Naloxone on Outcomes Affecting Patients' Daily Functioning in Comparison With Extended-release Tapentadol: A Systematic Review

Clinical Therapeutics/Volume 37, Number 1, 2015

Impact of Prolonged-release Oxycodone/Naloxone on Outcomes Affecting Patients' Daily Functioning in Comparison With Extended-release Tapentadol: A Systematic Review Deepika Thakur, MPharm1; Sara Dickerson, BSc2; Mohit Kumar Bhutani, MPharm1; and Rod Junor, PhD2 1

HERON Commercialization, PAREXEL Consulting, Chandigarh, India; and 2Napp Pharmaceuticals Ltd, Cambridge, United Kingdom

ABSTRACT Purpose: The objective of this systematic review was to assess the clinical efficacy, safety, tolerability, and health-related quality of life outcomes associated with management of moderate-to-severe chronic pain with oxycodone/naloxone and tapentadol, focusing on the effect of these treatments on patients’ daily functioning. Methods: Literature from a wide range of sources, including Embase, MEDLINE, MEDLINE In-Process, and the Cochrane Central Register of Controlled Trials, was searched to identify randomized controlled trials investigating tapentadol or oxycodone/naloxone for the treatment of patients with chronic pain. A network metaanalysis was conducted to determine the relative efficacy and safety profiles of these treatments. Findings: Oxycodone/naloxone was significantly better than tapentadol with respect to the Patient Assessment of Constipation Symptoms total score (risk ratio ¼ –3.60; 95% credible interval, 5.36 to 2.11) and revealed a significantly lower risk of dizziness (risk ratio ¼ 0.72; 95% credible interval, 0.42–0.98). Oxycodone/naloxone was directionally favored, although not significantly superior to tapentadol for headache, fatigue, dry mouth, dyspepsia, and withdrawals due to lack of efficacy. For the AE outcomes of constipation, nausea, and vomiting, as well as pain efficacy and all-cause withdrawals from studies, tapentadol was directionally favored without any statistical difference from oxycodone/naloxone. However, the two treatments were not wholly comparable for the evaluation of pain efficacy because of differences in on-study rescue medication and a higher baseline pain severity in the tapentadol studies. Implications: Oxycodone/naloxone offers significant improvements in Patient Assessment of

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Constipation Symptoms total score and dizziness and was directionally favored for fatigue and headache compared with extended-release tapentadol, which may translate to improved patient daily functioning and health-related quality of life. (Clin Ther. 2015;37:212–224) & 2015 The Authors. Published by Elsevier HS Journals, Inc. Key words: chronic pain, constipation, dizziness, oxycodone/naloxone, tapentadol.

INTRODUCTION Chronic pain is associated with a wide range of conditions, including cancer, neuropathic pain, osteoarthritis, and other musculoskeletal disorders, and represents a considerable burden on patients and health care systems. Prevalence of moderate-to-severe chronic pain is high, and in a large-scale computerassisted telephone survey of 46,394 adults in the general population across Europe and Israel, 19% of respondents reported having moderate-to-severe chronic pain.1 Health care costs associated with chronic pain are significant; therefore, the overall management of chronic pain represents a substantial burden to health care systems. In the United States, chronic pain was estimated to affect approximately 100 million people in 2008 and was associated with an annual national cost of between $560 billion and $635 billion.2,3 Studies conducted in Europe also report a considerable economic burden due to chronic Accepted for publication December 3, 2014. http://dx.doi.org/10.1016/j.clinthera.2014.12.001 0149-2918/$ - see front matter & 2015 The Authors. Published by Elsevier HS Journals, Inc. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).

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D. Thakur et al. pain, as indicated by a retrospective study from the United Kingdom in which patients with chronic lower back pain reported costs more than double those incurred by matched controls without chronic lower back pain (£1074 vs £516, Po0.05).4 Taken together, patients with chronic pain in the United Kingdom were reported to account for 4.6 million medical appointments per year in 2002, which incurred an overall annual cost of £69 million to the National Healthcare System.5 The biopsychosocial model of chronic pain is widely accepted and considers the social and psychological effects of a condition in addition to a purely biological perspective. Indeed, chronic pain may involve a complex combination of physical dysfunction with the beliefs, coping strategies, illness behaviors, and social interactions of the patient. Therefore, treatment of chronic pain is often multidisciplinary and multimodal, with the aim of maximizing pain relief and increasing patient motility, independence, and quality of life (QoL). Pharmacotherapy, including opioids, forms an important part of this multimodal approach. US guidelines for chronic pain from the Institute for Clinical Systems Improvement from 2013 recommend opioids for the treatment of patients with persistent moderate-to-severe pain in individuals whose pain is not responsive to initial therapies, as part of an overall pain management program, and when there is a favorable risk-benefit profile of prescribing opioids.6 This recommendation was in accordance with the World Health Organization 3-step ladder treatment paradigm (developed specifically for treatment of chronic pain in patients with cancer), which recommends administering aspirin, acetaminophen, and nonsteroidal anti-inflammatory drugs for mild pain, then escalating treatment to weak opioids (such as codeine or dihydrocodeine) and finally to stronger opioids (such as oxycodone, morphine, or hydromorphone) as necessary with increasing pain severity. As a result, opioids are the main treatment option for patients with moderate-to-severe pain, and a number of strong opioids are clinically available; for example, morphine, oxycodone, tapentadol (where available), hydromorphone, fentanyl, and buprenorphine are all widely used. One key drawback of opioid treatment is the adverse effect (AE) profile, including headache, dizziness, and fatigue, which can affect daily functioning and patient QoL.7–9 Another frequent AE of opioid treatment is opioid-induced

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bowel dysfunction (OIBD), an umbrella term used to describe the gastrointestinal AEs of opioids, including constipation, hard dry stools, bloating and abdominal distension, and abdominal cramps and spasms.10 In a multinational, Internet-based study of 322 patients taking daily opioids (PROBE 1), constipation was reported as the most common AE in 81% of patients, and it was considered to be the AE that was most bothersome and most often reported as severe, despite the use of laxatives in all patients. Because laxatives do not target the cause of OIBD, they have limited efficacy in this setting.11 In a survey of OIBD by Pappagallo12 and Kumar et al,13 more than half (54%) of patients treated with laxatives did not achieve the desired symptomatic improvement at least 50% of the time. The AEs experienced by patients treated with opioids, such as constipation, may lead to dose reduction (which can affect the effectiveness of their pain relief), reduced patient adherence, or treatment discontinuation to switch to a different opioid. Therefore, a need exists for opioid treatments that offer improved tolerability with fewer AEs. Oxycodone is an opioid receptor agonist commonly used for the treatment of patients with moderate-tosevere pain. As with other opioids, when used as a monotherapy, oxycodone stimulates opioid receptors in the gastrointestinal tract, disrupting normal bowel activity and reducing gut motility, resulting in constipation.14 Naloxone is an opioid antagonist that binds to opioid receptors in the gut with a higher affinity than oxycodone, thereby outcompeting oxycodone and acting directly to prevent AEs, such as constipation and bowel dysfunction, caused by binding of oxycodone at these receptors.15 Because of the extensive first-pass metabolism of naloxone in the liver, o3% of the naloxone dose reaches the systemic circulation and therefore does not interfere with the analgesic efficacy of oxycodone. Studies of oxycodone/naloxone (2:1) have found comparable analgesic efficacy compared with oxycodone alone.16 The oxycodone/naloxone combination therefore combines effective analgesia with improvements in opioid-induced bowel AEs, such as constipation.15,17 Prolonged-release (PR) oxycodone* can be given in a fixed-dose combination with naloxone at a ratio of 2:1.15

Trademark: Targinacts, Targins, or Targiniqs (Napp Pharmaceuticals Ltd, Cambridge, United Kingdom).

*

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Clinical Therapeutics The efficacy of oxycodone/naloxone as an analgesic with improved gastrointestinal tolerability was revealed in a number of clinical studies, including randomized controlled trials (RCTs), an open-label extension study, and an observational study.16,18–21 A randomized, double-blind, placebo- and active-controlled study by Vondrackova et al16 revealed the efficacy of oxycodone/ naloxone as an analgesic, reporting a significantly longer time to recurrence of pain events in this treatment group compared with placebo (Po0.0003). Furthermore, significant and clinically relevant improvements in Bowel Function Index scores were found in patients treated with oxycodone/naloxone compared with oxycodone in a study by Simpson et al.18 This was further supported by significant improvements in patient-reported measures of constipation, such as the stool and rectal subscales of the Patient Assessment of Constipation Symptoms (PAC-SYM) instrument (Po0.0001) compared with oxycodone alone.18 A study by Lowenstein et al19 reported rapid and significant improvement in bowel function in patients treated with oxycodone/naloxone compared with PR oxycodone after 4 weeks of treatment (the end of the study period), and improvements were seen after only 1 week. In an observational study of 588 patients, treatment with oxycodone/naloxone led to statistically significant improvements in both bowel function and QoL compared with patients treated with other strong opioids (Po0.0001 for both outcomes).20 The benefits of treatment with oxycodone/naloxone were found during a longer period in a 1-year open-label extension study, with a mean (SD) Bowel Function Index score that decreased from 35.6 (27.74) at the start of the extension study to a normal level (Bowel Function Index score r28.8) of 20.6 (24.01) after 1 year.21,22 Another prescribed opioid analgesic for chronic pain is tapentadol†, although it has only recently become available for use in the treatment of chronic pain after receiving European Medicines Agency and Food and Drug Administration approval for use in this indication in 2011 and is not yet available in every country. Tapentadol acts both as a μ-opioid receptor agonist and as a noradrenaline reuptake inhibitor to relieve pain.23 The efficacy of tapentadol has been found in preclinical models of nociceptive, neuropathic, visceral,

and inflammatory pain and in clinical trials on patients with nociceptive conditions, including postoperative orthopedic and abdominal pain and chronic pain due to osteoarthritis of the hip or knee.23 During these studies, tapentadol was found to offer comparable efficacy to other strong opioids.23 There are no published head-to-head RCT data comparing tapentadol with oxycodone/naloxone in patients with chronic pain. Therefore, the objective of this systematic review was to assess the clinical efficacy, safety, tolerability, and health-related QoL (HRQoL) outcomes associated with management of moderate-to-severe chronic pain with oxycodone/ naloxone and tapentadol, focusing on the effect of these treatments on patients’ daily functioning. In this systematic review, the safety profiles of the 2 treatments were investigated by network meta-analysis (NMA) to better inform clinicians on the relative risks and benefits of the 2 treatments and allow decisions on patient care to be made accordingly.

PATIENTS AND METHODS Literature Search A comprehensive search strategy was designed to retrieve evidence for comparison of oxycodone/naloxone with tapentadol in patients with chronic pain. The review was based on a search of Embase, MEDLINE, MEDLINE In-Process, and the Cochrane Central Register of Controlled Trials (Table). In addition to the database search, abstracts from conference proceedings were searched, including the International Association for the Study of Pain: World Congress on Pain and the American Academy of Pain Management. All databases were searched for literature published between January 2005 and October 2013 and for abstracts and posters published in the past 2 years. Bibliographic searching of included trials and pertinent systematic reviews was also performed in addition to registry searches; these registries included the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects, European Public Assessment Reports, and evidence-based reports from the Agency for Healthcare Research and Quality.

Selection of Studies †

s

Trademark: Nucyncta (Janssen Pharmaceuticals Inc, Titusville, NJ) and Palexias (Grünenthal Ltd, Uxbridge, United Kingdom).

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To be included in this review, studies had to meet predefined eligibility criteria. RCT evidence was the focus of the review and formed the basis of these

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D. Thakur et al.

Table. Data sources used to retrieve the evidence. Type

Source

Site

Databases (2005 to October 2013)

MEDLINE http://www.embase.com/ Embase MEDLINE In-Process (PubMed in-process http://www.ncbi.nlm.nih.gov/sites/entrez citations) Cochrane Central Register of Controlled http://mrw.interscience.wiley.com/ Trials (Cochrane Library) cochrane/cochrane_search_fs.html Conferences (2012 to IASP: World Congress on Pain (2012) 2013) American Academy of Pain Management (2012–2013) Additional sources Bibliographic searching of pertinent SRs Cochrane Database of Systematic Reviews Database of Abstracts of Reviews of Effects Registry search European public assessment reports Evidence-based reports in AHRQ AHRQ ¼ Agency for Healthcare Research and Quality; IASP ¼ International Association for the Study of Pain; SR ¼ systematic review.

analyses because evidence from RCTs represents the gold standard of clinical evidence. Only articles published in English were included. The patient population of interest in this review comprised adult patients of any race or sex with moderate-to-severe chronic cancer and noncancer pain. To be included, studies had to evaluate either oxycodone/naloxone or tapentadol extended release (ER) for the treatment of chronic pain; any included interventions in these studies were considered suitable comparators, such as oxycodone controlled release (CR) and placebo. Patients receiving placebo may have received symptomatic treatment for breakthrough pain; however, the placebo arm was not a true placebo. Studies investigating immediate-release (IR) formulations were excluded from this review, and only studies evaluating licensed doses of tapentadol ER and oxycodone CR were included in the analysis. Bibliographic details and abstracts of all citations detected by the literature search were extracted and duplicates of citations due to overlap in coverage of databases were excluded.

Validity Assessment All abstracts identified during searches were reviewed, and those that did not fulfill the eligibility criteria were excluded. Full-text copies of all

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references that fulfilled the criteria or for which it was not possible to include or exclude citations based on the abstract were reviewed, and the eligibility criteria were reapplied. Data were extracted from all studies that met the eligibility criteria. Review and data extraction for all citations were performed independently by 2 reviewers, and any disagreements were resolved by a third independent reviewer. Where more than one publication was identified describing a single trial, the data were compiled into a single entry in the data extraction table to avoid double counting of patients, and each publication was referenced to be easily recognizable when more than one publication contributed to the entry. All included RCTs were assessed for quality of evidence by means of a study grade and Jadad score.24 The risk of bias among included RCTs was evaluated using the German, French, and English health technology assessment checklists.25–27

Statistical Analysis For analysis of each outcome, studies were assessed for baseline comparability to rule out the effect of clinical heterogeneity. No study was excluded based on differences in the baseline characteristics from the overall studies included in the analyses. Studies with

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Clinical Therapeutics an enriched or seeded trial design were initially not included in analyses; in such trials, patients received active treatment during the open-label titration phase, after which patients experiencing AEs were excluded, and only responders were randomized to receive further treatment. Sensitivity analyses were conducted to explore the effect of including the studies with enriched randomized withdrawal design into the NMA. Bayesian NMA (mixed-treatment comparison), whereby treatments can be compared in the absence of head-to-head trials via a common comparator, was performed if the network consisted of at least one closed loop, for which direct and indirect evidence was available for comparison. The NMA was conducted using WINBUGS software that accommodates evidence from multiarm trials and calculates estimates using Markov Chain Monte Carlo methods. Point estimates and 95% credible intervals (CrIs; conceptually similar to CIs used in the frequentist approach)

RESULTS Search Results and Patient Characteristics

Outputs of the literature search were filtered as illustrated in Figure 1, with only 15 of the 741 citations initially yielded meeting all the criteria for inclusion after detailed review of the abstracts and full-text articles. Of the 15 included RCTs, 8 evaluated the efficacy and tolerability of tapentadol,28–35 and 7 investigated the efficacy and tolerability of oxycodone/naloxone.16,18,36–39 Most trials were in Phase III (11 trials), 2 trials were in Phase II,30,37 and 1 trial was in Phase IV.39 The phase of one trial was unclear.36 Among the 15 included studies, 2 studies used an enriched or seeded trial design.30,31

Identification

Records identified through database searching (N=741): Embase (n=639) Cochrane (n=59) MEDLINE In-Process (n=43)

Records excluded (n=526) Non-English (n=19) Review/editorial (n=316) Disease (n=36) Study design (n=24) Children only (n=3) Animal/in vitro (n=40) Intervention not of interest (n=37) Review objective (n=51)

Records after duplicates removed (n=669)

Screening Eligibility

were used to summarize the findings. Calculations for each analysis were based on using 70,000 iterations, discarding the first 10,000 iterations.

Records screened (n=669)

Full-text studies screened (n=143)

Full-text articles excluded (n=58) Copy/duplicate (n=1) Pooled study (n=16) Review/editorial (n=23) Disease (n=1) Intervention not of interest (n=10) Review objective (n=4) Outcomes not extractable (n=1) No SGA for disease (n=1) Full text not retrieved (n=1)

Conference abstracts (n=7) Bibliographic searching (n=35)

Included

Studies included (n=39 studies from 127 publications)

RCTs (n=15 studies)

n-RCTs (n=24 studies)

Comparative studies (n=3 studies)

Single-arm studies (n=21 studies)

Figure 1. Trial flow for the systematic review comparing tapentadol with oxycodone/naloxone for the treatment of chronic pain. n-RCT ¼ nonrandomized controlled trial; RCT ¼ randomized controlled trial; SGA ¼ subgroup analysis.

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D. Thakur et al. All the trials, with the exception of 2, were conducted in multiple settings internationally. The study by Cloutier et al36 and the OXN4502 trial39 were conducted at multiple centers in Canada and the United Kingdom, respectively. The method of randomization generation and concealment of allocation were judged to be adequate in 7 trials,28,29,31–33,36,37 whereas in the remaining 8 trials these were unclear. Wide variation in sample size was observed across the studies included in the review. Among the included studies, sample size ranged from 83 patients36 to 1121 patients.32 The mean age of enrolled participants was reported in 12 RCTs. The mean (SD) age reported in the studies ranged from 49.4 (13.2) years33 to 64.3 (9.6) years.37 The mean age of the recruited population was 455 years across all the studies, except in the study by Buynak et al33 (49.4 years). The proportion of females with chronic pain among the included studies generally ranged from 38.7%35 to 76.3%.29 The included RCTs investigating oxycodone/naloxone primarily recruited patients who were receiving opioids (pretreated) and had moderate-to-severe pain intensity. In contrast, patients enrolled in the tapentadol studies were diagnosed as having chronic pain of severe intensity. In addition, 450% of the patients recruited into tapentadol studies were opioid naive. Of the 13 studies reporting underlying diseases for chronic pain, most (76.92%) were investigating oxycodone/naloxone or tapentadol for the treatment of nonmalignant pain.

Pain Intensity and Pain Relief Analgesic efficacy was reported in 11 of the 15 RCTs included in the review using the Numerical Rating Scale (NRS) score, which is a commonly used pain assessment tool in which patients report their pain severity on a scale of 0 (no pain) to 10 (worst possible pain). Of these 11 trials, 3 trials were excluded from the primary analysis—2 with an enriched trial design and 1 investigating a nonlicensed dose of tapentadol.28,30,31 However, the mean baseline NRS score was lower in patients receiving oxycodone/naloxone compared with patients receiving tapentadol (weighted mean [SD] for oxycodone/naloxone = 3.56 [1.9]; weighted mean [SD] for tapentadol = 7.1 1.98]) (data not shown). The reduction in NRS score was not significant between oxycodone/naloxone and oxycodone CR

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alone (weighted mean difference [WMD] = 0.06; 95% CrI, 0.43 to 0.29). This result is in line with the pharmacokinetic properties of naloxone. Because naloxone is metabolized extensively in the liver, its antagonistic effects do not affect the efficacy of the opioid agonist oxycodone.15 The degree of pain relief between oxycodone/naloxone and tapentadol was not statistically significant when using the NRS score (WMD ¼ 0.17; 95% CrI, 0.35 to 0.67). Inclusion of the 2 seeded trials in the sensitivity analysis did not have an effect on the trend of these results.30,31 Patients in the placebo arm of the oxycodone/naloxone studies received IR oxycodone for breakthrough pain. Where reported, patients in the placebo arm of the tapentadol studies received treatment with nonopioid analgesics for breakthrough pain; however, this was not explicitly stated for all tapentadol studies.

Patient Assessment of Constipation Symptoms The PAC-SYM was performed in 5 of the 15 RCTs included in the review, of which 3 investigated tapentadol and 2 investigated oxycodone/naloxone. PAC-SYM is a sensitive and validated instrument designed specifically to measure constipation. The instrument comprises 3 domains: stool symptoms, abdominal symptoms, and rectal symptoms. These domains are assessed by 12 separate items rated on a Likert scale (0 indicating absence of symptoms; 1, mild; 2, moderate; 3, severe; and 4, very severe).40 A statistically significant reduction in PAC-SYM total score (denoting reduction in constipation symptoms) was observed with oxycodone/naloxone compared with placebo (WMD ¼ 3.50; 95% CrI, 5.27 to 2.00), oxycodone CR (WMD ¼ 3.86; 95% CrI, 5.62 to 2.37), and tapentadol (WMD ¼ 3.60; 95% CrI, 5.36 to 2.11) (Figure 2A). This result was statistically significant despite the lower weight assigned to oxycodone/naloxone studies in the review, which was assigned because of lower patient numbers. A sensitivity analysis was performed that included the study by Wild et al32; this study had initially been excluded because it was a subgroup analysis of patients with constipation at baseline, and results may therefore have not been fully reflective of the overall study population. The results of this analysis also revealed a significant reduction in PAC-SYM for oxycodone/naloxone compared with tapentadol, placebo, and oxycodone CR. Patients in the placebo arm

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Clinical Therapeutics

A

Comparison (N)

WMD (95% CrI)

B

Comparison (N)

RR (95% CrI)

OXN (292) vs Placebo (604)

–3.50 (–5.27 to –2.00)

OXN (446) vs Placebo (1151)

1.07 (0.61 to 1.48)

OXN (292) vs Oxycodone CR (820)

–3.86 (–5.62 to –2.37)

OXN (446) vs Oxycodone CR (1670)

0.68 (0.40 to 0.92)

OXN (292) vs Tapentadol (553)

–3.60 (–5.36 to –2.11)

OXN (446) vs Tapentadol (1875)

0.72 (0.42 to 0.98)

Tapentadol (1875) vs Placebo (1151)

1.48 (1.33 to 1.62)

Tapentadol (1875) vs Oxycodone CR (1670)

0.94 (0.88 to 1.01)

Tapentadol (553) vs Placebo (604)

0.10 (–0.10 to 0.31) –0.25 (–0.43 to –0.05)

Tapentadol (553) vs Oxycodone CR (820)

-5.62 0 <-Favors intervention

5.62 Favors comparator->

C

Comparison (N)

RR (95% CrI)

4 Favors comparator->

.4 1 <-Favors intervention

D

Comparison (N)

RR (95% CrI)

OXN (570) vs Placebo (1151)

0.86 (0.52 to 1.23)

OXN (284) vs Placebo (1151)

1.04 (0.50 to 1.52)

OXN (570) vs Oxycodone CR (1670)

0.93 (0.59 to 1.30)

OXN (284) vs Oxycodone CR (1510)

0.73 (0.37 to 1.05)

OXN (570) vs Tapentadol (1875)

0.81 (0.49 to 1.16)

OXN (284) vs Tapentadol (1875)

0.75 (0.37 to 1.10)

Tapentadol (1875) vs Placebo (1151)

1.07 (0.89 to 1.25)

Tapentadol (1875) vs Placebo (1151)

1.39 (1.18 to 1.57)

Tapentadol (1875) vs Oxycodone CR (1670)

1.15 (0.98 to 1.38)

Tapentadol (1875) vs Oxycodone CR (1510)

0.98 (0.88 to 1.08)

.4 <-Favors intervention

1

E

Comparison (N)

2 Favors comparator->

RR (95% CrI)

.3 <-Favors intervention

1

2 Favors comparator->

F

Comparison (N)

RR (95% CrI)

OXN (703) vs Placebo (1204)

1.13 (0.85 to 1.37)

OXN (664) vs Placebo (1160)

0.31 (0.12 to 0.66)

OXN (703) vs Oxycodone CR (1773)

0.89 (0.71 to 1.07)

OXN (664) vs Oxycodone CR (1773)

1.00 (0.41 to 2.00)

OXN (703) vs Tapentadol (1881)

1.13 (0.85 to 1.43)

OXN (664) vs Tapentadol (1881)

0.63 (0.23 to 1.34)

Tapentadol (1881) vs Placebo (1204)

1.01 (0.82 to 1.17)

Tapentadol (1881) vs Placebo (1160)

0.50 (0.35 to 0.72)

Tapentadol (1881) vs Oxycodone CR (1773)

0.79 (0.67 to 0.94)

Tapentadol (1881) vs Oxycodone CR (1773)

1.61 (1.00 to 2.50)

.4 <-Favors intervention

1

.1 <-Favors intervention

2 Favors comparator->

1

3 Favors comparator->

Figure 2. Summary forest plots comparing oxycodone/naloxone with tapentadol for Patient Assessment of Constipation Symptoms (PAC-SYM) total score (A), dizziness (B), headache (C), fatigue (D), allcause withdrawals (E), and withdrawals because of lack of efficacy (F). CR ¼ controlled release; CrI ¼ credible interval; OXN ¼ oxycodone/naloxone; RR ¼ risk ratio; WMD ¼ weighted mean difference.

may have received breakthrough pain.

symptomatic

treatment

for

Adverse Effects Dizziness Of the 15 RCTs included in the review, 11 reported dizziness as an AE, of which 4 were not included in the original NMA; 2 did not have enough data to undertake an analysis,28,35 whereas 2 were excluded because of enriched withdrawal design and were only included in the sensitivity analysis.30,31 The NMA found a significantly lower risk of dizziness in patients treated with oxycodone/naloxone

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compared with both tapentadol (risk ratio [RR] = 0.72; 95% CrI, 0.42–0.98) and oxycodone CR (RR = 0.68; 95% CrI, 0.40–0.92). Tapentadol was associated with a significantly higher risk of dizziness compared with placebo (RR = 1.48; 95% CrI, 1.33– 1.62) (Figure 2B). Inclusion of the 2 seeded trials in the sensitivity analysis did not have an effect on the trend of these results.30,31

Headache Headache was reported as an AE in 11 studies, of which 1 was excluded because data were only available for the maintenance phase, and 1 were excluded

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D. Thakur et al. from the original analysis because of enriched trial design.30,31 Of the 8 included studies, 4 each were investigating tapentadol and oxycodone/naloxone. Oxycodone/naloxone was directionally favored for a lower risk of headache compared with both tapentadol (RR = 0.81; 95% CrI, 0.49–1.16) and placebo (RR = 0.86; 95% CrI, 0.52–1.23), although these results were not significant (Figure 2C). Inclusion of the 2 seeded trials in the sensitivity analysis did not have an effect on the trend of these results.30,31

Fatigue Eight studies reported fatigue as an AE, of which 2 were excluded from the original NMA analysis (one because of seeded trial design and the other because of unavailability of safety data throughout the entirety of the study).30,36 A lower weighting was assigned to studies in which patients were treated with oxycodone/naloxone in the NMA compared with tapentadol as a result of the lower number of patients in oxycodone/naloxone studies (N=728 vs N=4092 for oxycodone/naloxone and tapentadol, respectively). Despite this, oxycodone/naloxone was directionally favored for a decreased risk of fatigue compared with tapentadol (RR = 0.75; 95% CrI, 0.37–1.10) and oxycodone CR (RR = 0.73; 95% CrI, 0.37–1.05) and a similar risk to placebo (RR = 1.04; 95% CrI, 0.50–1.52) (Figure 2D). The sensitivity analysis, which included the study using an enriched enrollment randomized withdrawal design,30 did not reveal a difference in overall trend, and results were similar to those of the original analysis.

Other AEs Other AEs evaluated in the systematic review included dry mouth, dyspepsia, diarrhea, gastrointestinal AEs, nausea, vomiting, and constipation (reported as an AE). Oxycodone/naloxone was directionally favored for a lower risk of both dry mouth (RR ¼ 0.61; 95% CrI, 0.02–1.22) and dyspepsia (RR ¼ 0.18; 95% CrI, 0.00–1.57) compared with tapentadol, although neither result was statistically significant. There was no statistically significant difference between tapentadol and oxycodone/naloxone with respect to diarrhea (RR ¼ 1.02; 95% CrI, 0.60–1.59), gastrointestinal AEs (RR ¼ 1.13; 95% CrI, 0.78–1.70), nausea (RR ¼ 1.06; 95% CrI, 0.83– 1.28), vomiting (RR ¼ 1.16; 95% CrI, 0.93–1.46), and constipation as an AE (RR ¼ 1.04; 95% CrI, 0.84–1.19).

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Although the risk of constipation was directionally favored for tapentadol, this difference was not statistically significant. Moreover, the measure of constipation as an AE may be much less sensitive than tools such as PAC-SYM, which is a validated measure developed specifically to measure the severity of constipation. PAC-SYM scores were significantly better with oxycodone/naloxone treatment compared with tapentadol, which is indicative of the benefits of the addition of naloxone in counteracting the effects of oxycodone on opioid receptors in the gastrointestinal tract.

Withdrawals All-cause withdrawals were reported in 14 of the 15 RCTs reviewed, of which 4 were excluded from the original analysis: 2 for enriched enrollment withdrawal design, 1 that investigated a nonlicensed dose of tapentadol, and 1 that only reported withdrawal data for the maintenance phase of the study.28,30,31,35 No significant difference was found in all-cause withdrawals in patients treated with oxycodone/naloxone compared with patients treated with tapentadol, although oxycodone/naloxone was directionally favored for a higher risk of all-cause withdrawals compared with tapentadol (RR = 1.13; 95% CrI, 0.85–1.43) and placebo (RR = 1.13; 95% CrI, 0.85– 1.37) (Figure 2E). Oxycodone/naloxone was directionally favored for a lower risk of all-cause withdrawal compared with oxycodone CR (RR ¼ 0.89; 95% CrI, 0.71–1.07). Withdrawals because of a lack of efficacy were reported in 13 of the 15 RCTs, of which 4 were excluded from the analysis (1 investigated a nonlicensed dose of tapentadol, 1 reported data only for maintenance, and 2 had an enriched withdrawal design).28,30,31,35 The results of the NMA indicated that oxycodone/naloxone was directionally favored for a lower risk of withdrawal because of a lack of efficacy in comparison with tapentadol, although this was not statistically significant (RR = 0.63; 95% CrI, 0.23–1.34) (Figure 2F). This finding is in contrast with the NRS score, in which tapentadol was directionally favored, but there was no significant difference in efficacy between the 2 treatments.

DISCUSSION Opioid agonists are a mainstay for treatment of chronic pain but are associated with significant

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Clinical Therapeutics AEs, including headaches, dizziness, fatigue, constipation, and other gastrointestinal effects. As such, treatments that offer improvements on any of the AE parameters can provide considerable benefit to the patient and may improve daily functioning. Oxycodone/naloxone and tapentadol are opioid therapies commonly prescribed for chronic pain, and there is a need for comparative evidence given the current absence of head-to-head data. In this systematic review, we investigated the comparative efficacy and safety of oxycodone/naloxone and tapentadol across all types of chronic pain and conducted mixed-treatment comparisons to quantitatively compare the 2 treatments. This study identified clear clinical benefits associated with oxycodone/naloxone; however, the efficacy and safety profile of oxycodone/naloxone may have been underestimated because of certain limitations of this analysis, for example, variability in patient populations included in the studies and the use of opioids as rescue medication for patients in the placebo arm. Although the findings from the NMA indicated that although the WMD in the NRS score (a patientreported pain scale) directionally favored tapentadol over oxycodone/naloxone, this difference was not statistically significant. In addition, because of variability in the patient populations between treatments, the result for oxycodone/naloxone may be an underestimate of the treatment’s true efficacy. In the studies included in this review that investigated the tolerability and efficacy of tapentadol, patients were primarily experiencing pain of severe intensity, whereas all patients treated with oxycodone/naloxone had received prior opioid treatment and were experiencing moderate-to-severe pain. This was reflected in a higher mean baseline NRS score for patients who received tapentadol compared with those who received oxycodone/naloxone. Cepeda et al41 found that patient-described pain relief correlates with initial pain intensity; therefore, patients with more severe pain may perceive a greater change in NRS score than patients with less severe pain at baseline, even if both patients obtained similar degrees of pain relief.41 As such, the more severe intensity of pain experienced at baseline by patients treated with tapentadol may have affected the comparison of analgesic efficacy in this NMA, leading to an underestimation of the efficacy of oxycodone/naloxone.

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Improvements in AEs associated with opioids can have a significant effect on the daily functioning of patients, and improvements in symptoms such as constipation, dizziness, and headache may therefore lead to an associated increase in HRQoL in patients.7,11,42 The findings from this NMA indicated that oxycodone/naloxone was significantly better than all other treatments included in the NMA, including tapentadol, with respect to the patient-reported constipation measure PAC-SYM total score. A common symptom for patients treated with opioids is OIBD, in particular constipation, which has a significant effect on QoL; therefore, improvements in constipation with oxycodone/naloxone, as indicated in this NMA by a reduction in PAC-SYM total score compared with tapentadol, may translate to significant QoL benefits for patients. Oxycodone/naloxone also had a significantly lower risk of dizziness compared with tapentadol, despite studies in patients treated with oxycodone/naloxone being assigned a lower weighting in the NMA for dizziness compared with studies investigating tapentadol. This significant improvement in patient-reported constipation and dizziness with oxycodone/naloxone is likely to have a considerable effect on daily functioning of patients being treated with opioids for chronic pain. Dizziness can negatively affect patient daily functioning and social relationships, especially in an aged population, and is generally associated with social isolation, functional disability, falls, and nursing home placement.42 Dizziness can also affect the social functioning of patients and may lead to psychological symptoms, including depression, anxiety, and avoidance behavior.43 In a study of 2064 randomly selected people aged 18 to 64 years, nearly half of those who had experienced dizziness reported some degree of handicap as a result (47%), whereas a similar proportion (46%) reported anxiety and/or avoidance behavior.43 Further evidence of the effect of dizziness on the mood and well-being of patients was provided by a cross-sectional study, which revealed a high degree of correlation between scores of patients on the Dizziness Handicap Inventory and the Hospital Anxiety and Depression Scale, and patients with higher Dizziness Handicap Inventory scores were significantly more likely to have abnormal scores on the anxiety and depression subscales of the Hospital

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D. Thakur et al. Anxiety and Depression Scale (P o 0.01 in all cases).44 Dizziness may also affect the ability of patients to follow a normal routine, their performance at work, or their ability to drive a car, which may have a significant effect on their QoL. In a study of 565 home-dwelling individuals aged 76 years in Sweden (of whom one-third of patients reported dizziness), individuals experiencing dizziness were more likely to have locomotor disorders, angina, urinary incontinence, stroke or paresis, and mental disorders than individuals who did not experience dizziness.8 Dizziness was also found to affect QoL in this study, as measured by the Nottingham Health Profile in all QoL dimensions and daily life areas except home life and, in women, social life.8 Improvements in the safety profile of opioids with respect to dizziness in patients treated with oxycodone/naloxone could therefore hold value for patients, leading to improvements in QoL and reducing risk of falls in elderly patients. Oxycodone/naloxone was directionally favored in the NMA for a lower risk of headache compared with tapentadol. Headache, although not life-threatening, is associated with personal and societal burdens of pain, disability, damaged QoL, and financial cost.45 Results of the NMA indicated that risk of headache was numerically lower with oxycodone/naloxone compared with tapentadol, and the results of the sensitivity analysis revealed that even when the results of the 2 seeded trials were included, the trend remained the same. Therefore, in patients with chronic pain who receive opioids, improvements in headache with oxycodone/naloxone may offer patients QoL benefits and improve the tolerability of opioid treatment when compared with tapentadol. The risk of fatigue was directionally favored in the NMA for oxycodone/naloxone when compared with patients treated with tapentadol, despite the lower weighting assigned to studies investigating oxycodone/ naloxone because of lower patient numbers in these studies. Tapentadol was also associated with a significantly higher risk of fatigue compared with placebo and an equivalent risk of fatigue compared with oxycodone CR. In contrast to tapentadol, although oxycodone/naloxone was associated with an equivalent risk of fatigue when compared with placebo, it was directionally favored for a lower risk of fatigue when compared with oxycodone CR. Fatigue can

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similarly lead to serious impairment in QoL, social activities, and the ability to go to work,9 and fatigue as a result of treatment may cause loneliness and social isolation of patients. This may be a particular problem for elderly patients who may already experience some degree of social isolation.9 Therefore, potential improvements in fatigue with oxycodone/naloxone may provide further patient benefits. Taken together, the NMA results suggest that oxycodone/naloxone offers improvements in patientreported constipation, dizziness, headache, and fatigue for patients compared with tapentadol and oxycodone CR, which may lead to benefits in the daily functioning of patients. In addition to the benefits in AE profile, patients receiving oxycodone/naloxone were less likely to withdraw from treatment because of a lack of efficacy than patients receiving tapentadol, although the difference was not statistically significant. Although a higher risk of all-cause withdrawals was reported with oxycodone/naloxone compared with tapentadol, this was not statistically significant. This result may be explained by the higher number of patients in the oxycodone/naloxone group receiving opioids at the time of study enrollment when compared with the tapentadol group and by the fact that dissatisfaction with current treatment was a criterion for inclusion in 2 of the tapentadol studies, meaning patients who received tapentadol may not have been receiving opioids at enrollment. As such, exposure to opioids may have been longer in patients treated with oxycodone/naloxone.29,33 Long-term evidence from 2 open-label studies of patients who were treated with oxycodone/naloxone for up to 52 weeks revealed relatively good safety and tolerability profiles with oxycodone/naloxone, and the reported AEs were found to be in line with those associated with opioid treatment.20 In light of this, although withdrawals due to AEs were numerically higher in patients treated with oxycodone/naloxone than with tapentadol, oxycodone/naloxone is tolerable for a longer period of treatment. Oxycodone/naloxone therefore has proven tolerability in the long term and may offer benefits with respect to efficacy compared with tapentadol. A separate, recent, indirect treatment comparison was reported for oxycodone/naloxone and tapentadol.46 Both oxycodone/naloxone and tapentadol were

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Clinical Therapeutics found to be cost-effective interventions compared with oxycodone CR, and tapentadol was found to be more cost-effective than oxycodone/naloxone46; however, that review had a number of methodologic limitations. Only patients with musculoskeletal pain were included, thereby significantly limiting the scope of the work, and some studies performed on patients with musculoskeletal pain within the period were not included.36 Literature searching was limited to only MEDLINE and did not include other biomedical databases. Further limitations in that review included use of a fixed-effects model as opposed to a random-effects model (which would consider heterogeneity across studies) and the use of qualitative comparisons using RR values generated from direct analysis of oxycodone/naloxone and tapentadol with oxycodone CR as opposed to an indirect treatment comparison between tapentadol and oxycodone/ naloxone. As an NMA comparing RCTs with different designs, this systematic review had some limitations that should be noted. First, the number of patients enrolled in the tapentadol studies was approximately 3 to 4 times that of patients recruited by studies investigating oxycodone/naloxone; therefore, studies investigating oxycodone/naloxone were assigned a lower weight in the NMA. Second, considerable variability was observed in the patient population recruited across the RCTs included in this review, with a clear difference in baseline characteristics between studies looking at oxycodone/naloxone and tapentadol, which may have affected the relative assessment of the treatments. Part of the inclusion criteria for the studies evaluating oxycodone/naloxone was previous opioid treatment (pretreated population), and patients in these studies had constipation caused or aggravated by opioids; in contrast, this corresponding information was not reported in studies evaluating tapentadol. Patients treated with oxycodone/naloxone may have therefore been treated with opioids for longer durations than patients treated with tapentadol, potentially leading to a higher likelihood of AEs. A further difference between the oxycodone/naloxone and tapentadol studies relates to the level of pain that patients were experiencing at baseline; patients treated with tapentadol were experiencing severe pain at baseline, whereas patients treated with oxycodone/naloxone were experiencing moderate-to-severe pain. Furthermore, patients in the placebo arm of the oxycodone/naloxone studies

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received IR oxycodone for breakthrough pain (where reported, patients in the placebo arm of the tapentadol studies received treatment with nonopioid analgesics for breakthrough pain; however, this was not explicitly stated for all tapentadol studies). This is likely to have caused an underestimation of the efficacy of oxycodone/naloxone as measured by the NRS score because of the perceived improvement in pain. Third, the studies investigating tapentadol enrolled patients who were dissatisfied with their previous treatment and may not have been receiving opioids at the time of enrollment; therefore, this may have had an effect on pain intensity scoring between the tapentadol and oxycodone/naloxone studies. Therefore, further studies are warranted that compare oxycodone/naloxone with tapentadol in a head-tohead RCT.

CONCLUSIONS Although a certain degree of caution should be taken with interpretation of these results, given the lack of head-to-head data comparing tapentadol with oxycodone/naloxone and the smaller sample sizes in oxycodone/naloxone studies, the results of this systematic review indicate that oxycodone/naloxone offers significant improvements in patient-reported constipation (PAC-SYM) and dizziness. In addition, oxycodone/naloxone was directionally favored for fatigue and headache compared with ER tapentadol. These end points are important when considering the daily experience of patients with chronic pain. The results of this study support the value of oxycodone/ naloxone as a key treatment option that may offer improvements in daily functioning and HRQoL for patients with chronic pain.

ACKNOWLEDGMENTS Fiona Sheppard, Jessica May, and Richard Tolley at PAREXEL International contributed to the preparation of the draft manuscript.

CONFLICTS OF INTEREST Deepika Thakur and Mohit Kumar Bhutani contributed to the study design, performed the systematic review, and contributed to the manuscript content; Rod Junor and Sara Dickerson aided with study design and manuscript content. Deepika Thakur and Mohit Kumar Bhutani are employees of PAREXEL. Sara Dickerson and Rod Junor are employees of Napp

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D. Thakur et al. Pharmaceuticals. This study was funded by Napp Pharmaceuticals. The authors have indicated that they have no other conflicts of interest regarding the content of this article.

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Address correspondence to: Sara Dickerson, BSc, Napp Pharmaceuticals Ltd, 191-198 Cambridge Science Park, Milton Road, Cambridge, CB4 0GW, United Kingdom. E-mail: [email protected]

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