Single-shot epidural-spinal anesthesia followed by oral oxycodone/naloxone and ketoprofen combination in patients undergoing total hip replacement: analgesic efficacy and tolerability




Many patients undergoing hip replacement have inadequate postoperative pain control, leading to suboptimal recovery. Oxycodone is effective in controlling pain, but is associated with adverse events such as postoperative nausea and vomiting (PONV). In patients with chronic pain, oral oxycodone-naloxone combination (OXN) provides comparable analgesia with fewer side effects. This retrospective, single-centre study evaluated analgesic effectiveness and tolerability of single-shot epidural spinal anaesthesia followed by OXN after total hip replacement.


Consecutive patients received perioperative spinal-epidural anaesthesia, OXN 10/5 mg and oral ketoprofen 100 mg q 12h for 4 days. Efficacy and tolerability were assessed on the evening post surgery and days 1-3 after. Efficacy endpoints included pain intensity at rest and upon movement (Numerical Rating Scale [NRS] Score), rescue analgesia and patient satisfaction (0-3 point scale).


Two hundred eighty-two patients were included in the observation (57.2% women, mean age 62.9±12 years). After surgery, pain intensity remained well controlled, both at rest (mean NRS: 1.1, 1.1, 1.2 and 1.2 on days 0-3 respectively; P=ns) and upon movement (2.1, 2.4, 2.1 and 2.0; P=ns). No patient reported severe pain throughout the observation. Rescue paracetamol was required on days 0–3 in 17.0%, 18.4%, 12.4% and 12.1% of patients, respectively (P<0.009); no patient required additional intravenous rescue morphine. Seventy-two percent of patients were ‘very satisfied’ with postoperative pain therapy.


Single-shot epidural spinal anaesthesia followed by OXN-based analgesia after hip replacement provided effective pain management, with high patient satisfaction rates. (Minerva Anestesiol 2015;81:19-27)

Key words

Oxycodone naloxone combination – Pain management – Postoperative nausea and vomiting – Arthroplasty, replacement, hip.

Acute postoperative pain experienced after hip replacement (HR) surgery is a mixture of nociceptive and neuropathic pain.1-3 Treatment guidelines advocate effective pain control to optimize recovery and regain mobility after total HR.3-5 Current therapy includes epidural and spinal analgesia, periarticular infiltration and/or oral analgesics.1 Despite effective analgesics, many patients do not achieve adequate pain control due to adverse effects of medication, or comorbid disease common in the typically elderly patients undergoing total hip replacement.3, 6, 7 Undertreated acute postoperative pain slows recovery, as it prevents initiation of physical therapy and limits mobility, and can become chronic leading to considerable long-term disability and reduced quality of life.8-12

Spinal or epidural local neuroaxial blockade, a widely used anesthetic technique for hip surgery, provides superior pain relief, faster mobilization, and reduced risk of deep vein thrombosis and other complications compared with general anaesthesia and standard postoperative intravenous (IV) patient-controlled analgesia; it has been shown to reduce morbidity and mortality in patients undergoing major orthopedic surgery on the lower extremities.13, 14 The regional combined spinal and epidural anaesthesia offers the advantage of a rapid onset of a predictable block, and a more rapid termination of the anesthesia.15

Oxycodone is an established WHO step II/III opioid pain medication (depending on dose used)16 commonly used for the management of moderate-to-severe postoperative pain in multimodal protocols.17, 18 Oral controlled-release oxycodone has been shown to be effective in the control of postoperative pain following knee and hip arthroplasty, with potential hospital cost savings and reduced use of healthcare resources.19, 20 Although very effective, oxycodone is associated with a range of adverse events such as postoperative nausea and vomiting (PONV), itching and constipation.21-24 Good gastrointestinal tolerability of analgesics is important after surgery, since other factors such as postoperative ileus, surgical stress, in addition to opioid effects, can impair bowel function, leading to delayed recovery.25, 26

In order to optimize the management of severe pain, an oral prolonged-release combination of oxycodone and naloxone is now available (OXN; Targin®, Mundipharma). Randomized, controlled trials and postmarketing studies show that OXN offers effective analgesia while improving opioid-induced bowel dysfunction.27-32 Favourable results have been also reported in patients with moderate-to-severe acute postoperative pain.33, 34

After its introduction in the Italian pharmaceutical market in spring 2011, OXN gradually replaced oxycodone in our postoperative analgesic regimen given the more favourable tolerability profile, and eventually has been adopted as the oral opioid of choice in the management of postoperative pain in patients undergoing total HR in our Hip Surgery Unit since Autumn 2011.

The aim of this retrospective study was to evaluate the analgesic effectiveness and tolerability of single-shot epidural-spinal anaesthesia followed by an oral analgesic combination of OXN and low-dose traditional NSAIDs in consecutive patients undergoing total HR surgery.

Materials and methods

Study design

This retrospective analysis of data from patients treated for postoperative pain for 4-days at a single centre, was performed in consecutive patients undergoing total HR from January 2012 to December 2012 at the Istituto Clinico Humanitas, Milan, Italy. Ethical approval for this retrospective study was obtained from the local Research Ethics Committee (number: 0806/2013) and the study was performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. All patients gave written consent for collection of their demographic and clinical data, which were anonymized before analysis.

All patients included in this retrospective analysis, had non-inflammatory hip osteoarthritis and underwent total HR with combined spinal-epidural anesthesia. Patients were not included if they had cognitive dysfunction not allowing appropriate pain assessment; any contraindication to epidural anaesthesia and/or a known allergy to local anesthetic drugs, morphine, oxycodone, ketoprofen and paracetamol; chronic constipation (less than three spontaneous bowel movements in a week despite the regular use of two or more laxatives); Crohn’s disease, ulcerative colitis or history of active gastrointestinal bleeding.


Perioperative interventions

All patients received saline infusion from 30 minutes prior to induction of anesthesia through to the end of surgery, and were kept normothermic during the surgical procedure. All patients were sedated with 0.02 mg/kg midazolam. Spinal-epidural anesthesia was performed by senior anesthetists at the L3-L4 level with a single puncture and predefined anesthetic doses (spinal: levobupivacaine hydrochloride 0.25% concentration, 6-7 mg; epidural: levobupivacaine hydrochloride 7.5% concentration, 70-75 mg, plus morphine 2 mg and atropine 0.15 mg). Surgery commenced after spinal anesthesia was deemed to be optimal. All patients were monitored during the intraoperative and immediate postoperative periods. No additional epidural or IV analgesics were administered in the recovery room, and all patients then received standard postoperative care and were discharged from the recovery room back to the general orthopedic ward according to standard practice in our hospital. Surgery was performed by a senior surgeon in all patients with the same HR technique.

Postoperative interventions

All patients received oral ketoprofen 100 mg plus ranitidine 50 mg on the evening of operation and, then, every 12 hours for the next four days. The morning after surgery, all patients also started oral OXN 10/5 mg every 12 hours (8 am and 8 pm daily) for the 4 days after surgery. If pain exceeded a Numerical Rating Scale (NRS) Score of 3, postoperative rescue analgesia included paracetamol as the first step (1 g by IV infusion over 15 minutes, up to three times a day). If pain >5 persisted after IV rescue paracetamol, IV morphine (1.25 mg/h) with elastomeric pump was started. Conversely, if pain NRS score 4-5 persisted after IV rescue paracetamol, IV paracetamol was repeated after 6 hours.

Other postoperative therapy included metoclopramide 10 mg IV (or ondansetron 8 mg IV in patients with a history of metoclopramide intolerance) for treatment of PONV. Oral rivaroxaban 10 mg was given as postoperative prophylaxis for deep vein thrombosis, starting the evening after surgery.

Assessments and endpoints

Patients’ demographic, clinical information and all endpoints were collected by trained personnel and recorded on a dedicated data form as standard practice, and were therefore easily available for this retrospective analysis.

Serial data on symptoms, side effects and their severity were collected by trained staff nurses on pre-defined dedicated forms. Postoperative clinical assessments started in the evening after surgery (day 0, 2 hours after the first administration of ketoprofen): then, pain was assessed three times daily (days 1-3 after surgery) before the administration of oral analgesics. Information on current pain intensity at rest and after movement was collected, and average daily pain intensity ‑ at rest and on movement – was computed and analyzed.

The efficacy endpoints were the pain intensity at rest and on movement, according to NRS score (Rest and Dynamic NRS), in which a score of 0 = no pain and 10 = worst imaginable pain, measured every 8 h on days 1, 2 and 3. When it exceeded a score of 3, rescue paracetamol was administered; then, if it exceeded a score of 5, IV morphine was started. Rest and dynamic NRS Score values were expressed as mean of each single day assessment for the three daily scores. The opioid dose and the proportion of patients requiring rescue analgesia and dose were also recorded.

Before discharge, patients were also asked to rate their satisfaction with postoperative pain management on a scale ranging from 0 (not satisfied at all) to 3 (very satisfied).

Tolerability endpoints included the presence of spontaneous bowel movements; the presence and intensity (absent [0]; mild and untreated [1]; moderate and requiring treatment [2]; severe and persistent despite treatment [3]) of the following adverse events (AEs) at day 1, 2 and 3: PONV, itching, tingling, abdominal pain, sedation, and dizziness or postural hypotension on mobilization. PONV was assessed using a 0-3-point scale: absent (0); mild and untreated (1); moderate and requiring treatment (2); and severe and persistent despite treatment (3).

Statistical analysis

Recorded data were used to produce descriptive statistics; in the event of early discontinuation or missing values, the last observation carried forward was used to impute missing data. Normal data distributions of continuous variables were assessed by the Shapiro-Wilk test. The significance of differences in continuous variables over time were evaluated by the analysis of variance (ANOVA test), or by Kruskal-Wallis analysis, as appropriate. The Cochran Q test was used to measure changes in frequencies of categorical variables across time. A P-value<0.05 was considered statistically significant (STATISTICA software, version 8.0, StatSoft® Inc., Tulsa, OK, US).

Table I. Patient characteristics and perioperative data
Age, years (mean ±SD)62.9 ± 12
Women, n (%)161 (57.2)
Height, cm (mean ±SD)167 ± 4.7
Weight, kg (mean ±SD)78± 14.6
ASA I34 (15)
ASA II151 (53.5)
ASA III89 (31.5)
Duration of surgery, min (mean ±SD)45.0 ± 6.7
SD: Standard Deviation; ASA, American Society of Anesthesiology patient classification status: ASA I –normal healthy; ASA II – mild sys temic disease; III – severe systemic disease.


Baseline demographics and clinical characteristics

Patient demographics and clinical characteristics at day 0 are shown in Table I.


Figure 1. Mean daily Numerical Rating Scale (NRS) pain scores at rest (continuous line) and on movement (dotted line) the evening after operation (day 0) and in the 3 days after surgery (inter-day variations: P=NS).


Data from 282 consecutive patients (57.2% women) aged 18-80 years (mean age 62.9±12 years) and weighing 50-98 kg, were analyzed. All patients had non-inflammatory hip disease including one 18-year-old patient with Behcet’s disease and severe coxofemoral joint disease.

All patients had successful perioperative anesthesia and had no pain on arrival in the recovery room. Hemodynamic parameters remained stable and blood losses were within the usual values throughout the 4 days of treatment. All but one patient underwent successful early rehabilitation. All patients completed the 4-day treatment observation and all analgesic doses as per protocol. No analgesics were administered before surgery as per protocol. For all the considered variables, we had no missing data.


The daily mean pain intensity remained constant and was of only mild severity throughout the 4 days of post-operative observation, both at rest and on movement (inter-day variations, P=NS) (Figure 1). Throughout the 4 days, no patient reported pain of severe intensity (NRS Scores >6), either at rest or upon movement. There were 5 patients (1.8%) complaining of pain at rest NRS score-4 on the day of operation, and 4 (1.4%), 1 (0.4%) and 1 (0.4%) on days 1, 2 and 3, respectively; in the remaining patients, postoperative pain at rest was always controlled to NRS≤3. The proportions of patients without, or with pain upon movement of mild (NRS scores 1-3) or moderate (NRS scores 4-6) intensity during the study are shown in Figure 2. The proportions of patients requiring rescue analgesia throughout the 4-day observation are reported in Figure 3: the need for rescue analgesia dropped significantly from day 0 to day 3 (Cochran Q test for change in the proportion of patients needing rescue analgesia over the 4 days of observation =11.5; P<0.009) (Figure 3).

Over the 4 days, among patients complaining of pain NRS Score>3 and requiring rescue analgesia, paracetamol 1000 mg IV was effective in controlling pain severity, and no patient required additional IV morphine for pain control. There were 203 (72%) patients who rated their satisfaction with postoperative pain therapy as “very satisfied”; 66 (22%) patients rated it “enough”, and 11 (6%) “insufficient”. There were no patients who were “not satisfied at all”.


Figure 2. Percentages of patients without (NRS=0) or with pain upon movement of mild (NRS=1-3) or moderate intensity (NRS=4-6) the evening after operation (day 0) and in the 3 days after surgery (no patient reported pain of NRS>6).



AEs reported during the observation are shown in Table II: all but PONV were mild (i.e. not requiring specific treatment), and the most frequently reported events were pruritus (itching), and gastric/abdominal pain. The numbers and proportion of patients reporting PONV are also shown in Table II: the incidence of severe PONV gradually decreased over the 4 days of postoperative evaluation (Cochran Q test for changes in frequencies from day 0 to day 3=133.1; P<0.0001): 56 patients (19.9%) complained of mild nausea and did not receive any treatment, and severe nausea/vomiting was reported by 9.9%, 4.4%, 1.1% and 1.1% of patients on days 0-3, respectively. There were no other severe AEs reported throughout the treatment.

Daily spontaneous bowel movements were reported by 102 (36.2%) patients at day 0, and by 109 (38.7%), 174 (73.0%), and 192 (68.1%) at days 1-3 postsurgery, respectively (Cochran Q test for change in frequencies from day 0 to day 3=176.2; P<0.0001).


Figure 3.Percentages of patients (%) using rescue analgesia (paracetamol 1000 mg IV) on the evening after the operation (day 0) and in the 3 days after surgery (change in the proportion of patients needing rescue analgesia statistically significant using Cochran Q test; P<0.009).


Table II. Adverse events reported during the study
 Patients, n (%)P value
Day 0Day 1Day 2Day 3
Sedation2 (0.7)000NS
Pruritus34 (12.0)53 (18.8)6 (2.1)10 (3.5)0.01
Gastric and/or abdominal pain26 (9.2)45 (15.9)10 (3.6)5 (1.8)<0.01
Vertigo1 (0.4)000NS
Dizziness012 (4.2)25 (8.9)1 (0.4)NS
PONV Mild Moderate Severe    <0.0001
56 (19.9)48 (17)15 (5.3)4 (1.5)
1 (0.4)1 (0.4)1 (0.4)0
28 (9.9)12 (4.2)3 (1.1)3 (1.1)
PONV: postoperative nausea and vomiting; Day 0, 1, 2 and 3: postoperative days 0–3 (day 0: the evening of the day of surgery); all adverse events but PONV were of mild intensity not requiring specific treatment; P value: at Cochran Q test; NS: not significant.


Regional combined spinal and epidural anesthesia blends the benefits of both spinal anesthesia and epidural anesthesia and analgesia, and is suitable whenever a rapid onset of analgesia is required but the period of analgesia required should exceed that of a single spinal injection.15 With this technique, the onset of analgesia in labouring women is quicker compared with epidural analgesia.15 The reduced dose of local anesthetic allows patients to stand up and walk only a few hours after surgery, thus shortening the postoperative stay; early mobilization enhances recovery.35

In our retrospective study, single-shot epidural-spinal anesthesia followed by a round-the-clock oral regimen of low-dose OXN (10/5 mg twice daily) in conjunction with standard dose NSAIDs, effectively controlled postoperative pain both at rest and on movement over the 4 days after total HR, with limited consumption of rescue analgesia. The opioid dose remained constant over the 4 days of postoperative treatment (OXN 10/5 mg twice daily), and the treatment was well tolerated with a low incidence of moderate-to-severe side effects in the first 36 hours after surgery, mainly PONV, and no unexpected effects throughout the 4 days’ OXN treatment. Of note, none of our patients required morphine as a further rescue analgesic in the postoperative period, and a single dose of paracetamol 1000 mg IV was sufficient as rescue analgesic even in subjects complaining of more intense pain (NRS>5). In a randomized study comparing oral OXN or patient-controlled IV morphine (PCA) for the management of pain early after cardiac surgery, OXN provided comparable analgesia to PCA, while reducing overall opioid dose, suggesting that postoperative pain, even after very painful procedures, can be managed with this new oral opioid agonist-antagonist combination.34

Our efficacy findings support those reported in previous studies of oxycodone in patients with acute postoperative pain, and specifically after HR.19,20,36 In our study, the proportion of patients requiring rescue analgesia was low and dropped significantly over the 4 days of treatment despite the increasing intensity of the rehabilitation program. This is similar to that reported in previous studies in which oral oxycodone has provided similar or greater pain relief compared with standard therapy with shorter hospital stays and reduced rescue analgesia in patients undergoing knee replacement and HR surgery.19,20 The OXN dose used is that recommended in the Targin® SmPC and other authors have reported using similar dosages of OXN 17, 37 or oxycodone 20 for post-operative pain management. These findings also corroborate preliminary findings demonstrating gastrointestinal tolerability of OXN in patients undergoing orthopaedic surgery.33

The advantages of a favourable tolerability are particularly valuable in older and more vulnerable patients who may be receiving other medications, are prone to the adverse gastrointestinal effects of immobility and surgery, and more likely to be affected by the negative impacts of gastrointestinal dysfunction on recovery.38 A simple regimen in which there is neither infusion therapy nor requirement to titrate analgesic dose to achieve pain intensity NRS<3, is very advantageous in this population. In clinical practice, the oral fixed-dose twice-daily OXN regimen, with its benign adverse event profile, is likely to result in greater adherence to therapy and better outcomes.

Few data are available regarding efficacy and tolerability of OXN in the postoperative state: a retrospective study demonstrated similar efficacy and better control of opioid-related side effects with OXN compared with oxycodone alone;33 a randomized trial in 85 women undergoing laparoscopic hysterectomy showed similar analgesic efficacy of OXN versus oxycodone alone for short-term postoperative pain management.37

All our patients had their resting postoperative pain controlled to NRS≤3 with OXN combination therapy, indicating mild-to-no pain from the early postoperative hours and maintained up to day 3 post surgery. Of relevance, pain upon movement was also controlled to NRS≤3 in more than three-quarter of subjects 3 throughout the 4 days of treatment. The rationale for the use of the NSAID ketoprofen as adjunct for the control of acute postoperative pain in this study was based on robust clinical evidence of its efficacy and tolerability in this setting. Ketoprofen provides effective pain relief and reduces the consumption of opioid pain medication in patients undergoing hip or knee arthroplasty.39 The ease of twice daily administration of oral ketoprofen and OXN early in the postoperative period could make this multimodal approach a viable alternative to epidural analgesia for postoperative pain relief after hip replacement. Although regional analgesia reduces postoperative pain and PONV, it requires a higher level of staff intervention for catheter monitoring, does not facilitate rehabilitation and has no effect on length of stay after total HR.40 Oral pain regimens for postoperative pain management result in fewer complications and have higher patient satisfaction; in addition, the absence of epidural and patient-controlled analgesia pump technology reduces opportunities for medication errors.41,42 The advantages of an oral postoperative analgesia strategy are particularly relevant in the current era of new effective anticoagulant agents and limited human resources.

In this study, the incidence of PONV was not insignificant, although the majority of events were not severe and occurred during the first hours after surgery. Nevertheless, the possibility that reducing the epidural morphine dose (2 mg in our original protocol) could attenuate PONV. Given the effectiveness of the analgesic protocol in controlling pain at rest and on movement in the current study, lower epidural dosages of morphine could be considered.

Study limitations that may limit the strength and reproducibility of our findings include lack of a control group and adjustment for baseline differences among the cohort, the single-centre nature of the study and its retrospective design. However, observational “real-life” studies serve an important purpose in clinical research43 and the large cohort investigated and its baseline characteristics may provide a more accurate reflection of outcomes achieved in clinical practice. In the assessment of pain intensity – NRS upon movement – the amount and type of movement were not standardized, and patients may have reported less pain due to the different physiokinetic and rehabilitation protocols used. In addition, the assessment of gastrointestinal effects of OXN in our patients was rather empiric; more appropriate scales to assess opioid-induced bowel dysfunction have been recently suggested.44


In patients undergoing total hip replacement, combined epidural-spinal anesthesia followed by a simple fixed-dose, prolonged-release OXN-based analgesic regimen, provided effective control of pain. The regimen was well tolerated with a small number of mainly mild-to-moderate AEs and a low rate of moderate and severe PONV. Patient satisfaction was high and, in addition to excellent pain control, the occurrence of typical complications often reported with opioid therapy was low, suggesting that oxycodone/naloxone therapy is a valid option for the treatment of acute postoperative pain in the orthopedic setting. Additional studies are warranted to establish the value of this oral analgesic combination for postoperative pain relief after hip replacement.


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