POOR-INT Systematic Review Protocol Based on the PRISMA-P 2015 checklist (Moher et al., 2015), the associated elaboration and explanation (Shamseer et al., 2015), the MOOSE checklist (Stroup et al., 2000)and the Cochrane Handbook for Systematic Reviews of Interventions (Higgins and Green, 2008). ADMINISTRATIVE INFORMATION Title Prescription opioid overdose risk and appropriate patient-focused interventions (POOR-INT): a systematic review Registration
Our systematic review protocol was registered with the International Prospective Register of Systematic Reviews (PROSPERO) on 28/03/18. Registration number 88508.
Authors
Name
Institutional affiliation
Email
Alexander Baldacchino
University of St Andrews and NHS Fife Glasgow Caledonian University and Health Protection Scotland University of Stirling NHS Lanarkshire University of Stirling University of Edinburgh and NHS Lothian NHS Fife and Scottish Government NHS Lothian University of Stirling
[email protected]
Andrew McAuley Catriona Matheson Duncan Hill Joe Schofield * Lesley Colvin Paul Cameron
[email protected] [email protected] [email protected] [email protected] [email protected] [email protected]
Rebecca Lawrence
[email protected] Tessa Parkes
[email protected] * Corresponding author. Drugs Research Network Scotland, Rm 4S31, Colin Bell Building, University of Stirling, FK9 4LA Contributions
AB is the guarantor for the review and conducted previous work that provided the foundation for the review. AB, DH, CM and TP conceived the need for the review. AB and JS designed the review and wrote the protocol. JS conducted searches, data collection and data management JS, AB, LC, RL, TP, PC and CM analysed the data. All authors read, provided feedback and approved the final protocol and subsequent amendments.
Amendments
In the event of protocol amendments, the date of each amendment will be accompanied by a description of the change and the rationale. Date
Support
Change
Rationale
The Drugs Research Network Scotland (DRNS) is the sponsor, meaning that the network provided secretariat, research assistant and researcher time to conduct the review. No funding has been received for this study.
INTRODUCTION Rationale Chronic, non-cancer pain is a major challenge with approximately 20% of the UK population suffering from pain that affects their quality of life. The prevalence of chronic pain increases with age and is associated with lower socio-economic status. The burden to society is enormous, with an estimated cost in Europe of €200 billion per annum and is likely to increase with a projected doubling of the population aged >65 over the next 40 years (van Hecke et al., 2013). Opioid prescribing for chronic non-cancer pain has increased significantly over the last 10-20 years (Joranson et al., 2000). A Chief Scientist Office (CSO)-funded study found that in 2012, 18% of the Scottish population were prescribed an opioid (weak and strong opioids) mostly for chronic non-cancer pain (Scottish Government Health Directorate, 2015). Several systematic reviews of the literature have found variable quality evidence of short- to medium-term benefits in terms of analgesia, with an associated increasing evidence of harm from chronic opioid use, particularly with higher doses (Paulozzi LJ, Jones C,
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Mack K, 2011). Most patients started on strong opioids remain on them long-term, regardless of concerns about adverse events, side effects and lack of effective analgesia (Manchikanti et al., n.d.; Thielke et al., 2013). A systematic review found evidence of opioid abuse in patients started on opioids for chronic pain with an associated increased risk of opioid related overdose within the same population (Chou et al., 2014). Logistic regression models have indicated that pain at baseline was associated with both prevalence (OR=2.05) and incidence (OR=2.15) of prescription opioid use related disorders including risk of overdose even when confounding variables such as demography and clinical covariates were adjusted for (Blanco et al., 2016). Treatment admissions for prescription opioid overdoses in the US have increased 6-fold in the last decade (Von Korff, 2013). In the US, unintentional overdose deaths involving opioid medication for analgesia have increased and, in some parts of the US, even exceeded deaths involving illicit heroin and cocaine combined (Johnson et al., 2013; Paulozzi et al., 2012). Prescription opioid overdose risk (POOR) is elevated if the medication is taken in conjunction with other central nervous system depressants (e.g. benzodiazepines, gabapentinoids and antidepressants) creating a potentially lethal ‘cocktail’ (European Monitoring Centre for Drugs and Drug Addiction, 2015). The pharmaceutical industry has developed combination products that include naloxone, but these are either indicated to counteract opioid related side effects such as constipation and restless leg syndrome (Targinact®) or indicated for opioid dependence (Naloxone®). Many people who are on opioid replacement treatment also have chronic pain. A recent study of people with a drug problem over 35 years found 52% self-reported chronic pain (OPDP report 2017). Thus there is considerable overlap in the two groups. Whilst individuals or even clinicians may consider there to be two distinct groups, clinically, in terms of opioid overdose risk, they have similarities. Cochrane reviews published in 2013 and 2017 concluded that there is currently still no evidence for the efficacy or safety of methods for reducing prescribed opioid use in chronic pain (Eccleston et al., 2017). A preventative approach to the risks of overdose secondary to prescribed opioids to both populations (opioid dependent individuals due to illicit opioid use and others who are prescribed opioids with a high risk of overdosing) is a logical direction to follow. In this review we attempt to describe the risks of prescription opioid overdose and to identify evidence on the characteristics of effective patient-focussed interventions to reduce this risk and associated harms. Objectives
There are two main components of this systematic review: 1.
To determine the risk of prescription opioid overdose in individuals who use drugs vs. those who do not use drugs among people prescribed opiate-containing therapeutics. In this context “people who use drugs” means those who use illicit drugs and/or those who misuse prescription drugs.
2.
To describe the type and effectiveness of patient-focused interventions designed to reduce risk of prescription opioid overdose among this population.
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METHODS Eligibility criteria
Studies will be selected according the following criteria:
Study design
Objective 1. Risk of prescription opioid overdose in individuals who use drugs vs. those who do not use drugs
Objective 2. Patient-focussed interventions designed to reduce risk of prescription opioid overdose
We will include studies described as:
We will include studies described as:
•
• • • • •
• • • • •
clinical (controlled / pragmatic / randomised clinical trials); comparative, evaluation, validation, systematic / scientific integrity reviews and meta analyses.
Population
Adults prescribed opioid-containing therapeutics for chronic non-cancer pain and/or dependent drug use, excluding those receiving palliative care.
Exposure
Prescribed opioids ± other drugs.
Intervention
[None, exposure only]
Any interventions delivered directly to patients to reduce the risk of overdose and associated morbidity/mortality.
Comparison
Risk of overdose among:
We will report the uptake and effectiveness of interventions vs. waiting list / care as usual.
• •
Information sources
epidemiological (incidence, prevalence, case-control, cohort, cross-sectional, longitudinal, observational); clinical (controlled / pragmatic / randomised clinical trials); comparative, evaluation, validation, systematic / scientific integrity reviews and meta analyses.
People who use drugs vs. those who do not. Among non-drug-using populations we will compare risk of overdose in opioid vs. nonopioid recipients.
Outcome
Fatal and non-fatal overdose incidents by patient self-report or clinical records.
Individuals’ knowledge of: overdose risk, riskreduction strategies, action to take on suspected overdose, Naloxone® carriage and use.
Timescale
Papers published since 01 January 2008.
Language
We will not exclude papers based on language.
We will develop a literature search strategy based on medical subject headings (MeSH) and text words relating to prescription opiate overdose identified through scoping searches and terms identified from relevant literature. We will search PubMed (via NCBI), CINAHL (via EBSCOhost), Medline (via EBSCOhost), Ovid Nursing (via Ovid), Embase (via Ovid), and the Cochrane database. We will search PROSPERO (NIHR) and the Centre for Reviews and Dissemination (University of York) for protocols and publications on emerging studies. To ensure saturation we will search Google Scholar, scan reference lists from key textbook chapters, scan reference lists from included studies and check the above databases for relevant cited and citing articles associated with selected papers. We will contact the investigators of relevant studies identified through a search of protocols that have no associated publications, requesting information on findings. Finally, we will circulate a bibliography of selected studies to the study team and experts identified by the team, asking them to identify relevant reports we may have missed.
Search strategy
Initial scoping searches will be conducted to inform development of the search strategy which will be shared with members of the study team for review.
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A draft PubMed search is included at Appendix 1. Once finalised, this will be adapted to the syntax, subject headings and thesauruses of the other databases. As relevant studies are identified, reviewers will check for additional relevant cited and citing articles. STUDY RECORDS Data Search strategies, numbers of results returned and lists of titles will be stored in an Excel document. management Citations will be stored and de-duplicated in RefWorks. Titles and abstracts will then be collated into a Word document for selection. A Word document containing study identifiers will be maintained to record the reasons for inclusion/exclusion and reviewers’ comments. Selection process
The review will be conducted and documented in line with the PRISMA-P (Moher et al., 2015) and MOOSE (Stroup et al., 2000) checklists. We will include all identified studies that describe human participants aged 18 years old and over who are prescribed opioid-containing regimens. We will include all trial methodologies (i.e. not restricted to RCT) and published in any language. One reviewer (JS) will conduct searches, collate results and de-duplicate these using RefWorks and manual review. JS will review titles and abstracts against two sets of eligibility criteria; one for each of the review objectives. Two reviewers (TP & CM) will provide quality assurance by independently checking a sample of twenty titles and abstracts; 10 selected and 10 rejected by JS. Areas of disagreement will be discussed by the team and the exclusion criteria refined if required. A list of excluded reports will be collated, including study ID and primary reason for exclusion.
Data collection process
JS will retrieve the full text of selected papers, extract the following data, and record in a Word document table, to be independently checked by other team members. Any discrepancies will be resolved by referral to the original studies. Data to be extracted from included reports: General
Methods
Participants
Exposure
Interventions
Outcomes
Objective 1: Risk of prescription Objective 2: Interventions designed to opioid overdose in people who reduce risk of prescription opioid overdose. use drugs vs. those who do not use drugs. • Study ID • Review author initials • Citation and contact details • Study design • Start and end dates • Duration • Country • Total number • Diagnostic criteria • Setting • Age, sex, ethnicity and other socio-demographic factors • Condition(s) for which opioids were prescribed • Other physical and mental health comorbidities, including Substance Use Disorder(s) • Overdose risk category info. • Name, type, dose and duration of prescription opioid(s) • Additional pharmacy • Non-prescription drugs • Alcohol consumption Not applicable • Number of intervention groups For each group: • Number of recipients • Intervention details • Fatal and non-fatal • Measures of individuals’ overdose o knowledge of overdose risk o knowledge of risk-reduction • Diagnostic criteria strategies
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o knowledge of action to take on suspected overdose o opioid antagonist carriage and use • Sample size • Reported results, including any subgroup analyses • Overdose incidents (fatal and non-fatal). Other • Funding source • Key conclusions and miscellaneous comments from authors • Miscellaneous comments by reviewers The quality of included studies will be assessed using the Effective Public Health Practice Project (EPHPP) Quality Assessment Tool for Quantitative Studies (Effective Public Health Practice Project, 1998). Results
Quality assessment of individual studies
REGISTRATION INFORMATION (additional fields from PROSPERO) Type of Epidemiologic, intervention, prevention, service delivery, systematic review. review Health areas
Substance use, health equity, mental health, public health (incl. social determinants of health), service delivery, accidents, pain.
Dissemination plan
The results of this systematic review will be disseminated by: • • •
Submission of an article for publication in a peer reviewed journal, Presentation in oral and/or poster formats at academic conferences and clinical meetings, Knowledge exchange events with policy-makers and clinical guideline developers.
The results will also inform development of associated academic and clinical research projects. Keywords
Prescribed, opioid, overdose, risk, assessment, intervention, prevention, naloxone, patient safety, pain.
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APPENDIX 1: PubMed search CONCEPT PRESCRIPTION
OPIOID
OVERDOSE
INTERVENTION
DATE FILTERS
# 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52
71 72
SEARCH TERMS Search drug prescription[MeSH Terms] Search prescrib* Search prescription Search (#1 OR #2 OR #3) Search analgesi* Search analgesics, opioid[MeSH Terms] Search buprenorphine Search *codeine Search fentanyl Search hydrocodone Search hydromorphone Search meperidine Search methadone Search morphine Search "narcotic analgesia" Search "narcotic analgesic" Search oxycodone Search oxymorphone Search papaverine Search pethidine Search "prescription opioid" Search thebaine Search tramadol Search tapentadol Search (#5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #12 OR #13 OR #14 OR #15 OR #16 OR #17 OR #18 OR #19 OR #20 OR #21 OR #22 OR #23 OR #24) Search "opioid overdose" Search ((drug-related side effects and adverse reactions[MeSH Major Topic])) Search "adverse drug event" Search bradypnea Search "drug overdose" Search "fatal overdose" Search "non-fatal overdose" Search overdose Search "respiratory depression" Search "unintentional overdose" Search (#26 OR #27 OR #28 OR #29 OR #30 OR #31 OR #32 OR #33 OR #34 OR #35) Search community pharmac* Search "overdose prevention" Search retail pharmac* Search ((prevention and control[MeSH Terms])) Search accident prevention[MeSH Terms] Search early medical intervention[MeSH Terms] Search “pain management” Search physiotherapy Search mindfulness Search patient education as topic[MeSH Terms] Search patient safety[MeSH Terms] Search pharmacists[MeSH Terms] Search (#37 OR #38 OR #39 OR #40 OR #41 OR #42 OR #43 OR #44 OR #45 OR #46 OR #47 OR #48) Search ("2008/01/01"[Date - Publication] : "3000"[Date - Publication]) Search (#4 AND #25 AND #36 AND #49 AND #50) Search (#4 AND #25 AND #36 AND #49 AND #50) Filters: Humans Search (#4 AND #25 AND #36 AND #49 AND #50) Filters: Clinical Study; Clinical Trial; Clinical Trial, Phase I; Clinical Trial, Phase II; Clinical Trial, Phase III; Clinical Trial, Phase IV; Comparative Study; Controlled Clinical Trial; Evaluation Studies; Journal Article; Meta-Analysis; Multicenter Study; Observational Study; Pragmatic Clinical Trial; Randomized Controlled Trial; Review; Scientific Integrity Review; Systematic Reviews; Validation Studies; Humans (#71) NOT NOT ((perioperativ* OR oncolog))
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