BACKGROUND: Opioids provide effective relief from moderate-to-severe pain and should be prescribed as part of a multifaceted approach to pain management when other treatments have failed. Fixed-dose oxycodone/naloxone prolonged-release tablets (OXN PR) were designed to address the opioid class effect of opioid-induced constipation (OIC) by combining the analgesic efficacy of oxycodone with the opioid receptor antagonist, naloxone, which has negligible systemic availability when administered orally. This formulation has abuse-deterrent properties, since systemic exposure to naloxone by parenteral administration would antagonize the euphoric effects of oxycodone.
METHODS: A literature search was conducted to assess the evidence base for OXN PR to treat moderate-to-severe pain and its impact on bowel function, based on published clinical trials and observational studies.
RESULTS: Extensive data demonstrate that OXN PR provides effective analgesia and clinically relevant improvements in bowel function in patients with OIC and moderate-to-severe cancer-related pain and noncancer pain types such as low back pain, neuropathic pain, and musculoskeletal pain. OXN PR has also been found to improve bowel function in patients with OIC refractory to multiple types of laxatives, and improve Parkinson's disease-related pain. No unanticipated safety concerns have been reported in elderly patients.
CONCLUSIONS: Evidence from clinical trials and observational studies confirms that for selected patients OXN PR significantly improves moderate-to-severe chronic pain and provides relief from OIC. Treatment should be tailored to individual patients to establish the lowest effective dose. An absence of analgesic ceiling effect was seen across the clinically relevant dose range investigated (≤ 160/80 mg/day).
BACKGROUND: A 2007 American College of Physicians guideline addressed pharmacologic options for low back pain. New evidence and medications have now become available.
PURPOSE: To review the current evidence on systemic pharmacologic therapies for acute or chronic nonradicular or radicular low back pain.
DATA SOURCES: Ovid MEDLINE (January 2008 through November 2016), Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and reference lists.
STUDY SELECTION: Randomized trials that reported pain, function, or harms of systemic medications versus placebo or another intervention.
DATA EXTRACTION: One investigator abstracted data, and a second verified accuracy; 2 investigators independently assessed study quality.
DATA SYNTHESIS: The number of trials ranged from 9 (benzodiazepines) to 70 (nonsteroidal anti-inflammatory drugs). New evidence found that acetaminophen was ineffective for acute low back pain, nonsteroidal anti-inflammatory drugs had smaller benefits for chronic low back pain than previously observed, duloxetine was effective for chronic low back pain, and benzodiazepines were ineffective for radiculopathy. For opioids, evidence remains limited to short-term trials showing modest effects for chronic low back pain; trials were not designed to assess serious harms. Skeletal muscle relaxants are effective for short-term pain relief in acute low back pain but caused sedation. Systemic corticosteroids do not seem to be effective. For effective interventions, pain relief was small to moderate and generally short-term; improvements in function were generally smaller. Evidence is insufficient to determine the effects of antiseizure medications.
LIMITATIONS: Qualitatively synthesized new trials with prior meta-analyses. Only English-language studies were included, many of which had methodological shortcomings. Medications injected for local effects were not addressed.
CONCLUSION: Several systemic medications for low back pain are associated with small to moderate, primarily short-term effects on pain. New evidence suggests that acetaminophen is ineffective for acute low back pain, and duloxetine is associated with modest effects for chronic low back pain.
PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. (PROSPERO: CRD42014014735).
BACKGROUND: Opioid drugs, including hydromorphone, are commonly used to treat neuropathic pain, and are considered effective by some professionals. Most reviews have examined all opioids together. This review sought evidence specifically for hydromorphone, at any dose, and by any route of administration. Other opioids are considered in separate reviews.This review is part of an update of a previous review, Hydromorphone for acute and chronic pain that was withdrawn in 2013 because it needed updating and splitting to be more specific for different pain conditions. This review focuses only on neuropathic pain.
OBJECTIVES: To assess the analgesic efficacy of hydromorphone for chronic neuropathic pain in adults, and the adverse events associated with its use in clinical trials.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), via the CRSO; MEDLINE via Ovid; and EMBASE via Ovid from inception to 17 November 2015, together with reference lists of retrieved papers and reviews, and two online study registries.
SELECTION CRITERIA: We included randomised, double-blind studies of two weeks' duration or longer, comparing hydromorphone (at any dose, by any route of administration, or in any formulation) with placebo or another active treatment in chronic neuropathic pain.
DATA COLLECTION AND ANALYSIS: Two review authors independently searched for studies, extracted efficacy and adverse event data, and examined issues of study quality. We did not carry out any pooled analyses. We assessed the quality of the evidence using GRADE (Grading of Recommendations Assessment, Development and Evaluation).
MAIN RESULTS: Searches identified seven publications relating to four studies. We excluded three studies. One post hoc (secondary) analysis of a study published in four reports assessed the efficacy of hydromorphone in neuropathic pain, satisfied our inclusion criteria, and was included in the review. The single included study had an enriched enrolment, randomised withdrawal design with 94 participants who were successfully switched from oral morphine to oral hydromorphone extended release (about 60% of those enrolled). These participants were then randomised to continuing hydromorphone for 12 weeks or tapering down the hydromorphone dose to placebo. The methodological quality of the study was generally good, but we judged the risk of bias for incomplete outcome data as unclear, and for study size as high.Since we identified only one study for inclusion, we were unable to carry out any analyses. The included study did not report any of our prespecified primary outcomes, which relate to the number of participants achieving moderate or substantial levels of pain relief. It did report a slightly larger increase in average pain intensity for placebo in the randomised withdrawal phase than for continuing with hydromorphone. It also reported the number of participants who withdrew due to lack of efficacy in the randomised withdrawal phase, which may be an indicator of efficacy. However, in addition to using an enriched enrolment, randomised withdrawal study design, there was an unusual choice of imputation methods for withdrawals (about 50% of participants); the evidence was of very low quality and inadequate to make a judgement on efficacy. Adverse events occurred in about half of participants with hydromorphone, the most common being constipation and nausea. A similar proportion of participants experienced adverse events with placebo, the most common being opioid withdrawal syndrome (very low quality evidence). Most adverse events were mild or moderate in intensity. One in eight participants withdrew while taking hydromorphone during the conversion and titration phase, despite participants being opioid-tolerant (very low quality evidence).We downgraded the quality of the evidence to very low because there was only one study with few participants, it did not report clinically useful efficacy outcomes, and it was a post hoc analysis.
AUTHORS' CONCLUSIONS: There was insufficient evidence to support or refute the suggestion that hydromorphone has any efficacy in any neuropathic pain condition.
Back pain affects most adults, causes disability for some, and is a common reason for seeking healthcare. In the United States, opioid prescription for low back pain has increased, and opioids are now the most commonly prescribed drug class. More than half of regular opioid users report back pain. Rates of opioid prescribing in the US and Canada are two to three times higher than in most European countries. The analgesic efficacy of opioids for acute back pain is inferred from evidence in other acute pain conditions. Opioids do not seem to expedite return to work in injured workers or improve functional outcomes of acute back pain in primary care. For chronic back pain, systematic reviews find scant evidence of efficacy. Randomized controlled trials have high dropout rates, brief duration (four months or less), and highly selected patients. Opioids seem to have short term analgesic efficacy for chronic back pain, but benefits for function are less clear. The magnitude of pain relief across chronic non-cancer pain conditions is about 30%. Given the brevity of randomized controlled trials, the long term effectiveness and safety of opioids are unknown. Loss of long term efficacy could result from drug tolerance and emergence of hyperalgesia. Complications of opioid use include addiction and overdose related mortality, which have risen in parallel with prescription rates. Common short term side effects are constipation, nausea, sedation, and increased risk of falls and fractures. Longer term side effects may include depression and sexual dysfunction. Screening for high risk patients, treatment agreements, and urine testing have not reduced overall rates of opioid prescribing, misuse, or overdose. Newer strategies for reducing risks include more selective prescription of opioids and lower doses; use of prescription monitoring programs; avoidance of co-prescription with sedative hypnotics; and reformulations that make drugs more difficult to snort, smoke, or inject.
Background: We updated a systematic review on the comparative efficacy, tolerability and safety of opioids and of their routes of application in chronic noncancer pain (CNCP).
Methods: We screened MEDLINE, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL) up until October 2013, as well as the reference sections of original studies and systematic reviews of randomized controlled trials (RCTs) of opioids in CNCP. We included randomized head-to-head comparisons of opioids (opioid of the sponsor of the study versus standard opioid) of at least 4 week’s duration. Using a random effects model, absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables. The quality of evidence was rated by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.
Results: We included 13 RCTs with 6748 participants. Median study duration was 15 weeks (range 4–56 weeks). Hydromorphone, morphine, oxymorphone and tapentadol were compared to oxycodone; fentanyl to morphine and buprenorphine to tramadol. In pooled analysis, there were no significant differences between the two groups of opioids in terms of mean pain reduction (low-quality evidence), the patient global impression to be much or very much improved outcome (low-quality evidence), physical function (very low-quality evidence), serious adverse events (moderate-quality evidence) or mortality (moderate-quality evidence). There was no significant difference between transdermal and oral application of opioids in terms of mean pain reduction, physical function, serious adverse events, mortality (all low-quality evidence) or dropout due to adverse events (very low-quality).
Conclusion: Pooled head-to-head comparisons of opioids (opioid of the sponsor of the study versus standard opioid) provide no rational for preferring one opioid and/or administration route over another in the therapy of patients with CNCP.
The English full-text version of this article is freely available at SpringerLink (under “Supplemental”).
BACKGROUND: Chronic musculoskeletal pain is a prevalent condition and a major cause of disability and absence from the workplace worldwide. Opioids are frequently used to treat chronic pain, although adverse effects often restrict their long-term benefits. Tapentadol is an opioid and norepinephrine re-uptake inhibitor, which may cause a lower incidence (and severity) of adverse effects compared to other strong opioids.
OBJECTIVES: To determine the efficacy, safety and tolerability of tapentadol extended release for moderate-to-severe pain for at least three months for any musculoskeletal cause.
SEARCH METHODS: We searched electronic databases (CENTRAL, MEDLINE, EMBASE, Web of Science) to March 2014, unrestricted by language, as well as trials registers and reference lists from retrieved studies. We contacted drug manufacturers for further information.
SELECTION CRITERIA: Randomised controlled trials (RCTs) of tapentadol in people with chronic musculoskeletal pain, compared to placebo or active control.
DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed risk of bias of included studies and extracted data. We performed two meta-analyses for the comparisons tapentadol extended release vs. placebo, and tapentadol extended release vs. active-control (oxycodone). We used random-effects and fixed-effect models according to the presence or not of heterogeneity, respectively. Also, we performed subgroup analyses. The primary efficacy outcome was pain control assessed by change in pain intensity scores and responder's rate (at least 50% pain relief). Primary safety outcome was withdrawal rate due to adverse effects.
MAIN RESULTS: Four parallel-design RCTs of moderate quality including 4094 patients with osteoarthritis or back pain, or both, met the inclusion criteria. Three trials were phase III studies with 12-weeks follow-up and the fourth trial was an open-label safety study of 52-weeks follow-up. All trials were oxycodone-controlled and three were also placebo-controlled. Two trials included patients with knee osteoarthritis, one evaluated patients with low back pain and one enrolled both. All studies reported last-observation-carried-forward (LOCF) as imputation method. We requested baseline-observation-carried-forward (BOCF) imputed analyses and any unpublished data from the manufacturer but the manufacturers denied the request. Two out of the four oxycodone-controlled studies and one out of the three placebo-controlled studies did not provided data on responder's rate. Two studies were considered to be of high risk of bias.In comparison to placebo, tapentadol was associated with a mean reduction of 0.56 points (95% confidence interval (CI) 0.92 to 0.20) in the 11-point numerical rating scale (NRS) at 12 weeks and with a 1.36 increase (95% CI 1.13 to 1.64) in the risk of responding to treatment (number needed to treat for an additional beneficial outcome (NNTB) 16; 95% CI 9 to 57, for 12-weeks). Moderate-to-high heterogeneity was found for the efficacy outcome estimates. Tapentadol was associated with a 2.7 fold increase (95% CI 2.05 to 3.52) in the risk of discontinuing treatment due to adverse effects number needed to treat for an additional harmful outcome (NNTH) 10; 95%CI 7 to 12, for 12 weeks).In comparison to oxycodone, pooled data showed a 0.24 points (95%CI 0.43 to 0.05) reduction in pain intensity from baseline in the 11-point NRS. The two studies that evaluated responder's rate showed a non-significant 1.46 increase (95% CI 0.92 to 2.32) in the risk of responding to treatment among tapentadol treated patients. Tapentadol was associated with a 50% risk reduction (95% CI 42% to 60%) of discontinuing treatment due to adverse effects (NNTB 6; 95% CI 5 to 7, for 12 weeks). Tapentadol was also associated with a 9% reduction (95% CI 4 to 15) in the overall risk of adverse effects (NNTH 18; 95% CI 12 to 35, for 12 weeks) and with a non-significant 43% reduction (95% CI 33 to 76) in the risk of serious adverse effects. Moderate to high heterogeneity was found for most efficacy (except for the primary outcome) and safety outcome estimates. Subgroup analysis showed a higher improvement with tapentadol among patients with knee osteoarthritis and among pooled results from studies of higher quality and shorter follow-up period, although there were no statistical significant differences in the effect size between these subgroups.
AUTHORS' CONCLUSIONS: Tapentadol extended release is associated with a reduction in pain intensity in comparison to placebo and oxycodone. However, the clinical significance of the results is uncertain due to the following reasons: modest difference between interventions in efficacy outcomes, high heterogeneity in some comparisons and outcomes, high withdrawals rates, lack of data for the primary outcome in some studies and impossibility to use BOCF as imputation method. Tapentadol is associated with a more favourable safety profile and tolerability than oxycodone.
Background: Increases in prescriptions of opioid medications for chronic pain have been accompanied by increases in opioid overdoses, abuse, and other harms and uncertainty about long-term effectiveness.
Purpose: To evaluate evidence on the effectiveness and harms of long-term (>3 months) opioid therapy for chronic pain in adults.
Data Sources: MEDLINE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, PsycINFO, and CINAHL (January 2008 through August 2014); relevant studies from a prior review; reference lists; and ClinicalTrials.gov.
Study Selection: Randomized trials and observational studies that involved adults with chronic pain who were prescribed long-term opioid therapy and that evaluated opioid therapy versus placebo, no opioid, or nonopioid therapy; different opioid dosing strategies; or risk mitigation strategies.
Data Extraction: Dual extraction and quality assessment.
Data Synthesis: No study of opioid therapy versus no opioid therapy evaluated long-term (>1 year) outcomes related to pain, function, quality of life, opioid abuse, or addiction. Good- and fair-quality observational studies suggest that opioid therapy for chronic pain is associated with increased risk for overdose, opioid abuse, fractures, myocardial infarction, and markers of sexual dysfunction, although there are few studies for each of these outcomes; for some harms, higher doses are associated with increased risk. Evidence on the effectiveness and harms of different opioid dosing and risk mitigation strategies is limited.
Limitations: Non-English-language articles were excluded, meta-analysis could not be done, and publication bias could not be assessed. No placebo-controlled trials met inclusion criteria, evidence was lacking for many comparisons and outcomes, and observational studies were limited in their ability to address potential confounding.
Conclusion: Evidence is insufficient to determine the effectiveness of long-term opioid therapy for improving chronic pain and function. Evidence supports a dose-dependent risk for serious harms.
Primary Funding Source: Agency for Healthcare Research and Quality.
PURPOSE: The objective of this systematic review was to assess the clinical efficacy, safety, tolerability, and health-related quality of life outcomes associated with management of moderate-to-severe chronic pain with oxycodone/naloxone and tapentadol, focusing on the effect of these treatments on patients' daily functioning.
METHODS: Literature from a wide range of sources, including Embase, MEDLINE, MEDLINE In-Process, and the Cochrane Central Register of Controlled Trials, was searched to identify randomized controlled trials investigating tapentadol or oxycodone/naloxone for the treatment of patients with chronic pain. A network meta-analysis was conducted to determine the relative efficacy and safety profiles of these treatments.
FINDINGS: Oxycodone/naloxone was significantly better than tapentadol with respect to the Patient Assessment of Constipation Symptoms total score (risk ratio = -3.60; 95% credible interval, -5.36 to -2.11) and revealed a significantly lower risk of dizziness (risk ratio = 0.72; 95% credible interval, 0.42-0.98). Oxycodone/naloxone was directionally favored, although not significantly superior to tapentadol for headache, fatigue, dry mouth, dyspepsia, and withdrawals due to lack of efficacy. For the AE outcomes of constipation, nausea, and vomiting, as well as pain efficacy and all-cause withdrawals from studies, tapentadol was directionally favored without any statistical difference from oxycodone/naloxone. However, the two treatments were not wholly comparable for the evaluation of pain efficacy because of differences in on-study rescue medication and a higher baseline pain severity in the tapentadol studies.
IMPLICATIONS: Oxycodone/naloxone offers significant improvements in Patient Assessment of Constipation Symptoms total score and dizziness and was directionally favored for fatigue and headache compared with extended-release tapentadol, which may translate to improved patient daily functioning and health-related quality of life.
BACKGROUND: The efficacy and safety of opioid therapy in chronic low back pain (CLBP) is under debate. We updated a recent systematic review on the efficacy and safety of opioids in CLBP.
METHODS: We screened MEDLINE, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL) up until October 2013, as well as reference sections of original studies and systematic reviews of randomized controlled trials (RCTs) of opioids in CLBP. We included double-blind randomized placebo-controlled studies of at least 4 weeks duration. Using a random effects model, absolute risk differences (RD) were calculated for categorical data and standardized mean differences (SMD) for continuous variables.
RESULTS: We included 12 RCTs with 17 treatment arms and 4375 participants. Median study duration was 12 (4-16) weeks. Of the 17 treatment arms, seven (41.2 %) used oxycodone; four (23.6 %) tramadol; buprenorphine and oxymorphone were each used in two (11.8 %) and hydromorphone and tapentadol each in one (5.8 %). The results for studies with parallel/cross-over design were as follows (with 95 % confidence interval, CI): opioids were superior to placebo in reducing pain intensity (SMD - 0.29 [- 0.37, - 0.21], p < 0.0001; six studies with 2896 participants). Opioids were superior to placebo in 50 % pain reduction (RD 0.05 [0.01, 0.10], p = 0.01; two studies with 1492 participants; number needed to benefit (NNTB) 19 [95 % CI 10-107]). Opioids were not superior to placebo in reports of much or very much improved pain (RD 0.16 [- 0.01, 0.34], p = 0.07; two studies with 1153 participants). Opioids were superior to placebo in improving physical functioning (SMD - 0.22 [- 0.31, - 0.12], p < 0.0001; four studies with 1895 participants). Patients dropped out less frequently with opioids than with placebo due to lack of efficacy (RD - 0.10 [- 0.16, - 0.04], p = 0.001; five studies with 3168 participants; NNTB 10 [8-13]). Patients dropped out more frequently with opioids than with placebo due to adverse events (RD 0.12 [0.05, 0.19], p = 0.0007; six studies with 2910 participants; number needed to harm (NNTH) 7 [95 % CI 6-8]). There was no significant difference between opioids and placebo in terms of the frequency of serious adverse events or deaths.
CONCLUSION: Opioids were superior to placebo in terms of efficacy and inferior in terms of tolerability. Opioids and placebo did not differ in terms of safety during the study period. The conclusion on the safety of opioids compared to placebo is limited by the low number of serious adverse events and deaths. Short-term and intermediate-term opioid therapy may be considered in selected CLBP patients. The English full-text version of this article is freely available at SpringerLink (under "Supplemental").
BACKGROUND: Some leading German pain medicine experts postulate that there is a type of chronic non-cancer pain (CNCP) with an opioid requirement. We tested whether opioids are superior to nonopioid analgesics in the management of CNCP in studies of at least 4 week's duration.
METHODS: We screened MEDLINE, Scopus and the Cochrane Central Register of Controlled Trials (CENTRAL) up until October 2013, as well as the reference sections of original studies and systematic reviews of randomised controlled trials (RCTs) of opioids in CNCP. We included double-blind RTCs comparing opioids to nonopioid analgesics of at least 4 week's duration. Relative risks differences (RD) of categorical data and standardized mean differences (SMD) of continuous variables were calculated using a random effects model.
RESULTS: We included 10 RCTs with 3046 participants. Median study duration was 6 weeks (range 4-12 weeks). Five studies compared tramadol with nonsteroidal anti-inflammatory drugs (NSAIDs) in osteoarthritis pain and one trial compared tramadol to flupirtine in low back pain. Morphine was compared to antidepressants (two studies), an anticonvulsant (one study) and an antiarrhythmic (one study) in different neuropathic pain syndromes. There was no significant difference between opioids and nonopioid analgesics in pain reduction (SMD 0.03 [95 % confidence interval, CI - 0.18, 0.24]; p = 0.76). Nonopioid analgesics were superior to opioids in improving physical function (SMD 0.17 [95 % CI 0.02, 0.32]; p = 0.03). Patients dropped out due to adverse events more frequently with opioids than with nonopioid analgesics (RD 0.09 [95 % CI 0.06, 0.13]; p < 0.0001). There was no significant difference between opioids and nonopioid analgesics in terms of serious adverse events or dropout rates due to lack of efficacy.
CONCLUSION: Nonopioid analgesics are superior to opioids in terms of improvement of physical function and tolerability in short-term (4-12 weeks) therapy of neuropathic, low back and osteoarthritis pain. Our results do not support the concept of an"opioid-requiring" CNCP. The English full-text version of this article is freely available at SpringerLink (under "Supplemental").
Opioids provide effective relief from moderate-to-severe pain and should be prescribed as part of a multifaceted approach to pain management when other treatments have failed. Fixed-dose oxycodone/naloxone prolonged-release tablets (OXN PR) were designed to address the opioid class effect of opioid-induced constipation (OIC) by combining the analgesic efficacy of oxycodone with the opioid receptor antagonist, naloxone, which has negligible systemic availability when administered orally. This formulation has abuse-deterrent properties, since systemic exposure to naloxone by parenteral administration would antagonize the euphoric effects of oxycodone.
METHODS:
A literature search was conducted to assess the evidence base for OXN PR to treat moderate-to-severe pain and its impact on bowel function, based on published clinical trials and observational studies.
RESULTS:
Extensive data demonstrate that OXN PR provides effective analgesia and clinically relevant improvements in bowel function in patients with OIC and moderate-to-severe cancer-related pain and noncancer pain types such as low back pain, neuropathic pain, and musculoskeletal pain. OXN PR has also been found to improve bowel function in patients with OIC refractory to multiple types of laxatives, and improve Parkinson's disease-related pain. No unanticipated safety concerns have been reported in elderly patients.
CONCLUSIONS:
Evidence from clinical trials and observational studies confirms that for selected patients OXN PR significantly improves moderate-to-severe chronic pain and provides relief from OIC. Treatment should be tailored to individual patients to establish the lowest effective dose. An absence of analgesic ceiling effect was seen across the clinically relevant dose range investigated (≤ 160/80 mg/day).
