Recommended for Practice

Oxycodone/Naloxone

for Constipation

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.

Systematic Review/Meta-Analysis

Leppert, W. (2014). Oxycodone/naloxone in the management of patients with pain and opioid-induced bowel dysfunction. Current Drug Targets, 15, 124-135. 

Purpose

STUDY PURPOSE: To review the literature evaluating approaches to the management of opioid-induced bowel dysfunction (OIBD) and the combination of an opioid agonist with an opioid receptor antagonist versus the administration of purely peripherally-acting opioid receptor antagonists
 
TYPE OF STUDY: General review, semisystematic

Search Strategy

DATABASES USED: PubMed and MEDLINE databases till July 31, 2013
 
KEYWORDS: Opioid-induced bowel dysfunction, opioid-induced constipation, opioid receptor antagonists, oxycodone/naloxone, pain
 
INCLUSION CRITERIA: All studies of were of oxycodone and naloxone and were randomized, controlled trials or open, uncontrolled studies. Studies on pharmacokinetics and pharmacodynamics of oxycodone/naloxone also were included.
 

Literature Evaluated

TOTAL REFERENCES RETRIEVED: 65
 
EVALUATION METHOD AND COMMENTS ON LITERATURE USED: Not explained

Sample Characteristics

FINAL NUMBER STUDIES INCLUDED = 18
 
KEY SAMPLE CHARACTERISTICS: Patients with chronic, nonmalignant pain; patients with cancer-related pain; and patients with postoperative pain

Phase of Care and Clinical Applications

PHASE OF CARE: Multiple phases of care
 
APPLICATIONS: Palliative care

Results

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.

Conclusions

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.

Limitations

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.

Nursing Implications

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.

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Research Evidence Summaries

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.

Study Purpose

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.  

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • In this sample, 133 of 184 patients (72.3%) completed the study.
  • Patients were aged 18 years or older. Mean patient age was 61.86 years (SD = 10.93, median = 62, range 36-84) in the OXN PR group and 64.3 years (SD = 9.63, median = 66, range 42-82) in the OxyPR group. 
  • The OXN PR group was 52% male and 48% female, whereas the OxyPR group was 50% male and 50% female.
  • Key disease characteristics were having a diagnosis of cancer and moderate or severe, chronic pain requiring around-the-clock opioid therapy, with constipation induced or worsened by the opioid medication.
  • Patients were excluded if they had clinically unstable disease; significant cardiovascular, renal, hepatic, or psychiatric disease; clinically significant gastrointestinal (GI) disease; significant structural abnormality of the GI tract; cyclic chemotherapy within two weeks before the screening visit; planned chemotherapy during the study; or radiotherapy that would influence bowel function or pain.

Setting

  • Multi-site
  • Outpatient
  • International  (64 study sites in Australia, Czech Republic, France, Germany, Hungary, Israel, Netherlands, Poland, and United Kingdom)

Phase of Care and Clinical Applications

Patients were undergoing the active treatment phase of care.

Study Design

This was a randomized, double-blind, active-controlled, double-dummy, parallel-group, phase II trial.

Measurement Instruments/Methods

  • Bowel Function Index (BFI)
  • Brief Pain Inventory (Short Form) (BPI-SF)
  • EuroQol EQ-5D
  • European Organization for Research and Treatment of Cancer Core Quality of Life Questionnaire (EORTC QLQ-C30)
  • Patient Assessment of Constipation Symptoms (PAC-SYM)
  • Modified Subjective Opiate Withdrawal Scale (SOWS)
     

Results

  • Mean BFI score was significantly lower in the OXN PR group (p ˂ 0.01) after four weeks of treatment.
  • Mean total laxative intake was 20% lower in the OXN PR group, but the difference was not statistically significant (p = 0.17).
  • Mean BPI-SF scores and analgesic rescue medication use were similar for both groups.
  • The OXN PR group had greater improvements in constipation-specific QOL assessments in terms of total symptom score (p = 0.014) and frequency of symptoms (p ˂ 0.01).
  • Adverse events were similar and low in both groups.

Conclusions

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.

Limitations

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. 

Nursing Implications

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.

Print

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. 

Study Purpose

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.

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • N = 474  
  • AGE = 362 aded 65 and younger; 112 older than age 65
  • MALES: 36.9%, FEMALES: 63.1%

Setting

  • SITE: Multi-site    
  • SETTING TYPE: Not specified

Phase of Care and Clinical Applications

  • PHASE OF CARE: Mutliple phases of care

Study Design

  • Pooled analysis of two Phase III double-blind, randomized studies

Measurement Instruments/Methods

  • Analgesia and bowel function were assessed at each study visit using average pain over last 24 hours scale and Bowel Function Index (BFI).
  • Treatment Satisfaction Questionnaire for Medication (TSQM) was assessed at end of study only.

Results

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.

Conclusions

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.

Limitations

  • Risk of bias (no control group)
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)

 

Nursing Implications

Prolonged-release oxycodone/naloxone (OXN PR) is a good option for patients with opioid-induced constipation.

Print

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. 

Study Purpose

To evaluate the efficacy and tolerability of prolonged-released (PR), fixed-dose oxycodone-naloxone

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • N = 206  
  • MEAN AGE = 61.3 years (SD = 2.9 years), 89 (43.2%) g5 years or older
  • MALES: 47.1%, FEMALES: 52.9%
  • KEY DISEASE CHARACTERISTICS: Advanced cancer; moderate to  severe chronic pain
  • OTHER KEY SAMPLE CHARACTERISTICS: Constipation

Setting

  • SITE: Single site  
  • SETTING TYPE: Outpatient
  • LOCATION: Clinic

Phase of Care and Clinical Applications

  • PHASE OF CARE: Multiple phases of care
  • APPLICATIONS: Elder care and palliative care 

Study Design

  • Retrospective, 28-day, observational analysis

Measurement Instruments/Methods

  • Visual Analog Scale (VAS)
  • Bowel Function Index (BFI)

Results

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.

Conclusions

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.

Limitations

  • Findings not generalizable
  • Other limitations/explanation: Retrospective observational design; short time of observation; and the single-center nature of the study

Nursing Implications

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.

Print

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. 

Study Purpose

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

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • N = 75  
  • MEDIAN AGE = 62 years (range = 40–80 years)
  • MALES: Unknown, FEMALES: Unknown
  • OTHER KEY SAMPLE CHARACTERISTICS: 53.3% of patients had cancer-related pain.

Setting

  • SITE: Multi-site    
  • SETTING TYPE: Not specified  
  • LOCATION: Netherlands

Phase of Care and Clinical Applications

  • PHASE OF CARE: Multiple phases of care
  • APPLICATIONS: Elder care 

Study Design

Pooled analysis

Measurement Instruments/Methods

  • Bowel Function Index (BFI)
  • Brief Pain Inventory Short Form (BPI-SF)
  • Documentation of adverse effects 

Results

The overall BFI score at screening was 62.5 (SD = 18.7) in patients with and without cancer-related pain, and it was 66.4 in patients with cancer-related pain. Scores on the BFI scale decreased at the end of the intervention period (in the second study, patients with cancer) showing a decrease of 19 (SD = 28.9) after 24.7 days of treatment (p = .0002). The number of patients who had a BFI score within the normal range increased in patients with cancer-related pain from 5.1% prior to randomization to 27.8% on day 8 and 36.4% on day 15. Patients in all studies reported using at least two types of laxatives prior to study enrollment, and 64% of patients in both groups used the study laxative during the intervention period. Throughout the intervention period, 36% of patients in both groups (cancer- and noncancer-related pain) stopped using laxatives (p < .001). Laxative use was more frequent in patients with cancer-related pain (82.5%, median = 6 [range = 1–20] tablets) compared to noncancer-related pain (42.9%, median = 10 [range = 1–36] tablets). The mean daily dose of study laxative in patients with cancer-related pain was 2.1 mg.
 
No difference was seen in pain scores. A nonsignificant trend was seen in improving pain scores in patients with cancer-related pain (mean change = -0.4, p = .311). A significant decrease was seen in the median dose of rescue medication (OXY IR) in patients with cancer-related pain from days 1–7 (3.93 mg) to days 29–35 (1.25 mg, p = .0018). 27.5% of patients with cancer-related pain reported adverse events, and severe adverse events were more common in patients with cancer-related pain versus noncancer-related pain (25% versus 2.9%). The most common adverse events were constipation (9.3%), nausea (9.3%), and vomiting (8%).

Conclusions

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.

Limitations

  • Small sample (< 100)
  • Findings not generalizable
  • Other limitations/explanation: The studies that were used differed in length of treatment (4 versus 12 weeks). Demographic information was limited although the authors stated that there was no difference between the groups. Only 40 patients with cancer-related pain were included in the analysis. It appears as though some of the patients with cancer-related pain were receiving end-of-life care, but this is not entirely clear. Limited outcomes were reported for pain.

Nursing Implications

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.

Print

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. 

Study Purpose

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

Intervention Characteristics/Basic Study Process

Patients were seen at three or four different times when starting long-acting oxycodone products.

Sample Characteristics

  • N = 131   
  • AGE = 62 years
  • MALES: 52.1%, FEMALES: 47.9%
  • CURRENT TREATMENT: Not applicable
  • KEY DISEASE CHARACTERISTICS: Solid tumor
  • OTHER KEY SAMPLE CHARACTERISTICS: Pain

Setting

  • SITE: Single site   
  • SETTING TYPE: Not specified    
  • LOCATION: Rome, Italy

Phase of Care and Clinical Applications

PHASE OF CARE: Multiple phases of care

Study Design

Retrospective, observational, three data collection time periods—T0, T30, and T60. T15 available for patients who needed closer monitoring.

Measurement Instruments/Methods

  • Pain intensity
  • Neuropathic pain using Douleur Neuropathique 4 questionnaire
  • Daily dose of medications
  • Dose increments
  • Quality of life
  • Chronic Pain Sleep Inventory
  • Physical and Mental Component Summary scores of the Short Form-12 Health Survey Questionnaire
  • Bowel Function Index
  • Safety evaluations

Results

The patients who received OXN had better early improvement in bowel function than the patients who received OXY (p < 0.001).

Conclusions

OXN and OXY have similar analgesic effects, but OXN seems to have better bowel outcomes.

Limitations

  • Baseline sample/group differences of import
  • Risk of bias (no control group)
  • Risk of bias (no blinding)
  • Risk of bias (no random assignment)
  • Key sample group differences that could influence results 
  • Measurement/methods not well described
  • Subject withdrawals ≥ 10%

Nursing Implications

OXN may have better bowel function outcomes compared with OXY in patients starting analgesics.

Print

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.

Study Purpose

To show the addition of naloxone improves constipation symptoms in patients with non-malignant pain receiving high-dose oxycodone prolonged release (PR).

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • The study reported on a sample of 222 patients (81.5% female and 18.5% male).
  • Mean age was 56.2 to 57.5 years (SD = 10.5) across both study groups.
  • Patients with cancer-related pain were excluded.
  • Predominant problems were musculoskeletal and connective tissue disorders.
  • Patients required 60 to 80 mg oxycodone PR equivalent per day and had constipation.

Setting

  • Multi-site
  • Outpatient
  • Germany

Study Design

This was a double-blind, placebo-controlled, randomized study with an extension phase.

Measurement Instruments/Methods

  • Bowel Function Index (BFI)
  • Pain Intensity Scale (numeric rating 0-10)
  • Patient Assessment of Constipation Symptoms Questionnaire (PAC-SYMN)
  • Subjective Opioid Withdrawal Scale (SOWS)
  • Patient diary

Results

  • During the first four weeks of the study in the double-blind phase, the difference in mean BFI scores was significantly different (PR = -14.9, p < 0.0001, 95% confidence interval [-17.9, -11.9]) in favor of the oxycodone-PR/naloxone-PR group.
  • There were no differences between groups in mean pain measures.
  • There were no substantial differences between groups in supplemental analgesic use.
  • Significantly fewer patients in the oxycodone-PR/naloxone-PR group took laxatives (p = 0.0009).
  • Most common events were nausea, pain, and headache in both groups.
  • Withdrawal scores were stable, low, and similar between groups.

Conclusions

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.

Limitations

  • The study period of 12 weeks is limited in the setting of much longer-term opioid use.
  • Although the study design specified a maximum number of laxative rescue doses, actual rescue laxatives taken were not described and were not analyzed between the two groups.
  • Patients with cancer-related pain were specifically excluded; therefore, application to that group is not clear.

Nursing Implications

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.

Print

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.

Study Purpose

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.

Intervention Characteristics/Basic Study Process

The study comprised three phases:

  1. Patients entered either a two-week titration or a seven-day run-in period. Patients were individually titrated and stabilized on an oxycodone PR dose of 40, 60, or 80 mg/day.
  2. Patients were randomized to four study groups, each comprising a balanced ratio of 40-, 60-, or 80-mg PR oxycodone with placebo or 10- to 40-mg naloxone. Rescue pain medication (up to five 10-mg oxycodone doses per week) was allowed during the maintenance phase.
  3. In a two-week open-label phase, patients stopped naloxone therapy and continued PR oxycodone.

Sample Characteristics

  • The study reported on a sample of 202 patients aged older than 18 years, with a mean age of 53.8 years.
  • The sample comprised 75 men (37.1%) and 127 women (62.9%).
  • Only 2.5% of the original 202 screened patients had cancer.
  • Most common pain-causing diseases or conditions were back pain (24.3%) and postoperative complications (15.3%).
  • Mean duration of pain was 149.3 months.

Setting

  • Multi-site
  • 28 sites in Germany

Study Design

This was a prospective, placebo-controlled, randomized, double-blind, parallel-group, phase II study.

Measurement Instruments/Methods

  • Bowel Function Index (BFI)
  • Numerical Analog Scale (NAS) for pain assessment

Results

  • At week 6, BFI score was statistically significantly different between the 40-mg naloxone and placebo control groups, showing a decrease of severity in bowel dysfunction with naloxone (p = 0.004). 
  • At the end of week 8, both 20- and 40-mg naloxone groups had significant differences in BFI scores compared with placebo (p < 0.05).
  • No differences existed in mean pain scores between treatment groups at any study time points.
  • Titration of participants off of PR oxycodone/naloxone back to single PR oxycodone regimens during the open-label phase resulted in decreased bowel function, and BFI scores returned almost to baseline.
  • The incidence of adverse events (AEs), most of which were mild to moderate, was comparable across all treatment groups, although the number of AEs increased along with naloxone dosage.

Conclusions

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.

Limitations

The study only looked at oxycodone for pain control and did not include many patients with cancer.

Nursing Implications

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.

Print

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. 

Study Purpose

  • To assess the analgesic efficacy of prolonged-release (PR) oxycodone in combination with orally administered naloxone PR in patients with severe, chronic pain; to evaluate the efficacy of that combination in improving bowel function
  • To evaluate the optimal dose ratio of oxycodone PR to naloxone PR
  • To evaluate patients’ and investigators’ treatment preference

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • The intent-to-treat (ITT) group, defined as those who were randomized and received at least one dose of naloxone or placebo and had at least one efficacy assessment, comprised 196 patients; 166 patients completed the study.
  • Patients were older than 18 years.
  • The sample was 62.9% female and 37.1% male.
  • Specific cancer type was not reported.

Setting

  • Multisite
  • Outpatient
  • Twenty-eight centers in Germany, May 2002 to April 2003

Study Design

Prospective randomized double-blind, parallel-group, phase II trial

Measurement Instruments/Methods

  • Rating scale (1 = very good, 7 = very poor), to measure efficacy and tolerability, used independently by investigators and patients
  • Preference, in regard to tolerability and efficacy, for maintenance phase or titration–run-in phase (1 = titration–run-in, 2 = maintenance, 3 = no preference)

Results

  • The efficacy of the 2:1 dose ratio of oxycodone PR to naloxone PR was ranked as good or very good by 70.4% of patients and investigators.
  • The tolerability of the 2:1 dose ratio was ranked as good or very good by 81.5% of patients and investigators.
  • The majority of patients in the treatment arm preferred the maintenance phase, in which they received both medications.
  • Naloxone PR had no impact on the analgesic efficacy of oxycodone PR; naloxone PR improved bowel function and reduced laxative intake.

Conclusions

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.

Limitations

  • Exclusion of patients with severe cardiovascular or pulmonary issues limits the applicability of findings to patients with advanced cancers and those taking more than five medications per week to control breakthrough pain.
  • Oxycodone PR dosing was limited to 40–80 mg/day.

Nursing Implications

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.

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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.

Study Purpose

To evaluate the safety and efficacy of combined prolonged-release (PR) oxycodone and PR naloxone for treatment of cancer-related pain in daily practice

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • The sample was composed of 7,836 patients.
  • Mean patient age was 65.8 years (SD = 13.6 years).
  • Approximately 61% of patients were female and 39% were male.
  • Of all patients, 17% had cancer; other diagnoses were musculoskeletal and nervous system disorders.
  • Of all patients, 75% had been treated with opioids and 25% were opioid naive.
  • Patients were treated by primary care physicians, anesthesiologists, and physicians with pain specialization.

Setting

  • Multisite
  • Outpatient
  • Germany (6,496 sites)

Study Design

Observational

Measurement Instruments/Methods

  • Brief Pain Inventory (BPI)
  • Numeric pain rating scale, 0–100
  • Bowel Function Index (BFI)
  • Global rating scale (1 = very good, 5 = very bad)

Results

  • At baseline, the strongest pain score was 6.8 (SD = 1.8). That score declined to 3.9 (SD = 2.1) at the final follow-up visit (p < 0.001). A similar decline occurred in least, current, and mean pain intensity scores (p < 0.001).
  • Rescue medication was prescribed to 11.5% of patients at the first visit and 9.5% at the first follow-up visit, one week later.
  • Authors observed significant improvement in bowel function as measured by the BFI (p < 0.001). Improvement in bowel function was greater in those previously treated with opioids.
  • Other symptoms associated with opioid use also declined.
  • A total of 3,881 adverse events occurred in 1,566 patients (20% of patients).
  • The most frequent adverse events were nausea, constipation, and diarrhea.
  • Treatment with PR oxycodone–PR naloxone was discontinued in 1,157 patients (14.8%) because of adverse events or lack of efficacy.
  • At the third follow-up visit, 54.5% of patients were receiving 10 mg-5 mg (PR oxycodone–PR naloxone) twice a day and 31.3% were receiving 20 mg-10 mg twice a day.

Conclusions

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.

Limitations

  • The study had risk of bias due to no appropriate control group.
  • The design was observational, with a limited follow-up period.
  • Authors did not discuss rescue medication or how rescue medications, medication changes, or other treatments may have affected results.
  • A relatively small proportion of patients had cancer. Authors provided no subgroup analysis of different groups of patients.

Nursing Implications

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.

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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.

Study Purpose

To demonstrate improvement in constipation in individuals on prolonged-release (PR) oxycodone and PR naloxone compared with individuals receiving single-agent PR oxycodone.

Intervention Characteristics/Basic Study Process

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.

Sample Characteristics

  • The study reported on a sample of 277 patients aged 18 years or older.
  • Patients had a documented history of the following:
    • Moderate-to-severe chronic noncancer pain (eg, musculoskeletal, neuropathic, visceral), needing 24-hour coverage with an oxycodone equivalent of 20 to 50 mg/day
    • Constipation caused or worsened by an opioid
    • Expectation of benefit from the World Health Organization (WHO) step III opioid therapy treatment for the duration of the study.

Setting

  • Multi-site
  • Outpatient
  • 4 European countries

Study Design

This was a randomized, double-blind, parallel-group, phase III study.

Measurement Instruments/Methods

  • Bowel Function Index (BFI)
  • Patient Assessment of Opioid Induced Constipation (PACOI)
  • Patient Assessment of Constipation Symptom Questionnaire (PAC-SYM)
  • Pain Intensity Scale
  • Brief Pain Inventory (Short Form) (BPI-SF)

Results

  • At week 4, the mean BFI score for the PR oxycodone/PR naloxone group decreased by 26.9 points. In contrast, the mean BFI score for the PR oxycodone group decreased by 9.4 points. The difference between those scores was significantly in favor of the PR oxycodone/PR naloxone group (p < 0.0001).
  • At week 4, the mean PACOI score in the PR oxycodone/PR naloxone group decreased to 6.4% compared to 9.4% in the PR oxycodone group, showing statistically significant improvement (p < 0.0001).
  • During the first four weeks, significantly fewer patients in the PR oxycodone/PR naloxone group took bisacodyl compared with the PR oxycodone group (p < 0.0001).
  • No statistically significant difference existed between the two groups for efficacy of pain control.
  • Mean pain intensity scores remained stable throughout the study.
  • Twelve patients (three in the PR oxycodone/PR naloxone group and 9 in the PR oxycodone group) experienced serious adverse events, including gastrointestinal bleeding, headache, and cerebrovascular accident.

Conclusions

PR oxycodone/PR naloxone demonstrated superiority in the management of constipation in patients with chronic noncancer pain without compromising analgesia.

Limitations

The study only included patients with noncancer pain.

Nursing Implications

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.

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