High-dose opioids for chronic non-cancer pain: an overview of Cochrane Reviews.

BACKGROUND: This overview was originally published in 2017, and is being updated in 2022.  Chronic pain is typically described as pain on most days for at least three months. Chronic non-cancer pain (CNCP) is any chronic pain that is not due to a malignancy. Chronic non-cancer pain in adults is a common and complex clinical issue, for which opioids are prescribed by some physicians for pain management. There are concerns that the use of high doses of opioids for CNCP lacks evidence of effectiveness, and may increase the risk of adverse events. OBJECTIVES: To describe the evidence from Cochrane Reviews and overviews regarding the efficacy and safety of high-dose opioids (defined as 200 mg morphine equivalent or more per day) for CNCP. METHODS: We identified Cochrane Reviews and overviews by searching the Cochrane Database of Systematic Reviews in The Cochrane Library. The date of the last search was 21 July 2022. Two overview authors independently assessed the search results. We planned to analyse data on any opioid agent used at a high dose for two weeks or more for the treatment of CNCP in adults. MAIN RESULTS: We did not identify any reviews or overviews that met the inclusion criteria. The excluded reviews largely reflected low doses or titrated doses, where all doses were analysed as a single group; we were unable to extract any data for high-dose use only. AUTHORS' CONCLUSIONS: There is a critical lack of high-quality evidence, in the form of Cochrane Reviews, about how well high-dose opioids work for the management of CNCP in adults, and regarding the presence and severity of adverse events.  No evidence-based argument can be made on the use of high-dose opioids, i.e. 200 mg morphine equivalent or more daily, in clinical practice. Considering that high-dose opioids have been, and are still being used in clinical practice to treat CNCP, knowing about the efficacy and safety of these higher doses is imperative.

Risk Factors for Developing Concurrent Posttraumatic Stress Injury After Work-Related Musculoskeletal Injury: A Case-Control Study.

OBJECTIVE: This study aimed to study risk factors for developing concurrent posttraumatic stress injury (PTSI) among workers experiencing work-related musculoskeletal injury (MSI). METHODS: A case-control study was conducted using workers' compensation data on injured workers undergoing rehabilitation programs for concurrent MSI and PTSI (cases) and MSI only (controls). A variety of measures known at the time of the compensable injury were entered into logistic regression models. RESULTS: Of the 1948 workers included, 215 had concurrent MSI and PTSI. Concurrent MSI and PTSI were predicted by type of accident (adjusted odds ratio [OR], 25.8), experiencing fracture or dislocation fracture or dislocation (adjusted OR, 3.7), being public safety personnel (adjusted OR, 3.1), and lower level of education (adjusted OR, 1.9). CONCLUSIONS: Experiencing a concurrent PTSI diagnosis with MSI after work-related accident and injury appears related to occupation, type of accident, and educational background.

Random drug and alcohol testing for preventing injury in workers.

BACKGROUND: Drug- and alcohol-related impairment in the workplace has been linked to an increased risk of injury for workers. Randomly testing populations of workers for these substances has become a practice in many jurisdictions, with the intention of reducing the risk of workplace incidents and accidents. Despite the proliferation of random drug and alcohol testing (RDAT), there is currently a lack of consensus about whether it is effective at preventing workplace injury, or improving other non-injury accident outcomes in the work place. OBJECTIVES: To assess the effectiveness of workplace RDAT to prevent injuries and improve non-injury accident outcomes (unplanned events that result in damage or loss of property) in workers compared with no workplace RDAT. SEARCH METHODS: We conducted a systematic literature search to identify eligible published and unpublished studies. The date of the last search was 1 November 2020. We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, two other databases, Google Scholar, and three trials registers. We also screened the reference lists of relevant publications known to us. SELECTION CRITERIA: Study designs that were eligible for inclusion in our review included randomised controlled trials (RCTs), cluster-randomised trials (CRTs), interrupted time-series (ITS) studies, and controlled before-after (CBA) studies. Studies needed to evaluate the effectiveness of RDAT in preventing workplace injury or improving other non-injury workplace outcomes. We also considered unpublished data from clinical trial registries. We included employees working in all safety-sensitive occupations, except for commercial drivers, who are the subject of another Cochrane Review. DATA COLLECTION AND ANALYSIS: Independently, two review authors used a data collection form to extract relevant characteristics from the included study. They then analysed a line graph included in the study of the prevalence rate of alcohol violations per year. Independently, the review authors completed a GRADE assessment, as a means of rating the quality of the evidence. MAIN RESULTS: Although our searching originally identified 4198 unique hits, only one study was eligible for inclusion in this review. This was an ITS study that measured the effect of random alcohol testing (RAT) on the test positivity rate of employees of major airlines in the USA from 1995 to 2002. The study included data from 511,745 random alcohol tests, and reported no information about testing for other substances. The rate of positive results was the only outcome of interest reported by the study. The average rate of positive results found by RAT increased from 0.07% to 0.11% when the minimum percentage of workers who underwent RAT annually was reduced from 25% to 10%. Our analyses found this change to be a statistically significant increase (estimated change in level, where the level reflects the average percentage points of positive tests = 0.040, 95% confidence interval 0.005 to 0.075; P = 0.031). Our GRADE assessment, for the observed effect of lower minimum testing percentages associating with a higher rate of positive test results, found the quality of the evidence to be 'very low' across the five GRADE domains. The one included study did not address the following outcomes of interest: fatal injuries; non-fatal injuries; non-injury accidents; absenteeism; and adverse effects associated with RDAT. AUTHORS' CONCLUSIONS: In the aviation industry in the USA, the only setting for which the eligible study reported data, there was a statistically significant increase in the rate of positive RAT results following a reduction in the percentage of workers tested, which we deem to be clinically relevant. This result suggests an inverse relationship between the proportion of positive test results and the rate of testing, which is consistent with a deterrent effect for testing. No data were reported on adverse effects related to RDAT. We could not draw definitive conclusions regarding the effectiveness of RDAT for employees in safety-sensitive occupations (not including commercial driving), or with safety-sensitive job functions. We identified only one eligible study that reflected one industry in one country, was of non-randomised design, and tested only for alcohol, not for drugs or other substances. Our GRADE assessment resulted in a 'very low' rating for the quality of the evidence on the only outcome reported. The paucity of eligible research was a major limitation in our review, and additional studies evaluating the effect of RDAT on safety outcomes are needed.

Adverse events associated with medium- and long-term use of opioids for chronic non-cancer pain: an overview of Cochrane Reviews.

BACKGROUND: Chronic pain is common and can be challenging to manage. Despite increased utilisation of opioids, the safety and efficacy of long-term use of these compounds for chronic non-cancer pain (CNCP) remains controversial. This overview of Cochrane Reviews complements the overview entitled 'High-dose opioids for chronic non-cancer pain: an overview of Cochrane Reviews'. OBJECTIVES: To provide an overview of the occurrence and nature of adverse events associated with any opioid agent (any dose, frequency, or route of administration) used on a medium- or long-term basis for the treatment of CNCP in adults. METHODS: We searched the Cochrane Database of Systematic Reviews (the Cochrane Library) Issue 3, 2017 on 8 March 2017 to identify all Cochrane Reviews of studies of medium- or long-term opioid use (2 weeks or more) for CNCP in adults aged 18 and over. We assessed the quality of the reviews using the AMSTAR criteria (Assessing the Methodological Quality of Systematic Reviews) as adapted for Cochrane Overviews. We assessed the quality of the evidence for the outcomes using the GRADE framework. MAIN RESULTS: We included a total of 16 reviews in our overview, of which 14 presented unique quantitative data. These 14 Cochrane Reviews investigated 14 different opioid agents that were administered for time periods of two weeks or longer. The longest study was 13 months in duration, with most in the 6- to 16-week range. The quality of the included reviews was high using AMSTAR criteria, with 11 reviews meeting all 10 criteria, and 5 of the reviews meeting 9 out of 10, not scoring a point for either duplicate study selection and data extraction, or searching for articles irrespective of language and publication type. The quality of the evidence for the generic adverse event outcomes according to GRADE ranged from very low to moderate, with risk of bias and imprecision being identified for the following generic adverse event outcomes: any adverse event, any serious adverse event, and withdrawals due to adverse events. A GRADE assessment of the quality of the evidence for specific adverse events led to a downgrading to very low- to moderate-quality evidence due to risk of bias, indirectness, and imprecision.We calculated the equivalent milligrams of morphine per 24 hours for each opioid studied (buprenorphine, codeine, dextropropoxyphene, dihydrocodeine, fentanyl, hydromorphone, levorphanol, methadone, morphine, oxycodone, oxymorphone, tapentadol, tilidine, and tramadol). In the 14 Cochrane Reviews providing unique quantitative data, there were 61 studies with a total of 18,679 randomised participants; 12 of these studies had a cross-over design with two to four arms and a total of 796 participants. Based on the 14 selected Cochrane Reviews, there was a significantly increased risk of experiencing any adverse event with opioids compared to placebo (risk ratio (RR) 1.42, 95% confidence interval (CI) 1.22 to 1.66) as well as with opioids compared to a non-opioid active pharmacological comparator, with a similar risk ratio (RR 1.21, 95% CI 1.10 to 1.33). There was also a significantly increased risk of experiencing a serious adverse event with opioids compared to placebo (RR 2.75, 95% CI 2.06 to 3.67). Furthermore, we found significantly increased risk ratios with opioids compared to placebo for a number of specific adverse events: constipation, dizziness, drowsiness, fatigue, hot flushes, increased sweating, nausea, pruritus, and vomiting.There was no data on any of the following prespecified adverse events of interest in any of the included reviews in this overview of Cochrane Reviews: addiction, cognitive dysfunction, depressive symptoms or mood disturbances, hypogonadism or other endocrine dysfunction, respiratory depression, sexual dysfunction, and sleep apnoea or sleep-disordered breathing. We found no data for adverse events analysed by sex or ethnicity. AUTHORS' CONCLUSIONS: A number of adverse events, including serious adverse events, are associated with the medium- and long-term use of opioids for CNCP. The absolute event rate for any adverse event with opioids in trials using a placebo as comparison was 78%, with an absolute event rate of 7.5% for any serious adverse event. Based on the adverse events identified, clinically relevant benefit would need to be clearly demonstrated before long-term use could be considered in people with CNCP in clinical practice. A number of adverse events that we would have expected to occur with opioid use were not reported in the included Cochrane Reviews. Going forward, we recommend more rigorous identification and reporting of all adverse events in randomised controlled trials and systematic reviews on opioid therapy. The absence of data for many adverse events represents a serious limitation of the evidence on opioids. We also recommend extending study follow-up, as a latency of onset may exist for some adverse events.

High-dose opioids for chronic non-cancer pain: an overview of Cochrane Reviews.

BACKGROUND: Chronic pain is typically described as pain on most days for at least three months. Chronic non-cancer pain (CNCP) is any chronic pain that is not due to a malignancy. Chronic non-cancer pain in adults is a common and complex clinical issue where opioids are routinely used for pain management. There are concerns that the use of high doses of opioids for chronic non-cancer pain lacks evidence of effectiveness and may increase the risk of adverse events. OBJECTIVES: To describe the evidence from Cochrane Reviews and Overviews regarding the efficacy and safety of high-dose opioids (here defined as 200 mg morphine equivalent or more per day) for chronic non-cancer pain. METHODS: We identified Cochrane Reviews and Overviews through a search of the Cochrane Database of Systematic Reviews (The Cochrane Library). The date of the last search was 18 April 2017. Two review authors independently assessed the search results. We planned to analyse data on any opioid agent used at high dose for two weeks or more for the treatment of chronic non-cancer pain in adults. MAIN RESULTS: We did not identify any reviews or overviews meeting the inclusion criteria. The excluded reviews largely reflected low doses or titrated doses where all doses were analysed as a single group; no data for high dose only could be extracted. AUTHORS' CONCLUSIONS: There is a critical lack of high-quality evidence regarding how well high-dose opioids work for the management of chronic non-cancer pain in adults, and regarding the presence and severity of adverse events. No evidence-based argument can be made on the use of high-dose opioids, i.e. 200 mg morphine equivalent or more daily, in clinical practice. Trials typically used doses below our cut-off; we need to know the efficacy and harm of higher doses, which are often used in clinical practice.