Cohort protocol paper: The Pain and Opioids In Treatment (POINT) study

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Cohort protocol paper: The Pain and Opioids In Treatment (POINT) study
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  STUDY PROTOCOL Open Access Cohort protocol paper: The Pain and Opioids In Treatment (POINT) study Gabrielle Campbell 1* , Richard Mattick  1 , Raimondo Bruno 1,2 , Briony Larance 1 , Suzanne Nielsen 1,3,4 , Milton Cohen 5 ,Nicholas Lintzeris 3,4 , Fiona Shand 6 , Wayne D Hall 7,8 , Bianca Hoban 1 , Chyanne Kehler 1 , Michael Farrell 1 and Louisa Degenhardt 1,9,10,11 Abstract Background:  Internationally, there is concern about the increased prescribing of pharmaceutical opioids for chronicnon-cancer pain (CNCP). In part, this is related to limited knowledge about the long-term benefits and outcomes of opioid use for CNCP. There has also been increased injection of some pharmaceutical opioids by people who injectdrugs, and for some patients, the development of problematic and/or dependent use. To date, much of theresearch on the use of pharmaceutical opioids among people with CNCP, have been clinical trials that haveexcluded patients with complex needs, and have been of limited duration (i.e. fewer than 12 weeks). The Pain andOpioids In Treatment (POINT) study is unique study that aims to: 1) examine patterns of opioid use in a cohort of patients prescribed opioids for CNCP; 2) examine demographic and clinical predictors of adverse events, includingopioid abuse or dependence, medication diversion, other drug use, and overdose; and 3) identify factors predictingpoor pain relief and other outcomes. Methods/Design:  The POINT cohort comprises around 1,500 people across Australia prescribed pharmaceuticalopioids for CNCP. Participants will be followed-up at four time points over a two year period. POINT will collectinformation on demographics, physical and medication use history, pain, mental health, drug and alcohol use,non-adherence, medication diversion, sleep, and quality of life. Data linkage will provide information on medicationsand services from Medicare (Australia ’ s national health care scheme). Data on those who receive opioid substitutiontherapy, and on mortality, will be linked. Discussion:  This study will rigorously examine prescription opioid use among CNCP patients, and examine itsrelationship to important health outcomes. The extent to which opioids for chronic pain is associated with painreduction, quality of life, mental and physical health, aberrant medication behavior and substance use disorders willbe extensively examined. Improved understanding of the longer-term outcomes of chronic opioid therapy willdirect community-based interventions and health policy in Australia and internationally. The results of this study willassist clinicians to better identify those patients who are at risk of adverse outcomes and who therefore requirealternative treatment strategies. Keywords:  Opioids, Chronic non-cancer pain, Pain, Quality of life, Dependence, Non-adherence * Correspondence: g.campbell@unsw.edu.au 1 National Drug and Alcohol Research Centre, UNSW, Sydney, NSW 2052,AustraliaFull list of author information is available at the end of the article © 2014 Campbell et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the CreativeCommons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, andreproduction in any medium, provided the srcinal work is properly credited. The Creative Commons Public DomainDedication waiver (http://creativecommons.org/publicdomain/zero/1.0/ ) applies to the data made available in this article,unless otherwise stated. Campbell  et al. BMC Pharmacology and Toxicology   2014,  15 :17http://www.biomedcentral.com/2050-6511/15/1/17  Background Chronic non-cancer pain (CNCP) is a worldwide, com-mon complaint. The prevalence of chronic pain (definedas pain present daily for three months or more) in theAustralian population is 17% for males and 20% for females[1]. In one survey of 16 European countries, between10% and 30% of participants reported chronic pain, 16%of whom said that some days the pain made them  “ wantto die ”  [2]. Chronic pain can have a major impact on anindividual and the community, with social, financial,employment and health costs [2].CNCP is caused by many factors, including trauma.The varied aetiology probably impacts upon the effect-iveness of treatment [1,3-5]. Physical and psychologicalfactors such as depression and anxiety, a history of psy-chological trauma, and sleep problems moderate the painexperience [3]. Context is also important: relationships,occupational setting and culture all affect the experienceand expression of pain [3]. Between 30-50% of those withchronic pain in the above study reported that their painwas not  “ adequately controlled ”  [2].Effective behavioural treatments and non-opioid phar-macotherapy exist for CNCP [3], but even when a com-bination of interventions is used, some patients continueto suffer. The increase in the use of opioid analgesics forCNCP would suggest that there is conclusive evidence re-garding their positive impact on pain reduction and qual-ity of life. Indeed, qualitative and quantitative reviews of the evidence have concluded that chronic opioid therapy does produce clinically significant reductions in pain, al-beit in the range of 2 to 3 points on a 0 to 10 visualanalogue scale, or around 30% [6-8]. Nevertheless, re- viewers have cautioned that patients need to be carefully selected and monitored, given that opioids are also associ-ated with potentially serious harms and significant treat-ment drop out due to adverse effects [6,7]. Further, thedegree to which pain reduction is achieved varies, and evi-dence on changes to quality of life and functional status isinconclusive [6]. Some of this variability in pain reductionmay be related to the type of opioid used, with one meta-analysis finding that strong but not weak opioids reducedpain more effectively than other analgesics [9].Controlled trials have evaluated pharmaceutical opioidsin the treatment of a range of CNCP conditions and havedemonstrated modest attenuation of pain [10]. Evidenceindicates a modest short-term benefit; no studies have yetrun for long enough to demonstrate long-term benefit of opioids for chronic non-cancer pain. The three systematicreviews of opioids for chronic non-cancer pain publishedto date provide evidence for a modest, short-term anal-gesic benefit [9,11,12]. This is a best-case scenario becauseRCTs select the sub-set of patients most likely to receive aclinical benefit and have short follow-up periods (averagetrial duration of five weeks), meaning they do not reporton longer term outcomes [13,14]. An ongoing systematicreview shows that the only evidence of long-term anal-gesic benefit (improved physical function and quality of life) is weak, because it is based on non-blinded studieswith significant potential for reporting bias [6].There is support from peak pain organisations of theuse of opioids in the treatment of CNCP [2,15-17]. Debatecontinues about how, when, and in what manner opioidsshould be prescribed for this diverse patient group[3,18-22]. Consensus statements have recommendedthat prescription of opioids for chronic pain is consideredonly after following: a thorough assessment of the patient ’ spain problem and history; development of a treatmentplan; consultation with a pain specialist, if necessary; andregular reviews of patient progress [2,15].Over the past decade, there has been increasing profes-sional and public concern in a number of countries aboutpharmaceutical opioid use and related harms [23,24]. Thishas been driven by increases in prescribing of these drugs,especially in the USA and Canada. The increase in pre-scribing in Australia has been less than in Europe andthe United States (US) [25-28], but nonetheless, be-tween 1992 – 2007 the number of opioid prescriptions inAustralia increased by around 300% [23]. This increasein prescribing has been accompanied by increased injec-tion of some opioids by people who inject drugs [29]; in-creased concern about the appropriateness of prescribingthese drugs for chronic non-cancer pain (CNCP) [6]; andfor some patients, the development of problematic and/ordependent use.The use of opioids, within, and outside the bounds of adoctor ’ s prescription has been cause for concern becauseof the risk of iatrogenic dependence [30], and opioid over-doses, with pharmaceutical opioids now comprising themajority of fatal and non-fatal drug overdoses in the US[24,31]. A review of 67 studies found that 11.5% of chronicpain patients engaged in aberrant drug-related behaviourssuch as diversion, prescription forgery, injecting, multipleepisodes of prescription loss, escalating doses, and doctorshopping, 3.3% developed opioid abuse/dependence [32].Despite this increasing concern, little is known aboutthe magnitude of risk of such adverse events in patientsprescribed opioids. Clinical trials, because they often ex-clude more complex patients, including those with comor-bid conditions that may increase risks for developingopioid related problems (e.g. history of substance usedisorder), typically find far lower rates of aberrant drug-related behaviours and abuse/dependence [32]. Many studies have also been of limited duration (~12 weeks)and few have examined aberrant drug use behaviours.Those of longer duration have had a small number of participants and therefore lack statistical power. Otherstudies have examined treatment of localised condi-tions, e.g. low back pain, or have evaluated a single drug Campbell  et al. BMC Pharmacology and Toxicology   2014,  15 :17 Page 2 of 9http://www.biomedcentral.com/2050-6511/15/1/17  or formulation of a drug. Only a few of the studiesreviewed were prospective or longitudinal, thus limitingthe conclusions that can be drawn. Further, there is lit-tle consensus regarding the diagnosis of opioid depend-ence in the context of chronic opioid treatment forchronic pain [33].Little is known about the patterns of opioid prescrib-ing for individual patients, and the long term outcomesfor these patients. Small retrospective cohort studiesconducted elsewhere have examined treatment duration,side effects, pain reduction, and adverse events [34] andaberrant behaviours [35]. Larger retrospective cohort stud-ies have examined the risk of overdose [36], the impact ondisability [37], non-medical use [38], conditions treated inolder adults [39], and rates of adverse events [40].The Pain and Opioid IN Treatment (POINT) study isan Australian-first study that aims to document patternsof pharmaceutical opioid prescribing, and risk of adverseevents, in a prospective cohort of patients prescribedopioids for chronic non-cancer pain. Methods/Design Study aims 1. To examine patterns and outcomes of opioidanalgesic use in a cohort of patients prescribedopioids for chronic non-cancer pain (CNCP).2. To examine the demographic and clinical predictorsof adverse events among a cohort of CNCP patients,including opioid abuse or dependence, medicationdiversion, other drug use, and overdose.3. To identify factors which predict poor self-reportedpain relief and other clinical outcomes. Study design and setting The POINT study is a prospective cohort study of 1,500persons who have been prescribed opioids for chronicnon-cancer pain that follows their progress over two years and examine the predictors of clinical outcomesover this period. Participants provided consent to linkdata on health service utilisation and mortality data; thestudy will utilise data linkage to examine other clinical out-comes in the longer-term, such as opioid substitution ther-apy utilisation and hospital admissions. Prospective cohortstudies can provide highly reliable and detailed data abouta range of outcomes with the advantage of collecting dataat the time or close to the time an event occurs, reducingthe effects of recall bias [41] and making it easier to draw causal inferences about associations with later outcomes. Ethics The study was approved by the Human Research EthicsCommittee of the University of New South Wales (HRECreference: # HC12149). The study also received A1National Pharmacy Guild Approval to approach pharma-cists to assist with recruitment of participants (Approvaln. 815). Approval was obtained by the Strategic Informa-tion Design and Governance Branch of the Department of Human Services to access Medicare data of participantsthat consent to access of their records (reference number:2012/C011091). Sample size calculations Power analyses were conducted to estimate minimumsample size required to assess the potential effects of opi-oid use on key clinical outcomes. We examine, dropoutdue to adverse events as an indicative example.Power analyses were conducted using GLIMMPSE[42] to determine the minimum sample size to examinethe potential effect of opioid use on key outcomes. As aconservative indicative example, we consider changes inpain score. Data on Australian prescriptions suggeststhat approximately 10% of opioid analgesic scripts canbe defined as high dose [43]; we therefore assumed thatat least 10% of the POINT cohort will be on a high doseof opioid analgesics. The variability of changes in painscore from baseline over a six month period was esti-mated from a recent Cochrane review [6]. Even with adrop-out rate as high as 25%, with an initial sample of 1500 we will be able to detect differences between low and high dose groups over time as small in magnitudeas 0.30 at above 80% power and a Type I error rate of 5%. These calculations consider the effect of repeatedobservations over time (base correlation of 0.5 betweenadjacent repeated measures, with a linear exponentialautoregressive decay rate of 0.05) and controlling for anormally distributed baseline covariate explaining up to20% of the variation in pain scores. Given that otherresearch questions relate to more equally balanced sub-groups (e.g. comparisons of chronic neck/back pain vs.other types of pain which are distributed in a ratio of 4:1) or outcomes with less variability (e.g. changes inquality of life: [42]) then we can be confident that thePOINT cohort is sufficiently powered to address theprimary outcomes. Eligibility criteria POINT participants were: 18 years or older; competentin English; and mentally and physically able to completetelephone and self-complete interviews; without memory or comprehension difficulties; living with chronic non-cancer pain (defined as pain present daily for a period of three months or more); prescribed a Schedule 8 opioid(an Australian classification of drugs of dependence thatare subject to additional regulatory controls regardingtheir manufacture, supply, distribution, possession and use[44 and had taken such opioids for CNCP for more than6 weeks. Campbell  et al. BMC Pharmacology and Toxicology   2014,  15 :17 Page 3 of 9http://www.biomedcentral.com/2050-6511/15/1/17  A history of injecting drug use (IDU) was not an ex-clusion criterion, but those currently prescribed pharma-ceutical opioids for opioid substitution therapy (OST)for heroin dependence were not eligible. Nor were thosetaking opioids for cancer pain. Recruitment A database of pharmacies and chemists across Australiaand their contact details was purchased in May 2012[45]. The list included 7,136 pharmacies. After removingduplicates, those that had closed down, or were not suit-able for the study (i.e. located in a hospital or were acompounding pharmacy), we had a final list of 5,994pharmacies.Each fortnight, approximately, 100 – 150 pharmacieswere randomly allocated into a Wave (with the exceptionof Tasmania which was sampled first). A flyer inviting toparticipate in research was faxed to all pharmacies inthe Wave that had a fax number. Any pharmacies whoexpressed a lack of interest were not contacted further.Those who indicated they were interested in more in-formation, or who did not respond to the fax, werecalled and the study was explained to a pharmacist whowas asked if they were willing to participate.Interested pharmacists were enrolled in the study for a6-week period because it was expected that most peopleon prescription opioids would renew their script withinthis time. Pharmacists were asked to approach any cus-tomers that were prescribed a Schedule 8 opioid forCNCP for a period of greater than 6 weeks. We wereconfident that pharmacists were able to identify cus-tomers who had CNCP, rather than chronic cancer pain,by examining the customer ’ s record for other prescribedmedications. Pharmacists were also able to use themedication history to confirm that customers had beenon a prescription opioid for more than 6 weeks.Customers who fit the above criteria were given a flyerabout the study by the pharmacist. Interested customerswere asked whether they would like the pharmacists tosend their details to researchers, or if they wanted tocontact researchers themselves. All flyers had a uniquepharmacy number and pharmacists were reimbursed$20 for each eligible participant they referred into thestudy. POINT staff made reminder calls every fortnightfor the 6 week period to pharmacists.POINT staff determined the eligibility of those whowere referred to the study, or who contacted the POINTteam. Eligible participants went through a voluntary in-formed consent process. Those who were willing to par-ticipate, after being given details of the study, were bookedin for their initial interview which was conducted overthe phone and took approximately 1 – 1.5 hours. De-tailed locator information was collected at Baseline toprevent sample attrition and this was updated at allfollow-up assessments. Interview procedure This study had four assessment waves: Baseline, T2 follow up (3 months), T3 follow up (12 months), and T4 follow up (24 months) (see Table 1).Phone interviews were conducted by trained inter- viewers at the baseline and 24-month time-point. Inter- viewers had suicide assistance training, a minimum 3-yearhealth or psychology degree, and were provided glossariesof general and chronic pain medications and conditions(see Additional files 1, 2 and 3). A self-completion survey was sent to all participants at each time-point. Participantswere able to nominate to complete the self-complete sur- vey either, online, by pen and paper, or on the telephonewith a POINT team member. Participants were reim-bursed $40 for the baseline interview, $25 at each 3-month and the 12-month time point and $60 at thefinal time point. Cohort maintenance strategies There were a number of methods used to prevent attri-tion in the current study. Firstly, interested participants(pharmacists or participants) were called within a weekfrom their expression of interest in the study. Secondly,participants were offered a variety of study completionmethods, i.e. telephone, pen and paper and online. Inaddition to this, we offered to record verbal consent toparticipants who found it difficult to return the consentforms via mail. A variety of methods of study completionthat are flexible and accommodating have been found toincrease retention [46]. Thirdly, a detailed locator formwas completed at the initial contact with participants.This form gathered detailed information on contactdetails of the participants, as well as the contact detailsof two secondary contacts (i.e. family, friends, medicalprofessionals etc.). Finally, participants and pharmacistswere reimbursed within a timely manner for their timeand contribution to the research. Other methods to im-prove retention were letters thanking the participant for Table 1 Time-points and data collection method of the POINT prospective cohort Baseline T2 3 months T3 12 months T4 24 months •  Phone interview  •  Self-complete questionnaire(paper and pencil and onlineversions) •  Self-complete questionnaire(paper and pencil and onlineversions) •  Phone interview •  Self-complete questionnaire(paper and pencil and onlineversions) •  Self-complete questionnaire(paper and pencil and onlineversions) Campbell  et al. BMC Pharmacology and Toxicology   2014,  15 :17 Page 4 of 9http://www.biomedcentral.com/2050-6511/15/1/17  Table 2 Measures, tools, domains and time-points for data collection for the POINT study Domain Measure Baseline T1 T2 T3 Those whodiscontinueopioidsDemographics Age and sex  ✓  ✕ ✕ ✕ ✕ Marital status, employment, income  ✓ ✓ ✓ ✓ ✓ Educational attainment  ✓  ✕ ✕ ✕  ✓ Pain Pain Brief pain Inventory (BPI) [49]  ✓ ✓ ✓ ✓ ✓ Current chronic pain diagnosis, incident pain  ✓ ✓ ✓ ✓  ✕ Illness and disability history Chronic Conditions section of the CIDI3.0 [50,51] ✓ ✓ ✓ ✓  ✕ Current physical disabilities 6-items from the Washington Group [52]  ✓ ✓ ✓ ✓ ✓ Physical functioning Physical functioning Brief Pain Inventory (BPI) [51], Short-Form(SF)-12 [53] ✓ ✓ ✓ ✓ ✓ Exercise Exercise routine and how pain effects this  ✓ ✓ ✓ ✓ ✓ Falls Un-standardised questions examining falls  ✓  ✕  ✓ ✓ ✓ Sleep Medical Outcome Sleep scale (MOS) [54]  ✓ ✓ ✓ ✓ ✓ Coping and pain Pain: Self-Efficacy Questionnaire (PSEQ) [55,56]  ✓ ✓ ✓ ✓ ✓ Treatment Past week use of prescription and OTCmedications and doseSelf-complete 7 day medication diary  ✓ ✓ ✓ ✓ ✓ Current prescribed medications and days of usein last month ✓ ✓ ✓ ✓ ✓ Other treatments for chronic pain  ✓ ✓ ✓ ✓ ✓ Perceived effect of treatment Patients ’  Global Impression of Change scale(PGIC) [57] ✓ ✓ ✓ ✓  ✕ Beliefs about medicines Beliefs about Medicines Questionnaires [58]  ✓  ✕  ✓ ✓ ✓ Convenience of accessing medications  ✓  ✕ ✕ ✕ ✕ Side-effects of opioid medication Pain Assessment and Documentation Tool(PADT) [59] ✓ ✓ ✓ ✓  ✕ Barriers to treatment  ✓ ✓ ✓ ✓ ✓ Reasons for discontinuance of opioids  ✕ ✕ ✕ ✕  ✓ Aberrant opioid medication-related behaviours Opioid Related Behaviours In Treatment ORBIT scale [60] ✓ ✓ ✓ ✓  ✕ Opioid Difficulties Prescribed Opioid Difficulties Scale (PODS) [61]  ✓  ✕  ✓ ✓ ✓ Quality of life  WHO-QoL-BRIEF [62]  ✓ ✓ ✓ ✓ ✓ Mental health Mental health history  ✓  ✕ ✕ ✕ ✕ Depression Patient Health Questionnaire  − 9 (PHQ-9) [63,64]  ✓ ✓ ✓ ✓ ✓ General Anxiety disorder Patient Health Questionnaire (GAD) [65]  ✓ ✓ ✓ ✓ ✓ Social Anxiety Social Interaction Anxiety Scale (SIAS) [66]  ✓ ✓ ✓ ✓ ✓ Social Phobia Social Phobia Scale (SPS) [66]  ✓ ✓ ✓ ✓ ✓ Agoraphobia From the MINI International NeuropsychiatricInterview [67] ✓ ✓ ✓ ✓ ✓ Post-Traumatic Stress Disorder PC-PTSD [68]  ✓ ✓ ✓ ✓ ✓ Borderline personality disorder screener Screener from the CIDI 3.0 [50]  ✓  ✕ ✕ ✕ ✕ Child abuse Childhood Trauma Questionnaire [69]  ✓  ✕ ✕ ✕ ✕ Campbell  et al. BMC Pharmacology and Toxicology   2014,  15 :17 Page 5 of 9http://www.biomedcentral.com/2050-6511/15/1/17
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