Prolonged-release Naloxone Research Articles

Long-term effect of oxycodone/naloxone on the management of postoperative pain after hysterectomy: a randomized prospective study

The analgesic efficacy of oxycodone prolonged-release (PR) combined with naloxone PR (OXN) in postoperative pain management is recognized, however, few studies have examined the efficacy of OXN on pain relief and bowel function following hysterectomy. This study compared the effect of OXN vs. standard treatment for post-operative pain management and bowel function following hysterectomy. This randomized prospective study included 83 women who underwent laparoscopic/laparotomic hysterectomy. General anesthesia was induced by propofol (1.5-2 mg/kg), fentanyl (50-100 μg) and rocuronium (0.6-1 mg/kg) and maintained with sevoflurane (MAC 0.8-1) and fentanyl (1-2 μg/kg). Intraoperative analgesia was performed with ketorolac (30 mg), paracetamol (1 g) and morphine (0.1 mg/kg). Postoperative analgesia in the control group (N.=41) included morphine (0.2-0.4 mg/kg/day), whereas the OXN (N.=42) group only received oxycodone (10 mg)/naloxone (5 mg) for the first 48 hours. As rescue analgesic, both groups received paracetamol (3 mg). Bowel Function Index (BFI) and pain numeric rating scales (NRS) were measured at day 0, 1, 2, 3, 5 and 7, whereas vital parameters, rescue medication and side effects were recorded for the first three days only. Bowel function indices were significantly improved in OXN-treated patients at all time points compared to morphine-treated patients. Mean static pain NRS was significantly decreased at day 2 and day 3 and dynamic pain NRS at day 3 in the OXN group. Side effects, rescue analgesic and antiemetics were more frequent in the control group. Improved pain control, bowel function and reduced side effects were observed with OXN compared to morphine in patients who underwent hysterectomy.

The role of naldemedine in the treatment of patients with opioid-induced constipation

Opioid-induced bowel dysfunction (OIBD) and opioid-induced constipation (OIC) significantly decrease patients’ quality of life (QoL), lead to complications and opioid non-compliance resulting in pain exacerbation. Traditional laxatives are first-line preventive and therapeutic measures, although they display limited efficacy and several adverse effects (AE). Non-pharmacology measures, prokinetics, opioid switch, all have little evidence and do not target OIBD and OIC pathophysiology both associated with activation of predominantly μ-opioid receptors mostly peripherally in the gastrointestinal (GI) tract. A combination of prolonged-release (PR) oxycodone with PR naloxone in one tablet with a ratio of 2:1 is available, although limitations include maximal daily dose of 160 mg/80 mg, respectively, and normal liver function. Peripherally acting μ-opioid receptor antagonists (PAMORA) block opioid receptors in the GI tract without compromising analgesia as they do not cross the blood–brain barrier. Currently three drugs are available: methylnaltrexone, naloxegol and naldemedine. Naldemedine has proven efficacy superior to placebo in the treatment of OIC in both cancer and non-cancer patients while improving patient-reported constipation symptoms and patients’ QoL. It is well tolerated with mostly mild to moderate intensity GI adverse effects such as abdominal, pain, nausea, and diarrhea, without compromising analgesia. Naldemedine dosing is convenient as it is administered once daily by an oral route. Moreover, naldemedine may be safely used in patients with renal failure and mild to moderate hepatic impairment. Effective prevention and treatment of OIC is of paramount importance in patients receiving long-term opioid therapy. Palliat Med Pract 2019; 13, 3: 113–128

The role of oxycodone/naloxone in the management of patients with pain and opioid-induced constipation

ABSTRACTIntroduction: Common opioid adverse effects (AE) of the gastrointestinal tract include opioid-induced constipation (OIC) and opioid-induced bowel dysfunction (OIBD) with traditional laxatives being of limited efficacy, having AEs and not addressing the pathophysiology of OIC or OIBD. Targeted treatment comprises of PAMORA (peripherally acting mu-opioid receptor antagonists) and a combination of an opioid receptor agonist with its antagonist, namely prolonged-release oxycodone with prolonged-release naloxone (OXN) tablets at a fixed ratio of 2:1. Oxycodone provides analgesia, whereas naloxone prevents binding or displaces it from opioid receptors located in the gut wall.Areas covered: The authors review the role of OXN in the management of patients with pain and OIC. A literature search was performed using the search terms ‘oxycodone/naloxone’ and ‘opioid-induced constipation’ using the PubMed database up to October 2018.Expert opinion: OXN delivers analgesia comparable (or superior versus placebo and in observational studies) to oxycodone alone and other opioids with a limited or decreased disturbing effect on bowel function. OXN in daily doses of up to 160 mg/80 mg provides effective analgesia with little negative impact on bowel function. OXN may be successfully used in patients with chronic pain, to prevent or treat symptoms of OIC and OIBD.

Long-term efficacy and safety of oxycodone–naloxone prolonged release in geriatric patients with moderate-to-severe chronic noncancer pain: a 52-week open-label extension phase study

BackgroundTwo-thirds of older people suffer from chronic pain and finding valid treatment options is essential. In this 1-yearlong investigation, we evaluated the efficacy and safety of prolonged-release oxycodone–naloxone (OXN-PR) in patients aged ≥70 (mean 81.7) years.MethodsIn this open-label prospective study, patients with moderate-to-severe noncancer chronic pain were prescribed OXN-PR for 1 year. The primary endpoint was the proportion of patients who achieved ≥30% reduction in pain intensity after 52 weeks of treatment, without worsening bowel function. The scheduled visits were at baseline (T0), after 4 weeks (T4), and after 52 weeks (T52).ResultsFifty patients completed the study. The primary endpoint was achieved in 78% of patients at T4 and 96% at T52 (P<0.0001). Pain intensity, measured on a 0–10 numerical rating scale, decreased from 6.0 at T0 to 2.8 at T4 and to 1.7 at T52 (P<0.0001). Mean daily dose of oxycodone increased from 10 to 14.4 mg (T4) and finally to 17.4 mg (T52). Bowel Function Index from 35.1 to 28.7 at T52. No changes were observed in cognitive functions (Mini-Mental State Examination evaluation), while daily functioning improved (Barthel Index from 53.1 to 61.0, P<0.0001). The Screener and Opioid Assessment for Patients with Pain-Revised score at 52 weeks was 2.6 (standard deviation 1.6), indicating a low risk of aberrant medication-related behavior. In general, OXN-PR was well tolerated.ConclusionThis study of the long-term treatment of chronic pain in a geriatric population with OXN-PR shows satisfying analgesic effects achieved with a stable low daily dose, coupled with a good safety profile and, in particular, with a reduction of constipation, often present during opioid therapy. Our findings support the indications of the American Geriatrics Society, suggesting the use of opioids to treat pain in older people not responsive to acetaminophen or nonsteroidal anti-inflammatory drugs.

Intractable restless legs syndrome: role of prolonged-release oxycodone-naloxone.

Restless legs syndrome (RLS) is a common neurological disorder characterized by an irresistible urge to move the legs accompanied by uncomfortable sensations that occur at night or at time of rest. Pharmacological therapy should be limited to patients who suffer from clinically relevant symptoms. Chronic RLS is usually treated with either a dopamine agonist (pramipexole, ropinirole, rotigotine) or an α2δ calcium-channel ligand (gabapentin, gabapentin enacarbil, pregabalin). Augmentation is the main complication of long-term dopaminergic treatment, and frequently requires a reduction of current dopaminergic dose or a switch to non-dopaminergic medications. Opioids as monotherapy or add-on treatment should be considered when alternative satisfactory regimens are unavailable and the severity of symptoms warrants it. In a recent Phase III trial, oxycodone–naloxone prolonged release (PR) demonstrated a significant and sustained effect on patients with severe RLS inadequately controlled by previous treatments. The adverse-event profile was consistent with the safety profile of opioids. The most frequent adverse events were fatigue, constipation, nausea, headache, hyperhidrosis, somnolence, dry mouth, and pruritus. Adverse events were usually mild or moderate in intensity. No cases of augmentation were reported. Oxycodone–naloxone PR is approved for the second-line symptomatic treatment of adults with severe to very severe idiopathic RLS after failure of dopaminergic treatment. Further studies are needed to evaluate if oxycodone–naloxone PR is equally efficacious as a first-line treatment. Moreover, long-term comparative studies between opioids, dopaminergic drugs and α2δ ligands are needed.

Differential Gastrointestinal Effects of Who-Step III Opioids in Low Back Pain Patients with vs. Without Constipation: Post-Hoc Analysis of Data from a 12-Week Prospective, Open-Label Blinded Endpoint Streamlined Study

Objective: Opioid-induced constipation (OIC) is the most prevalent patient complaint associated with longer-term opioid use and interferes with analgesic efficacy, functionality, quality-of-life, and patient compliance. To compare effects of prolonged release (PR) oxycodone and PR naloxone (OXN), vs. PR oxycodone (OXY) vs. PR morphine (MOR) on bowel function under real-life conditions in chronic low back pain (LBP) patients with vs. those without pre-existent constipation.

Oxycodone/Naloxone PR: A Review in Severe Refractory Restless Legs Syndrome.

An oral, fixed-dose combination of prolonged-release (PR) oxycodone with PR naloxone (Targin(®), Targiniq(®), Targinact(®); hereafter referred to as oxycodone/naloxone PR) is approved in Europe for the second-line symptomatic treatment of patients with severe to very severe idiopathic restless legs syndrome (RLS), after failure of dopaminergic therapy. Coadministration of naloxone represents a targeted approach to counteracting opioid-induced bowel dysfunction without compromising therapeutic efficacy; because of its very low oral bioavailability, naloxone blocks the action of oxycodone at opioid receptors locally in the gut. The efficacy of oxycodone/naloxone PR in patients with severe RLS inadequately controlled by previous (mainly dopaminergic) treatment has been demonstrated in RELOXYN, a 12-week, randomized, double-blind study with a 40-week open-label extension. In this pivotal study, oxycodone/naloxone PR significantly improved RLS symptoms compared with placebo from week 2 onwards; a beneficial effect of oxycodone/naloxone PR was maintained through 1 year of treatment. Furthermore, improvements in RLS symptoms in oxycodone/naloxone PR recipients were accompanied by similarly sustained improvements in disease-specific quality of life and subjective sleep variables. Oxycodone/naloxone PR was generally well tolerated, with a treatment-related adverse event profile (e.g. gastrointestinal disorders, CNS disorders, fatigue and pruritus) that was consistent with that expected for opioid therapy. Notably, there were no confirmed cases of augmentation among oxycodone/naloxone PR recipients throughout the course of the study. Results from the well-designed RELOXYN trial have thus demonstrated the value of oxycodone/naloxone PR as a second-line therapy for severe refractory RLS; further investigation of this combination product as a first-line treatment for severe RLS is now warranted.

Emerging therapies for patients with symptoms of opioid-induced bowel dysfunction.

Opioid-induced bowel dysfunction (OIBD) comprises gastrointestinal (GI) symptoms, including dry mouth, nausea, vomiting, gastric stasis, bloating, abdominal pain, and opioid-induced constipation, which significantly impair patients’ quality of life and may lead to undertreatment of pain. Traditional laxatives are often prescribed for OIBD symptoms, although they display limited efficacy and exert adverse effects. Other strategies include prokinetics and change of opioids or their administration route. However, these approaches do not address underlying causes of OIBD associated with opioid effects on mostly peripheral opioid receptors located in the GI tract. Targeted management of OIBD comprises purely peripherally acting opioid receptor antagonists and a combination of opioid receptor agonist and antagonist. Methylnaltrexone induces laxation in 50%–60% of patients with advanced diseases and OIBD who do not respond to traditional oral laxatives without inducing opioid withdrawal symptoms with similar response (45%–50%) after an oral administration of naloxegol. A combination of prolonged-release oxycodone with prolonged-release naloxone (OXN) in one tablet (a ratio of 2:1) provides analgesia with limited negative effect on the bowel function, as oxycodone displays high oral bioavailability and naloxone demonstrates local antagonist effect on opioid receptors in the GI tract and is totally inactivated in the liver. OXN in daily doses of up to 80 mg/40 mg provides equally effective analgesia with improved bowel function compared to oxycodone administered alone in patients with chronic non-malignant and cancer-related pain. OIBD is a common complication of long-term opioid therapy and may lead to quality of life deterioration and undertreatment of pain. Thus, a complex assessment and management that addresses underlying causes and patomechanisms of OIBD is recommended. Newer strategies comprise methylnaltrexone or OXN administration in the management of OIBD, and OXN may be also considered as a preventive measure of OIBD development in patients who require opioid administration.

Oxycodone/Naloxone in the Management of Patients with Pain and Opioid–Induced Bowel Dysfunction

Common opioids adverse effects include opioid-induced bowel dysfunction (OIBD), which comprises opioid-induced constipation, dry mouth, nausea, vomiting, gastric stasis, bloating, and abdominal pain. Traditional laxatives which are often prescribed for the prevention and treatment of OIBD possess limited efficacy and display adverse effects. A targeted approach to OIBD management is the use of a combination of an opioid agonist with opioid receptor antagonist or administration of purely peripherally acting opioid receptor antagonists. A literature search with terms "oxycodone/naloxone" in the PubMed and MEDLINE database updated on 31(st) July 2013. All studies of oxycodone/naloxone (randomized, controlled trials and open, uncontrolled studies) were included. In addition, studies on pharmacokinetics and pharmacodynamics of oxycodone/naloxone were included. A combination of prolonged-release oxycodone with prolonged-release naloxone (OXN) in one tablet with a fixed 2:1 ratio provides effective analgesia with limited disturbing effect on bowel function. Oxycodone is a valued opioid administered either as the first strong opioid or when other strong opioids have been ineffective. Naloxone is an opioid receptor antagonist that displays local antagonist effect on opioid receptors in the gastrointestinal tract and is nearly completely inactivated in the liver after oral administration. As demonstrated in controlled studies conducted in patients with chronic non-malignant and cancer-related pain OXN in daily doses up to 80 mg/40 mg provided equally effective analgesia with an improved bowel function compared to oxycodone administered alone. OXN is an important drug for chronic pain management, prevention and treatment of OIBD.

Oxycodone/Naloxone Prolonged-Release: A Review of Its Use in the Management of Chronic Pain While Counteracting Opioid-Induced Constipation

A combination of prolonged-release (PR) oxycodone with PR naloxone (Targin(®), Targiniq(®), Targinact(®)) in one tablet with a fixed 2:1 ratio is available for the treatment of patients with severe pain, which can only be adequately managed with opioid analgesics. The aim of this formulation is to counteract opioid-induced constipation through the local antagonist effect of naloxone in the gut wall, while maintaining analgesia due to the low bioavailability of oral naloxone. Three large, 12-week, randomized, double-blind, phase III trials in patients with moderate to severe, chronic, non-malignant pain, plus a prospectively planned pooled analysis of two of these studies, demonstrated that oxycodone/naloxone PR improved bowel function, as measured by the bowel function index, compared with oxycodone PR. Additionally, oxycodone/naloxone PR relieved pain more effectively than placebo and no less effectively than oxycodone PR after 12weeks. Phase II efficacy data in cancer patients are consistent with those observed in patients with non-malignant pain. Oxycodone/naloxone PR was generally well tolerated; the most frequently reported adverse events were of gastrointestinal origin, consistent with those known to occur with opioid therapy. Of note, numerically lower rates of constipation were observed in the oxycodone/naloxone PR group compared with the oxycodone PR group. A cost-utility analysis predicted that oxycodone/naloxone PR would be a cost-effective option compared with oxycodone PR in patients with non-malignant pain. Although more comparative data are needed, oxycodone/naloxone PR is an effective option for use in patients with severe chronic pain, particularly among those with opioid-induced constipation.

Cancer pain therapy with a fixed combination of prolonged-release oxycodone/naloxone: results from a non-interventional study.

BackgroundStrong opioids, including oxycodone, are the most effective analgesics used to combat moderate to severe cancer pain, but opioid-induced bowel dysfunction is a relevant problem associated with the therapy. Clinical studies have demonstrated equivalent analgesic efficacy and improved bowel function in treatment with a fixed combination of prolonged-release (PR) oxycodone and PR naloxone compared to oxycodone alone in patients with nonmalignant pain. Here, we report of a prospective, non-interventional study evaluating the effectiveness and safety of PR oxycodone/PR naloxone in a subgroup of patients with severe cancer pain.Patients and methodsWithin the non-interventional multicenter study, 1,178 cancer patients with severe chronic pain received PR oxycodone/PR naloxone, dosed according to pain intensity, for 4 weeks. Recorded variables included pain intensity, patient-reported bowel function (Bowel Function Index), and pain-related functional impairment as a measure of quality of life (QoL).ResultsDuring treatment with PR oxycodone/PR naloxone, clinically relevant improvements in pain intensity were observed in opioid-naïve patients and in patients pretreated with weak or strong opioids, as reflected by reductions in pain scores of 51%, 53%, and 33%, respectively. Improvement in analgesia was paralleled by a significant reduction of opioid-induced bowel dysfunction in opioid-pretreated patients. The reductions in the mean Bowel Function Index of −20.5 and −36.5 in patients pretreated with weak and strong opioids, respectively, represent clinically relevant improvements in bowel function. Pain-related functional impairment decreased consistently across all seven domains, which is equivalent to a substantial improvement in QoL.ConclusionThis subgroup analysis of cancer patients within a large non-interventional study demonstrates that treatment with PR oxycodone/PR naloxone provides effective analgesia with minimization of bowel dysfunction and improved QoL. These data extend our knowledge of the effectiveness and tolerability of PR oxycodone/PR naloxone to the population of patients with cancer under real-life conditions.

A comparison of oxycodone prolonged‐release vs. oxycodone + naloxone prolonged‐release after laparoscopic hysterectomy

Targiniq®, an oxycodone prolonged-release (PR) formulation combined with the opioid antagonist naloxone PR, aims to prevent opioid-induced constipation without impairing the analgesic efficacy. This has been confirmed during prolonged use in chronic pain or cancer patients. The purpose of our study was to compare clinical effects of oxycodone PR with oxycodone PR + naloxone PR for short-term post-operative pain management. This randomised, double-blind, prospective study included 85 women undergoing laparoscopic hysterectomy. The two groups received either oxycodone PR 10 mg or oxycodone PR 10 mg + naloxone PR 5 mg as pre-medication and twice daily for 3 days. As rescue analgesic, the patients received oxycodone intravenous during the first 24 h post-operatively and oxycodone tablets in the 24-72-h period. Constipation, other side effects, pain and satisfaction were registered during the first 7 post-operative days. Demographic, pre- and perioperative variables and the use of rescue analgesics were similar in the groups. There were no significant differences in variables related to constipation. In the oxycodone PR + naloxone PR group, 25% had no defecation during the first 72 h post-operatively, compared with 20% in the oxycodone PR group (mean 1.2 ± 1.1 vs. 2.1 ± 2.4 defecations). Other opioid-induced effects and side effects showed no significant differences. Only 7% were dissatisfied with their oral pain treatment. Addition of naloxone to oxycodone PR tablets in a pain regimen administered twice daily the first three post-operative days had no significant clinical effects on constipation or other variables during the first week after hysterectomy.

Reviews The place of oxycodone/naloxone in chronic pain management

Opioid analgesics are usually effective in the management of severe chronic pain. However, symptoms of opioid-induced bowel dysfunction (OIBD) are common during opioid therapy. Opioid-induced bowel dysfunction is often unsuccessfully managed due to limited effectiveness and numerous adverse effects of traditional laxatives. Newer treatment possibilities directed at the pathomechanism of OIBD comprise combined prolonged-release oxycodone with prolonged-release naloxone (oxycodone/naloxone) tablets. Oxycodone/naloxone provides effective analgesia with limited impact on bowel function as oxycodone displays high oral bioavailability and naloxone act as local antagonist on opioid receptors in the gastrointestinal tract due to nearly complete inactivation in the liver. Oxycodone/naloxone is administered to opioid-naive patients with severe pain and those unsuccessfully treated with weak opioids. Oxycodone/naloxone may be also administered to patients treated with strong opioids who experience intense symptoms of OIBD. Studies conducted to date indicate that oxycodone/naloxone is an important drug in chronic pain management, prevention and treatment of OIBD.

Non-Analgesic Effects of Opioids: Management of Opioid-Induced Constipation by Peripheral Opioid Receptor Antagonists: Prevention or Withdrawal?

The therapeutic action of opioid analgesics is compromised by peripheral adverse effects among which opioid-induced constipation (OIC) is the most disabling, with a prevalence reported to vary between 15 and 90 %. Although OIC is usually treated with laxatives, there is insufficient clinical evidence that laxatives are efficacious in this indication. In contrast, there is ample evidence from double- blind, randomized and placebo-controlled trials that peripheral opioid receptor antagonists (PORAs) counteract OIC. This specific treatment modality is currently based on subcutaneous methylnaltrexone for the interruption of OIC in patients with advanced illness, and a fixed combination of oral prolonged-release naloxone with prolonged-release oxycodone for the prevention of OIC in the treatment of non-cancer and cancer pain. Both drugs counteract OIC while the analgesic effect of opioids remains unabated. The clinical studies show that more than 50 % of the patients with constipation under opioid therapy may benefit from the use of PORAs, while PORA-resistant patients are likely to suffer from non-opioid-induced constipation, the prevalence of which increases with age. While the addition of naloxone to oxycodone seems to act by preventing OIC, the intermittent dosing of methylnaltrexone every other day seems to stimulate defaecation by provoking an intestinal withdrawal response. The availability of PORAs provides a novel opportunity to specifically control OIC and other peripheral adverse effects of opioid analgesics (e.g., urinary retention and pruritus). The continuous dosing of a PORA has the advantage of few adverse effects, while intermittent dosing of a PORA can be associated with abdominal cramp-like pain.

Opioid antagonists for prevention and treatment of opioid-induced gastrointestinal effects

The therapeutic action of opioid analgesics is compromised by peripheral adverse effects, among which constipation is the most disabling as laxatives often fail to provide satisfactory relief. This review highlights recent advances in the specific control of opioid-induced constipation by opioid receptor antagonists with limited systemic bioavailability or a peripherally restricted site of action. The specific management of opioid-induced bowel dysfunction is currently based on three drug entities: oral alvimopan for the shortening of postoperative ileus associated with opioid-induced pain control after bowel resection, subcutaneous methylnaltrexone for the reduction of opioid-induced constipation in patients with advanced illness, and a fixed combination of oral prolonged-release naloxone with prolonged-release oxycodone for the treatment of noncancer and cancer pain. All three drug entities have been shown to attenuate opioid-induced motor stasis in the gut with a favorable adverse effect profile, while the analgesic effect of opioids remains unabated. The availability of opioid receptor antagonists with restricted access to the central nervous system provides a novel opportunity to specifically control opioid-induced constipation and other peripheral adverse effects of opioid analgesics. Further studies are needed to evaluate the long-term efficacy, safety and cost-effectiveness of this approach.

The role of opioid receptor antagonists in the treatment of opioid-induced constipation: a review

Opioid-induced constipation (OIC) is associated with negative impact of opioid analgesics on opioid receptors located in the gut wall. Until recently, OIC was treated symptomatically only, with different laxatives which did not target the pathophysiology of OIC. Recently, several opioid receptor antagonists have been introduced in the treatment of OIC. Methylnaltrexone (MNTX) is a peripheral mu-opioid receptor antagonist for subcutaneous administration, which does not evoke symptoms of opioid abstinence. MNTX is indicated for patients with OIC who are not amenable to therapy with oral laxatives. In clinical trials, the effectiveness of MNTX assessed as its ability to induce spontaneous bowel movement, is 50%-60% of treated patients; MNTX demonstrates significant superiority over placebo. Another product is combination of oral formulation of prolonged release oxycodone and prolonged release naloxone (PR oxycodone/PR naloxone), indicated for patients who require opioid administration for chronic pain and have already developed OIC, and for those who need opioid therapy and take the drug to prevent OIC. Naloxone administered orally displays local, antagonist effects on opioid receptors in the gut wall, negligible systemic bioavailability, and significantly reduces the oxycodone constipating effect. PR oxycodone/PR naloxone has similar analgesic efficacy, but causes less constipation and less laxative consumption in comparison with patients treated with oxycodone alone. Both products are expensive, therefore their administration should be carefully considered. On the other hand, uncontrolled OIC and the necessity to perform rectal invasive procedures (enema, manual evacuation) lead not only to increased health care costs, but most importantly, cause severe patient suffering.

Long-term efficacy and safety of combined prolonged-release oxycodone and naloxone in the management of non-cancer chronic pain

Objective:The aim of this study was to assess safety and efficacy of fixed combination oxycodone prolonged release (PR)/naloxone PR in terms of both analgesia and improving opioid-induced bowel dysfunction (OIBD) and associated symptoms, such as opioid-induced constipation (OIC), in adults with chronic non-cancer pain.Study design:These were open-label extension studies in which patients who had previously completed a 12-week, double-blind study received oxycodone PR/naloxone PR for up to 52 weeks. The analgesia study assessed pain using the modified Brief Pain Inventory-Short Form (BPI-SF). The bowel function study assessed improvements in constipation using the Bowel Function Index (BFI).Results:At open-label baseline in the analgesia study (n = 379), mean score [± standard deviation (SD)] for the BPI-SF item ‘average pain over the last 24 h’ was 3.9 ± 1.52, and this remained low at 6 months (3.7 ± 1.59) and 12 months (3.8 ± 1.72). Mean scores for BPI-SF item ‘sleep interference’, and the BPI-SF ‘pain’ and ‘interference with activities’ subscales also remained low throughout the 52-week study. In the bowel function study (n = 258), mean BFI score (± SD) decreased from 35.6 ± 27.74 at the start of the extension study to 20.6 ± 24.01 after 12 months of treatment with oxycodone PR/naloxone PR. Pain scores also remained low and stable during this study. Adverse events in both extension phases were consistent with those associated with opioid therapy; no additional safety concerns were observed.Conclusion:Results from these two open-label extension studies demonstrate the long-term efficacy and tolerability of fixed combination oxycodone PR/naloxone PR in the treatment of chronic pain. Patients experienced clinically relevant improvements in OIBD while receiving effective analgesic therapy.

Validation of the Bowel Function Index to detect clinically meaningful changes in opioid-induced constipation

Objective: The Bowel Function Index (BFI) is a clinician-administered, patient-reported, 3-item questionnaire to evaluate opioid-induced constipation in cancer and non-cancer chronic pain patients. The objective of the present analysis was to evaluate the psychometric characteristics of the BFI using data from clinical studies of oral prolonged release (PR) oxycodone/naloxone.Methods: OXN2401 was a multicenter, controlled, randomized, double-blind, parallel-group study including oral PR oxycodone combined with oral PR naloxone as well as oral PR oxycodone combined with corresponding naloxone placebo. OXN3401 and OXN3001 were 12-week multicenter, controlled, randomized, double-blind, parallel-group studies of a fixed combination of oral PR oxycodone/naloxone versus PR oxycodone. In addition, a placebo group was included in study OXN3401. BFI psychometric characteristics (reliability, reproducibility, convergent/known groups validity, and responsiveness) were evaluated.Results: Demographic data (n=985) were comparable and analyses indicated a high degree of internal consistency (Cronbach's alpha >0.7). Change of less than 5 points in BFI was indicative of high reproducibility. Correlations between BFI item and total scores to stool frequency were statistically significant and in the low-to-moderate range (OXN2401 –0.23 to –0.29, p < 0.001; OXN3401 range –0.26 to –0.40, p < 0.001; OXN3001 –0.14 to –0.15, p < 0.05). Data indicate that a BFI score change of ≥12 points represents a clinically meaningful change in constipation.Limitations: This publication for validation of BFI only includes data from three clinical trials. However, another publication of an additional specifically designed cross-sectional validation study is in preparation.Conclusion: The BFI is a valid and reliable instrument for the assessment of opioid-induced constipation in chronic pain patients. Psychometric analyses from clinical trials support the BFI's psychometric properties.

New therapeutic principles for adverse effects on upper and lower gastrointestinal tract in patients treated with opioid analgesics

Recent large scale surveys document that patients on opioid analgesics suffer adverse effects from increased tone in sphincters of both the upper and lower part of the gastrointestinal tract, decreased secretions into and increased absorption of fluids out of the bowel. These adverse effects often cause patients to discontinue opioid analgesics. Also patients treated with opioids for acute pain after surgery and in the intensive care units suffer gastrointestinal adverse effects. Constipation is the most common adverse effect of opioids. Most patients self-medicate with over-the-counter laxatives but suffer unpredictable responses and bothersome adverse effects of laxatives. Potent prescription laxatives may further adversely impact quality of life of chronic pain patients. Opioid-induced dysfunctions of the upper gastrointestinal tract are often misinterpreted by health care providers, and they are not relieved by laxatives. Two therapeutic developments make specific and effective prophylaxis and treatment possible: (1) Peripherally acting opioid antagonists that do not cross the blood brain barrier (methylnaltrexone and alvimopan), and (2) the opioid antagonist naloxone added to an opioid agonist in prolonged-release oral formulations (tilidin or oxycodone). Orally administered prolonged-release naloxone is almost completely eliminated during the first-pass through the liver and will therefore not reach opioid receptors in the central nervous system. These drugs relieve both upper and lower gastrointestinal adverse effects of opioid agonists, although their effects on constipation have been the focus of most clinical studies. These new pharmacological principles promise improved management of pain with opioids both for acute and chronic pain conditions.

Combined prolonged-release oxycodone and naloxone improves bowel function in patients receiving opioids for moderate-to-severe non-malignant chronic pain: a randomised controlled trial

Background: This randomised, double-blind, double-dummy, parallel-group multicentre study assessed the impact of a total daily dose of 60-80 mg oral oxycodone prolonged-release (PR)/naloxone PR (OXN PR) as fixed-ratio combination for patients with opioid-induced constipation (OIC) having moderate-to-severe, non-malignant pain. Methods: During pre-randomisation patients receiving opioids for moderate-to-severe non-malignant pain were converted to oxycodone PR (OXY PR) and titrated to an effective analgesic dose. During randomisation 265 patients on a stable OXY PR dose (60-80 mg/day) and with OIC were included in the full analysis population to receive OXN PR or OXY PR alone. Primary outcome was improvement in symptoms of constipation as measured by the Bowel Function Index (BFI). Secondary/exploratory outcomes examined analgesic efficacy and other bowel function parameters. Results: After 4 weeks of treatment, patients receiving OXN PR showed a significant improvement in bowel function compared with those in the OXY PR group (-14.9; 95% CI: -17.9, -11.9; p<0.0001) as measured by BFI which was seen after only 1 week of treatment continuing to the end of the study. After 4 weeks of treatment, patients receiving OXN PR had a median number of 3.0 complete spontaneous bowel movements (CSBM) per week compared with only 1.0 for OXY PR alone. Laxative intake was lower in the OXN PR than the OXY PR group. Furthermore, improvements in bowel function were achieved without loss of analgesic efficacy; pain intensity scores were comparable between the groups and consistent for duration of the study. Most frequently reported adverse events were consistent with those reported for opioid analgesics; no new or unexpected adverse reactions attributable to OXN PR used in higher doses were observed. Conclusion: This study shows that the fixed-ratio combination of OXN PR is superior to OXY PR alone in terms of bowel function, while providing effective equivalent analgesia.