Oxycodone is an opiate analgesic. Naloxone is a competitive opioid-receptor antagonist. At therapeutic oral doses, naloxone exerts a local inhibitory effect on opioid action in the gastrointestinal system. Researchers have studied oxydocone-naloxone, a combination medication, in regard to pain management and in regard to potential to reduce gastrointestinal side effects, such as constipation, in patients who require opioids for pain management.
Leppert, W. (2014). Oxycodone/naloxone in the management of patients with pain and opioid-induced bowel dysfunction. Current Drug Targets, 15, 124-135.
PHASE OF CARE: Multiple phases of care
APPLICATIONS: Palliative care
Oxycodone plus naloxone (OXN) appeared to provide similar analgesic effects as oxycodone, but it also improved bowel function, defined as more frequent and complete spontaneous bowel movements and less consumption of laxatives. In addition, OXN improved the passing of urine in patients with postoperative pain while reducing OIBD, improving compliance, and enhancing quality of life. OXN may be administered to opioid-naïve patients with moderate to severe pain and to patients not responding to weak opioids. The evidence from studies of chronic nonmalignant and cancer-related pain demonstrated the role of OXN in the prevention and treatment of OIBD in patients who required opioid therapy for moderate to severe pain. An evaluation of the value of the literature and studies was not evident in this article.
OIBD is a common complication in patients receiving long-term opioid treatment. The use of OXN was demonstrated by a number of studies to be effective for the management of pain and to have a role in the prevention of OIBD in patients with moderate to severe chronic nonmalignant and cancer-related pain.
Demographic characteristics were generally well-balanced between OXN groups and placebo or oxycodone groups. However, there was a larger sample size of patients with cancer-related pain in one specific study that could have altered the results. There was a high rate of variability in the type of studies that were included, and there was no critical analysis of the literature.
OXN appears to provide similar analgesic effects as oxycodone, but it improves bowel function, defined as more frequent and complete spontaneous bowel movements and a less frequent consumption of laxatives. In addition, patients receiving OXN had improved quality of life scores with decreased OIBD complications.
Ahmedzai, S.H., Nauck, F., Bar-Sela, G., Bosse, B., Leyendecker, P., & Hopp, M. (2012). A randomized, double-blind, active-controlled, double-dummy, parallel-group study to determine the safety and efficacy of oxycodone/naloxone prolonged-release tablets in patients with moderate/severe, chronic cancer pain. Palliative Medicine, 26, 50-60.
To determine whether oxycodone/naloxone prolonged-release tablets (OXN PR), as compared with oxycodone prolonged-release tablets (OxyPR), can improve constipation and maintain analgesia in patients with moderate or severe chronic cancer pain.
Stopping their prestudy opioid and laxative medication, eligible patients were randomized to receive one of two treatments, OXN PR or OxyPR, for a four-week double-blind treatment phase. After beginning the study, patients attended three additional clinic visits, once weekly. Oxycodone immediate-release capsules were available as pain rescue medication and bisacodyl tablets were available as laxative rescue medication. Evaluations of bowel function, pain control, use of rescue medication, and use of laxative medication during the prior seven days were performed at each clinic visit. Quality-of-life (QOL) assessments were conducted at screening and study end.
Patients were undergoing the active treatment phase of care.
This was a randomized, double-blind, active-controlled, double-dummy, parallel-group, phase II trial.
OXN PR, as compared with OxyPR, seems to provide comparable analgesia for patients with moderate or severe cancer pain while significantly improving bowel function and reducing symptoms of constipation.
Demographic characteristics were generally well balanced between treatment groups, with the exception of a slightly higher percentage of patients aged 65 years or younger in the OXN PR group.
OXN PR seems superior to OxyPR with respect to bowel function by reducing constipation without compromising pain relief. In addition, patients receiving OXN PR had improved QOL with decreased opioid-induced constipation complications.
Blagden, M., Hafer, J., Duerr, H., Hopp, M., & Bosse, B. (2014). Long-term evaluation of combined prolonged-release oxycodone and naloxone in patients with moderate-to-severe chronic pain: Pooled analysis of extension phases of two phase III trials. Neurogastroenterology and Motility, 26, 1792–1801.
To evaluate the maintenance of efficacy and safety during long-term treatment with combined oxycodone/naloxone prolonged-release tablets (OXN PR) in adults with moderate-to-severe chronic pain.
474 patients received open-labeled OXN PR during 52 weeks of extension phases of two studies, having completed 12 weeks of double-blinded, randomized treatment with oxycodone prolonged-release tablets (Oxy PR) (n = 160) or OXN PR (n = 162). The starting dose was the effective analgesic dose of OXY or OXN that the patient received at the end of the double-blind phase. Dose titration was to a maximum of 80 mg per day (OXN3001S) or 120 mg per day (OXN3006S) at the discretion of the investigator. Use of laxatives and analgesic rescue therapy was recorded in patient diaries. Oxycodone immediate-release (IR) and bisacodyl were provided for the first seven days of the extension phase. Protocols for rescue medicines and laxatives were prescribed according to standard protocols of the investigational sites. There were seven mandated office visits.
Improvement in bowel function was seen when patients switched from Oxy PR in the double-blinded phase to OXN PR in the extension phase, resulting in a clinical reduction (greater points) in BFI score: At the start of the extension phases, mean BFI score was 44.3 (SD = 28.13) and was 29.8 (SD = 2.36) for patients who had received OXN PR in the double-blinded phase. One week later, BFI scores were similar for the two groups (26.5 [SD = 24.4] and 27.5 [SD = 25.6], respectively), as was observed throughout the following months. Fewer than 10% of patients received laxatives regularly. Mean 24-hour pain scores were low and stable throughout the extension phases. No unexpected adverse events were observed.
Pooled data demonstrated OXN PR in patients with moderate-to-severe chronic pain is an effective long-term therapy for patient opioid-induced pain. Improvement in bowel function was seen during the double-blinded studies and was continued throughout the 52 weeks of OXN PR versus Oxy PR in this pooled analysis. No new or unexpected safety issues were observed, and patient satisfaction was high and maintained throughout the 52 weeks.
Prolonged-release oxycodone/naloxone (OXN PR) is a good option for patients with opioid-induced constipation.
Cuomo, A., Russo, G., Esposito, G., Forte, C.A., Connola, M., & Marcassa, C. (2014). Efficacy and gastrointestinal tolerability of oral oxycodone/naloxone combination for chronic pain in outpatients with cancer: An observational study. American Journal of Hospice and Palliative Medicine, 31, 867–876.
To evaluate the efficacy and tolerability of prolonged-released (PR), fixed-dose oxycodone-naloxone
Patients were prescribed an oral PR oxycodone-naloxone combination for pain control at a dose according to level of pain, age, health status, and previous opioid use.
The reported pain at baseline was severe (VAS = 70.9, SD = 7.8, range = 55–94). Less than a fourth of patients reported somatic or visceral pain only. The majority of patients (73.3%) complained of mixed neuropathic and nociceptive pain. At the first visit, 37.6% of patients reported one to four BTCP episodes (mean = 0.9 + 1.2) during background treatment. The mean baseline BFI score was 43.2 + 14.8, indicating that some degree of bowel dysfunction was already present before starting the new PR oxycodone-naloxone treatment. Almost all (97.6%) patients had abnormal baseline BFI values (i.e. > 28.8, 26), and 41% of patients were already taking laxatives.
This combination was a highly effective analgesic in ambulatory outpatients with cancer experiencing chronic pain. Combination PR oxycodone-naloxone was not associated with adverse effects on bowel function and was equally efficacious and well-tolerated in and opioid-naive and -experienced patients and in young and old patients alike.
This study may provide useful guidance for the daily management of outpatients with advanced cancer experiencing chronic pain. The long-term effectiveness of fixed-combination PR oxycodone-naloxone deserves additional investigation.
Koopmans, G., Simpson, K., De Andres, J., Lux, E. A., Wagemans, M., & Van Megen, Y. (2014). Fixed ratio (2:1) prolonged-release oxycodone/naloxone combination improves bowel function in patients with moderate-to-severe pain and opioid-induced constipation refractory to at least two classes of laxatives. Current Medical Research and Opinion, 30, 2389–2396.
To determine the effect of a combination of oxycodone and naloxone prolonged release tablets (OXN PR) on opioid-induced constipation and pain in patients with moderate to severe cancer- or noncancer-related pain
Patients had received OXN PR in prior double-blinded, multicenter, randomized studies. In one previous study (also a pooled analysis of two Phase III studies), patients with noncancer-related pain received 12 weeks of OXN PR or oxycodone prolonged release (Oxy PR) at the dose equivalent of 20–50 mg per day or 60–120 mg per day. After a 7–28-day period, patients were titrated to an effective analgesic dose of Oxy PR. In a previous Phase II study, patients with moderate to severe cancer-related pain were screened for 3–10 days and then switched to OXN PR or Oxy PR for four weeks (20–120 mg per day). In all prior studies, bisacodyl at 10 mg per day could be taken orally as a rescue laxative 72 hours after a previous bowel movement or when the patient experienced discomfort for a maximum of five doses in seven consecutive days. In all previous studies, data were collected at screening, at the start of the intervention period, and at the end of the intervention period. Laxative use was documented throughout the intervention period in all studies.
The high BFI score at the time of screening indicated that both groups of patients experienced constipation and that patients with cancer-related pain experienced more symptoms. OXN PR clinically and statistically improved constipation in patients with chronic cancer- and noncancer-related pain. Laxative use decreased during the intervention period, and more patients fell within the range of normal bowel habits as the intervention progressed. Pain scores did not change during the intervention period although there was a nonsignificant trend of pain improvement in patients with cancer-related pain.
OXN PR may be a viable pharmacologic intervention to achieve pain control in patients with cancer-related pain while minimizing the symptoms of opioid-induced constipation. OXN PR reduced laxative use and increased the number of patients who reported normal bowel function. OXN PR did not change pain scores.
Lazzari, M., Greco, M.T., Marcassa, C., Finocchi, S., Caldarulo, C., & Corli, O. (2015). Efficacy and tolerability of oral oxycodone and oxycodone/naloxone combination in opioid-naive cancer patients: A propensity analysis. Drug Design, Development and Therapy, 9, 5863–5872.
To compare the analgesic efficacy and safety, and quality of life of oxycodone (OXY) compared with oxycodone/naloxone (OXN) combination in treating opioid-naïve patients
Patients were seen at three or four different times when starting long-acting oxycodone products.
PHASE OF CARE: Multiple phases of care
Retrospective, observational, three data collection time periods—T0, T30, and T60. T15 available for patients who needed closer monitoring.
The patients who received OXN had better early improvement in bowel function than the patients who received OXY (p < 0.001).
OXN and OXY have similar analgesic effects, but OXN seems to have better bowel outcomes.
OXN may have better bowel function outcomes compared with OXY in patients starting analgesics.
Lowenstein, O., Leyendecker, P., Hopp, M., Schutter, U., Rogers, P.D., Uhl, R., . . . Reimer, K. (2009). 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. Expert Opinion on Pharmacotherapy, 10, 531-543.
To show the addition of naloxone improves constipation symptoms in patients with non-malignant pain receiving high-dose oxycodone prolonged release (PR).
Patients were randomized to receive either oxycodone PR and naloxone PR or oxycodone PR plus matched oxycodone PR/naloxone placebo. Patients had oxycodone PR titrated to an effective analgesic dose over a 7- to 28-day period and were converted to the study laxative, bisacodyl. Oxycodone immediate release was used as pain rescue medication. Patients were eligible to participate in a 52-week open-label extension. Mean pain over the past 24 hours and bowel function were measured at each study visit and in patient diaries on a daily basis.
This was a double-blind, placebo-controlled, randomized study with an extension phase.
Oxycodone PR/naloxone PR was superior to oxycodone PR at improving bowel function and symptoms of constipation. That improvement was achieved without affecting the analgesic efficacy of the oxycodone component.
The combination of oxycodone PR/naloxone PR in patients with cancer warrants investigation to determine potential benefits in reducing opioid-induced constipation in this population.
Meissner, W., Leyendecker, P., Mueller-Lissner, S., Nadstawek, J., Hopp, M., Ruckes, C., . . . Reimer, K. (2009). A randomised controlled trial with prolonged-release oral oxycodone and naloxone to prevent and reverse opioid-induced constipation. European Journal of Pain (London, England), 13, 56-64.
To assess the impact of orally administered prolonged-release (PR) naloxone on the analgesic effectiveness of PR oxycodone and on constipation in patients with severe chronic pain.
The study comprised three phases:
This was a prospective, placebo-controlled, randomized, double-blind, parallel-group, phase II study.
The study provided evidence that a combination of PR oxycodone/PR naloxone in a 2:1 ratio could enable patients with chronic pain to achieve both adequate pain control and bowel evacuation function.
The study only looked at oxycodone for pain control and did not include many patients with cancer.
An oral combination of PR oxycodone/PR naloxone in a 2:1 ratio seems to improve bowel function without compromising analgesia in patients with chronic pain. Additional study should include patients with cancer and a variety of other opioids.
Nadstawek, J., Leyendecker, P., Hopp, M., Ruckes, C., Wirz, S., Fleischer, W., & Reimer, K. (2008). Patient assessment of a novel therapeutic approach for the treatment of severe, chronic pain. International Journal of Clinical Practice, 62, 1159–1167.
In this three-phase study, patients with inadequate pain control entered the titration period, with stabilization at 40, 60, or 80 mg oxycodone PR/day. Those on stable oxycodone dosing who used laxatives to have three bowel movements per week were entered in the maintenance phase after a seven-day run-in period. After patients were stabilized, they were randomized into three naloxone treatment groups or a placebo group. Oxycodone was given open label; naloxone was given in double-blind fashion. After a patient was in the maintenance phase, no titration of oxycodone PR doses was allowed. Those using laxatives were advised to stop unless no bowel movement had occurred for three days. Patients were studied for four weeks, then assessed in a two-week follow-up phase. In the follow-up phase, no one received naloxone PR.
Prospective randomized double-blind, parallel-group, phase II trial
Concurrent administration of oxycodone PR and naloxone PR is effective for the treatment of patients with severe chronic pain, cancer-related or not. Patients tolerated naloxone PR well; naloxone created no additional untoward effects.
This study's results relate to pain control and bowel function of patients with cancer. Additional research, to investigate widening application of the findings, is warranted.
Schutter, U., Grunert, S., Meyer, C., Schmidt, T., & Nolte, T. (2010). Innovative pain therapy with a fixed combination of prolonged-release oxycodone/naloxone: A large observational study under conditions of daily practice. Current Medical Research and Opinion, 26, 1377–1387.
To evaluate the safety and efficacy of combined prolonged-release (PR) oxycodone and PR naloxone for treatment of cancer-related pain in daily practice
Patients with severe chronic pain requiring strong analgesics entered a four-week observational period, during which they received PR oxycodone–PR naloxone. The physician determined dosage. Dose adjustments, comedication, rescue medication, and other treatments were also at the discretion of the physician. Follow-up visits occurred after the first week and at the end of the four-week observation. Data were gathered using interviewer-administered questionnaires.
PR oxycodone–PR naloxone was associated with effective analgesia and reduction in symptoms of opioid-induced bowel dysfunction. This combination was associated with minimal adverse events.
The fixed combination of PR oxycodone–PR naloxone may be effective in managing chronic pain and cause few problems, such as constipation, which opioids typically cause.
Simpson, K., Leyendecker, P., Hopp, M., Muller-Lissner, S., Lowenstein, O., De Andres, J., . . . Reimer, K. (2008). Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe noncancer pain. Current Medical Research and Opinion, 24, 3503-3512.
To demonstrate improvement in constipation in individuals on prolonged-release (PR) oxycodone and PR naloxone compared with individuals receiving single-agent PR oxycodone.
Prerandomization comprised a run-in phase for conversion and titration of prestudy pain medication regimen to the PR oxycodone and bisacodyl laxative regimen. In the double-blind phase, patients were randomized to receive one of the following for 12 weeks: PR oxycodone/PR naloxone in a 2:1 ratio and PR oxycodone placebo, or PR oxycodone alone and PR oxycodone/PR naloxone placebo. All patients completing the double-blind phase were eligible to enter a 52-week extension phase and receive PR oxycodone/PR naloxone.
This was a randomized, double-blind, parallel-group, phase III study.
PR oxycodone/PR naloxone demonstrated superiority in the management of constipation in patients with chronic noncancer pain without compromising analgesia.
The study only included patients with noncancer pain.
PR oxycodone/PR naloxone may be effective in the management of constipation without compromising pain control for patients with chronic pain. However, the study did not include patients with cancer or patients receiving doses of oxycodone equivalent higher than 50 mg/day. Additional studies are warranted with higher doses of opioids and the inclusion of patients with cancer.