oxycodone in pain management after gynaecological laparoscopy—A randomised, double blind, active control, double-dummy clinical comparison with intravenous administration. Br J Clin Pharmacol 2019;85:1798-807.  Back to cited text no. 13
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  [Table 1]


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