Comparative Overdose Mortality, Morbidity and Abuse of Common Prescription Opioids

Comparative Overdose Mortality, Morbidity and Abuse of Common Prescription Opioids | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparative Overdose Mortality, Morbidity and Abuse of Common Prescription Opioids Jessie Channell, Stephan Schug This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4269986/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective : assess the overdose mortality of buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol in Australia and the morbidity and abuse rates in Western Australia. Design : Retrospective observational study. Setting : Australian and/or Western Australian data from the following sources; National Coronial Information System (NCIS), Western Australian Poisons Information Centre (WAPIC), Western Australian Mental Health Commission (WAMHC). Main outcome measures : Overdose mortality (deaths attributed to opioid toxicity by the coroner), morbidity (calls to WAPIC regarding moderate to severe opioid toxicity) and abuse (number of new opioid abuse WAMHC cases and calls to WAPIC where the opioid toxicity was related to abuse) of prescription opioids, per 100,000 grams oral morphine equivalent dispensed. Results : The overall risk of overdose mortality per prescription opioid dispensed increased by 7% over the study period. The risk of mortality, with morphine as the reference opioid, in order from highest to lowest mortality is; oxycodone 69% lower; tramadol 78%; fentanyl 84%; buprenorphine 87%; hydromorphone 91%; and tapentadol at 96% lower. Analysis of morbidity data found a significant 17% decline in the rate of cases detected for buprenorphine and a significant 11% increase in cases for oxycodone. Abuse data was insufficient to achieve statistical significance. Conclusions : The rates of overdose mortality, morbidity and abuse differ according to the opioid dispensed even once availability and opioid strength is accounted for. These differences may be due to the inherent difference in the pharmacokinetics of each opioid and their unique effect upon the individual. Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Key Points The risk of overdose mortality amongst common prescription opioids is highest for morphine followed by oxycodone, tramadol, fentanyl, buprenorphine, hydromorphone and tapentadol. The risk of morbidity has increased over time for oxycodone and decreased for buprenorphine, other morbidity data is inconclusive. The average rate of abuse is highest for morphine, buprenorphine, oxycodone and fentanyl and lowest for tramadol, tapentadol and hydromorphone in Western Australia, however due to a lack of data, no significant comparisons between opioids can be made. 1. Introduction Prescription opioid use continues to be of great concern to the health of Australians, with 56% of all opioid related deaths attributed to pharmaceutical opioids only in 2019 [ 1 ]. This is set against a backdrop of ever increasing use of prescription opioids with 3.1 million Australians dispensed opioid prescriptions in 2016-17 [ 2 , 3 ]. In 2019, opioid analgesics were the fourth most common group of pharmaceuticals used for non-medical purposes behind cannabis, cocaine and ecstasy. Within Australia, 2.7% of the population aged 14 and over reported recently using prescription opioids for non-medical purposes. Promisingly, this rate has reduced from 3.6% in 2016. However, misuse of prescription opioids has the highest contribution to the global burden of disease amongst illegal drugs [ 4 , 5 ]. There were 4,963 deaths in Australia due to opioid poisoning excluding heroin for the period 2001–2012 [ 6 ]. This represents an increase from 21.9 deaths per million population in 2001 to 36.2 in 2012. The term ‘prescription opioids’ encompasses several opioids with varying mechanisms of action [ 8 ]. Buprenorphine has its effects on the classical opioid receptors, being a partial agonist at the µ opioid receptor and an antagonist at the ĸ (kappa)-receptor [ 9 ]. Oxycodone exhibits agonist activity on the µ- (mu), ĸ- and δ- (delta) opioid receptors [ 10 ]. The efficacy of tapentadol is believed to be due to µ-opioid receptor agonist activity and inhibition of noradrenaline reuptake resulting in increased noradrenaline concentrations [ 11 ]. Tramadol, a phenylpiperidine analogue of codeine is thought to work via the same activity as tapendadol, with the added effect of serotonin reuptake modulation [ 12 ]. Fentanyl, a synthetic opioid has µ-opioid receptor agonist activity [ 12 ]. Morphine is considered to be predominately a µ-opioid receptor agonist, but also has some degree of agonistic efficacy on the ĸ- and δ-opioid receptors [ 12 ]. Hydromorphone, a semi synthetic opioid selectively binds the µ-opioid receptor to provide an agonistic effect [ 13 ]. With the varying mechanism of action, it therefore follows that overdose mortality, morbidity and abuse between these prescription opioids may also differ. Differing rates of overdose mortality, morbidity and abuse have been established in the USA [ 14 , 15 ], and to a lesser degree in Australia [ 6 , 16 ]. Understanding of each medications’ overdose mortality, morbidity and abuse potential is necessary to make an informed choice as to which medication(s) reflect the lowest risk to patients. This study aims to evaluate the overdose mortality, morbidity and abuse of buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol. 2. Objectives To compare overdose mortality attributable to buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol. To compare morbidity attributable to buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol. To compare abuse of buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol. Hypothesis A significant difference exists in the overdose mortality, morbidity and abuse of buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol once availability and strength are accounted for. 3. Methods 3.1. Study Design This retrospective observational study utilised several sources to assess the overdose mortality, morbidity and abuse rates of buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol. Overdose mortality: National Coronial Information System (NCIS) – deaths, Australia wide data, 2000–2017 Morbidity: Western Australian Poisons Information Centre (WAPIC), Western Australian data, 2007–2017. Abuse: Western Australian Mental Health Commission (WAMHC), 2015–2017 and Western Australian Poisons Information Centre (WAPIC), 2007–2017. 3.2. Data Sources National Coronial Information System Data provided: overdose mortality Population: Australia The NCIS is a database containing information on deaths reported to a Coroner in Australia or New Zealand [ 17 ]. Deaths are required to be investigated and reported to the Coroner which “appear unexpected, unnatural or violent or have resulted directly or indirectly from an accident or injury, or are related to a medical procedure” [ 18 ]. Data was extracted by conducting a search of closed NCIS cases from 01/07/2000 to 31/12/2015 by NCIS research officers to identify those where primary opioid toxicity was the mechanism of death. QLD data was only available from 01/01/2001 onwards. The opioid fatalities represent the number of instances the drug was judged as contributing to a death, not the total number of deaths, unless otherwise stated. Western Australian Poisons Information Centre Data provided: morbidity and abuse Population: Western Australia In Australia four poison information centres, located in Western Australia, New South Wales, Victoria and Queensland, run the Poisons Information hotline. The hotline is a free, nationwide, 24-hour service for health professionals and the public. The specialist trained staff, provide risk assessment and management information for all types of poisonings, recording the case information in a database [ 19 ]. The WAIPC receives calls predominantly from members of the public and health professionals in Western Australia, South Australia and the Northern Territory. There is a rotation system between the four poisons information centres, which cover calls for after-hours. Due to a lack of a centralised database and shared after-hours scheduling (A-M Lynch 2018, personal communication), the WAIPC database contains a mixture of records of poisoning events from around Australia, however most calls originating in Western Australia are received by WAPIC. The WAPIC database was provided for the dates 2007 to 2017. Morbidity data extracted from the WAPIC database include cases of poisoning involving prescription opioids whereby the poisoning severity score was moderate to severe [ 20 ]. Abuse data extracted from the WAIPC database includes calls made to WAPIC regarding prescription opioid poisoning, whereby the intention of the individual poisoned was recorded as “Intentional: Abuse”. The number of cases reflect the number of single or multiple drug toxicity events. The opioid each poisoning case was attributed to for this paper was based upon the assessment of the WAPIC personnel. Western Australian Mental Health Commission Data provided: abuse Population: Western Australia The WAMHC funds the provision of drug and alcohol support services and programs to the community. In Western Australia they are the only provider of publicly funded services which include community based and residential rehabilitation programs [ 21 ]. The number of new cases whereby a prescription opioid was the primary drug of concern was provided for the period 2015 to 2017. In cases of polysubstance abuse, the case was attributed to the main drug of abuse. IQVIA Opioid Sales Data Data provided: pharmaceutical dispensation Population: Australia Pharmaceutical sales data for all opioid medications sold in Australia was provided via a third-party request through Seqirus Australia, the manufacturers of Palexia [ 22 ], for the period 2000–2017. Data was provided as number of packs sold for each brand and pack size per state per month across retail and hospitals. The number of grams per pack was calculated and double-checked by a scientist with a background in pharmacy. Oral Morphine Equivalent (OME) for each route of administration of each opioid and was used to calculate the OME for individual opioids. For a patch route of administration, the delivery rate per hour was used to calculate the total opioid delivered over the suggested life of the patch. This is the method used by the National Drug and Alcohol Research Centre, Australia [N.Gisev 2019, personal communication]. 3.3. Definitions Poisoning Severity Score: A standardized scale for grading the severity of poisoning [ 20 ]. The following scores may be given: NONE (0) - No symptoms or signs related to poisoning; MINOR (1) - Mild, transient and spontaneously resolving symptoms; MODERATE (2) - Pronounced or prolonged symptoms; SEVERE (3) - Severe or life-threatening symptoms; FATAL (4) – Death [ 20 ]. Toxicity intent of “Intentional: Abuse”: defined by WAPIC according to the WHO as a deliberate exposure to an agent on which the person is dependent, or in order to achieve a euphoriant or psychotropic effect. Unintentional misuse differs from intentional misuse in that the exposure was unplanned or not foreseen by the patient [ 23 ]. Abuse potential: Products with abuse potential contain substances that have central nervous system activity (CNS) and produce a change in mood such as euphoria, hallucinations, and effects consistent with CNS depressants or stimulants [ 24 ]. 3.4. Analysis Opioids selected for analysis include buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol. These were selected due to their prevalence as common choices for prescription opioid analgesic medication in Australia. Methadone was not included in the study as it was unable to be isolated from the NCIS overdose mortality data provided. All cases where exposure to one or more of these opioids resulted in death or moderate to severe morbidity were included for analysis of opioid toxicity. All cases where abuse of one of these opioids was noted was included for analysis of opioid abuse. No distinction was made in this study between formulation (e.g. immediate or extended release, abuse-deterrent), method of administration, reason for prescription (chronic vs acute pain) or the presence of a prescription due to lack of available information. Statistical analysis of overdose mortality and morbidity data was completed using negative binomial regression with 100,000 grams OME dispensed as an exposure variable. OME, an assessment of opioid potency, was calculated using the conversion factors listed in Table 1 . Separate regression modelling assessed overdose mortality by; a) change over time owing to all opioids combined; b) change over time within each opioid; and c) comparative overdose mortality to the reference opioid morphine. Morbidity was modelled by; a) change over time within each opioid; and b) change over time comparing opioids. Regression modelling of abuse data was not completed owing to the small amount of data available at the time. For the analyses, incidence rate ratio (IRR) changes according to the variable. For opioid the IRR represents the difference in rates between an opioid and the reference opioid, expressed as a %. For time, IRR represents the change in rate of each increment year. Table 1 Oral morphine equivalents (OME) conversion factors for commonly prescribed opioids. Molecule Route of administration OME Conversion Factor to convert to mg/day [ 28 , 29 ] Buprenorphine Parenteral 75 mg/day [ 28 ] Patch 2.2 mcg/hr [ 28 ] Buccal/Sublingual 38.8 mg/day [ 28 ] Fentanyl Patch 2.7 mcg/hr [ 28 ] Buccal/Sublingual .1 mcg/day [ 28 ] Hydromorphone Parenteral 17.5 mg/day [ 28 ] Tablet or Lozenge 5 mg/day [ 28 ] Morphine Parenteral 3 mg/day [ 28 ] Tablet or Lozenge 1 mg/day [ 28 ] Oxycodone Parenteral 3 mg/day [ 28 ] Tablet or Lozenge 1.5 mg/day [ 28 ] Suppository 1.5 mg/day [ 28 ] Tapentadol Tablet or Lozenge 0.4 mg/day [ 28 ] Tramadol Parenteral 0.33 mg/day [ 29 ] Tablet or Lozenge 0.2 mg/day [ 28 ] 4. Results 4.1. Overdose mortality Analysis of the seven opioids combined found a 7% increase in overdose mortality each year between 01/07/2000 and 12/12/2015 (IRR = 1.07 95%CI:1.05, 1.09, p < 0.001). Amongst the seven opioids analysed, morphine was identified as the leading cause of absolute mortality and relative mortality per 100,000 grams OME dispensed (Table 2 , Table 3 , Fig. 1 ). Tapentadol was associated with the lowest average mortality per 100,000 grams OME dispensed. Testing for change over time within each opioid detected nil significant change for buprenorphine and tapentadol. However, for all the other opioids, a significant increase in rates of death for each yearly increment was detected; hydromorphone 37%; fentanyl 33%; tramadol 6%; morphine 5%; and oxycodone 4%. To avoid the risk of false positives through a high number of comparisons, morphine was selected as the reference opioid to compare all other opioids to. After adjusting for variation in overdose mortality rates over time, analysis found all other opioids had a significant lower rate of death. Oxycodone had the least comparative decrease in overdose mortality, at 69% lower (IRR = 0.31, 95%CI: 0.25, 0.39, p < 0.001), tramadol at 78% (IRR = 0.22, 95%CI: 0.17, 0.27, p < 0.001), fentanyl at 84% (IRR = 0.16, 95%CI: 0.12, 0.20, p < 0.001), buprenorphine at 87% (IRR = 0.13, 95%CI: 0.09, 0.18, p < 0.001), hydromorphone at 91% (IRR = 0.09, 95%CI: 0.06, 0.13, p < 0.001) and tapentadol at 96% lower (IRR = 0.04, 95%CI: 0.02, 0.11, p < 0.001) (Fig. 2 ). Table 2 Relative rates of Australian overdose mortality data for commonly prescribed opioid analgesics, 01 July 2000–2015 (QLD from 01 January 2001). Opioid Absolute overdose mortality Total grams dispensed Average overdose mortality per 100,000g dispensed, OME IRR, change over time within each opioid 95% CI, change over time within each opioid p value, change over time within each opioid Buprenorphine 136 70 025 2.5 0.95 0.88–1.02 0.151 Fentanyl 547 114 507 4.3 1.33 1.27–1.40 < 0.001 Hydromorphone 66 409 092 2.1 1.37 1.21–1.55 < 0.001 Morphine 3644 19 416 258 16.1 1.05 1.03–1.06 < 0.001 Oxycodone 1851 21 199 522 5.8 1.04 1.03–1.06 < 0.001 Tapentadol* 6 1 375 118 1.1 0.59 0.13–2.72 0.502 Tramadol 855 109 178 842 3.9 1.06 1.03–1.08 < 0.001 *Tapentadol data is calculated for the shortened date range of 2013–2015, as tapentadol was first dispensed in Australia in 2013. Table 3 Australian overdose mortality, absolute, for commonly prescribed opioid analgesics by year 01 July 2000–2015 (QLD from 01 January 2001). To protect the identity of the individuals, where deaths are less than 4, they have been recorded as < 4. DEATHS 2000 2001 2002 2003 2004 2005 2006 2007 Buprenorphine 0 < 4 0 < 4 < 4 < 4 < 4 9 Fentanyl < 4 < 4 0 0 0 < 4 < 4 < 4 Hydromorphone Morphine 133 208 200 192 221 233 183 213 Oxycodone 6 20 27 36 44 59 59 96 Tapentadol Tramadol 0 15 32 37 45 30 38 50 Other 477 396 380 418 444 454 329 494 DEATHS 2008 2009 2010 2011 2012 2013 2014 2015 Buprenorphine 4 9 12 17 9 17 25 26 Fentanyl 11 15 31 55 77 91 121 136 Hydromorphone < 4 < 4 < 4 < 4 15 10 15 20 Morphine 247 276 243 199 254 219 310 313 Oxycodone 104 130 154 177 200 224 271 244 Tapentadol < 4 0 5 Tramadol 46 67 56 47 79 89 107 117 Other 608 665 637 643 665 656 781 812 4.2. Morbidity The number of moderate and severe opioid poisonings cases in WA, handled by the WAPIC between 2007 and 2017 in regards to statistical analysis is low and varies markedly each year (Fig. 3 ). As a result, there are few statistically significant results. The average number of moderate and severe poisoning cases per 100,000 grams OME dispensed is highest for tramadol, with 3.9 cases and lowest for fentanyl with 1.3 (Table 4 ). A significant 17% decline in the rate of cases was detected for buprenorphine over time (IRR = 0.83, 95%CI: 0.72, 0.95, p = 0.008) and for oxycodone a significant 11% increase in cases per year (IRR1.11, 95%CI: 1.02,1.21, p = 0.02). No significant changes over time were detected for the remaining opioids (Table 3 ). A comparison of all opioids against the others in terms of pattern over time (interaction IRRs) was completed, one significant result was achieved for the 21 comparisons made with multiple testing correction applied; Oxycodone has a 34% greater change over time in moderate and severe poisonings than buprenorphine (IRR = 1.34, 95%CI: 1.14, 1.58, p = 0.001). Table 4 Moderate and severe opioid poisoning cases, WA, 2007–2017 Opioid Moderate poisoning cases Severe poisoning cases Average moderate and severe poisoning cases per 100,000g OME dispensed IRR, change over time within each opioid 95% CI, change over time within each opioid p value, change over time within each opioid Buprenorphine 21 3.5 0.83 0.72–0.95 0.008 Fentanyl 8 5 1.3 1.04 0.86–1.25 0.706 Hydromorphone 8 0 1.6 0.9 0.66–1.22 0.504 Morphine 22 4 2.0 0.97 0.85–1.09 0.576 Oxycodone 47 14 2.6 1.11 1.02–1.21 0.022 Tapentadol 9 6 3.3 1.01 0.56–1.81 0.985 Tramadol 92 16 3.9 0.94 0.88–1.01 0.091 4.3. Abuse For the period 2015–2017, the number of inpatient and outpatient treatment episodes commenced in Western Australia, where the primary drug of abuse was a prescription opioid, was highest for morphine, followed by oxycodone and buprenorphine (Table 4 , Fig. 4 ). Tapentadol and Hydromorphone are not individually recorded but are grouped under ‘other opioids’ in the WAMHC database as the rates are nil, or extremely low [R. O’Regan 2018, personal communication]. Treatment episodes per 100,000 grams OME dispensed are highest for morphine. Calls received by WAPIC between 2007 and 2017 where the intent of the individual was abuse of opioids, was greatest for morphine (1.3) and least for hydromorphone (0.0) and tapentadol (0.0), per 100,000 grams OME dispensed (Table 5 ). Fentanyl has increased since 2012, to now record the highest average for 2017 (Fig. 5 ). Nil statistical modelling was attempted for either sources of abuse data owing to the small amount of data. Table 5 Rate of new commencement of opioid addiction treatment by WAMHC, 2015–2017. Primary drug of abuse Treatment episodes commenced Treatment episodes per 100,000g OME dispensed Buprenorphine 343 122.6 Fentanyl 64 26.7 Morphine 363 139.0 Oxycodone 380 60.2 Tramadol 81 9.6 Table 6 Intentional abuse of prescription opioids as handled by WAPIC, WA only, 2007–2017 Opioid Cases handled by WAPIC with abuse intent Cases handled by WAPIC with abuse intent per 100,000g OME dispensed Buprenorphine 7 1.0 Fentanyl 6 0.6 Hydromorphone 0 0.0 Morphine 16 1.3 Oxycodone 23 1.0 Tapentadol 0 0.0 Tramadol 22 0.8 5. Limitations The conclusions in this paper must be regarded with limitations in mind. Screening for each of the listed opioids was not routinely performed until recently, with the date of implementation differing from state to state. Previously the opioids tested for was at the discretion of the coroner. Each death due to opioid toxicity is the judgement of the coroner. Differing coroners may attribute the cause of death differently and as such the overdose mortality data may be an under- or over-estimate of the true number. This is especially difficult when differentiating between a death due to heroin or morphine toxicity, or a combination of both. In cases where the individual has died suddenly after administration of heroin, the metabolite of heroin 6-MAM will not be produced. In these cases, the death will be attributed to morphine, unless the history points to a heroin-related death (e.g. needle in situ). It is therefore likely that some cases were incorrectly attributed to morphine related fatalities, resulting in an over-estimation of morphine related fatalities. A recent paper cites 25% of the deaths attributed to morphine were in fact due to heroin as a result of their further investigation [ 25 ]. The formulation of the opioids and the source of the opioids (diverted/prescribed/illicit manufacture) was unable to be determined due to limitations in the source date. Additionally, confounding factors regarding patient demographic were unable to be determined owing to the lack of detail in the source information. The poisons information centre data was limited as the proportion of WAPIC data capture of Western Australian opioid poisonings is only anecdotally known. Additionally, the quality of the information in the WAPIC database relies heavily upon the expertise of the toxicologist entering the data. The temporal relationship between the data captured and reality also differs. Each call reflects the information given by the caller at a discrete moment in time. The severity of poisonings however, vary over time, and the information captured in the database is unlikely to represent the greatest severity experienced by the individual, which this analysis assumes. The intent of callers is not recorded for many cases of opioid poisoning. Thus, the absolute number is likely an underestimation. Furthermore, these instances of abuse intent reflect only a small subset of the population in that they are also currently experiencing symptoms of opioid poisoning. It is only useful as a comparison between the opioids and is not reflective of the amount of abuse in the community. The comparison may be further limited in that opioids with fewer instances of poisoning have a higher likelihood of being an underestimation, whereas opioids which more readily induce side-effects are likely to be over-represented in the data. The relative rates of prescription opioid abuse requiring drug rehabilitation services in Western Australia is an underestimate as whilst the WAMHC is the sole public provider of these services, a small number of private providers also provide drug rehabilitation services in Western Australia. IQVIA data is estimated to cover over 94% of all pharmaceutical sales nationally [ 26 ] making it a robust index. This analysis however assumes that 100% of all opioids available in the community are reflected in the data. No estimate for illegally imported or manufactured opioids is available for Australia. The data and trends presented in this paper cannot be assumed to reflect the situation today. Nevertheless, insights which are relevant for today can be drawn from the data presented in this paper as the formulations and regulatory environments have not changed since the most recent data from this paper. 6. Discussion This retrospective observational study presents a high-level overview of the comparative overdose mortality, morbidity and abuse of buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol in Australia and Western Australia. This study was restricted to data sources which were accessible and allowed for differentiation between opioids. This has resulted in a mixed collection of study populations, time periods and geographical locations. WA specific data cannot be assumed to reflect the Australia-wide data. Nevertheless, this paper which combines Australian data on the comparative overdose mortality, morbidity and abuse of seven common prescription opioids is the largest comparison to date. The comparative overdose mortality, morbidity and abuse of common prescription opioids shows a mixed picture in Australia. Overall, there was a statistically significant increase of 7% in overdose mortality each year for all analysed opioids combined. This result is similar to that reported by Roxburgh et al [ 6 ] at 6%, who analysed a smaller number of prescription opioids and for an earlier time period. Of the opioids, morphine recorded the highest absolute overdose mortality, highest comparative overdose mortality per 100,000 grams OME dispensed, and the fourth highest increase in overdose mortality each year, at 5%. Important to note is that mortalities attributed to morphine may be an overestimation (Section 5) and some may be due to heroin toxicity [ 25 ]. Oxycodone was the second highest overdose mortality, at 69% lower than morphine, with a yearly increase of 4%. This was followed by tramadol at 78% lower with a yearly increase of 6%, fentanyl at 84% lower with a yearly increase of 33%, buprenorphine 87% lower, hydromorphone 91% lower with 37% yearly increase and finally tapentadol with the lowest overdose mortality at 96% lower than morphine. Statistical significance was achieved for each of the above results. The large swings in overdose mortality per 100,000 grams OME for buprenorphine are due to one death in 2001 and three deaths in 2004 during which only small amounts of buprenorphine were sold (2001: 2414 grams per OME, 2004: 2058 grams per OME), approximately 0.002% of yearly sales in 2017. The underlying reason for the difference in the rate of overdose mortality between common prescription opioids has not been thoroughly researched. A 2018 paper [ 14 ] proposes that the potency of the opioid accounts for 96% of the difference in serious adverse side effects. However, considering the variation in rate of overdose mortality per 100,000 grams OME dispensed, which corrects for potency, and the availability of the opioid in the community, it would follow that other causes of the difference exist. Assuming the overdose mortality and dispensation data is a true reflection of reality, a possible explanation could be the inherent difference in the pharmacokinetics of each opioid and their unique effect upon the individual in terms of risk of overdose mortality, morbidity and abuse potential. Illegally produced opioids, not captured in the dispensation data could also account for the difference in rates of overdose mortality. However, this is unlikely as the difference between the opioids are generally consistent over time. This points to an inherent difference in the pharmacokinetics rather than a difference in availability, which would be expected to result in a frequent change of overdose mortality which is not the case. Anecdotally, illegal Fentanyl, or riskier use, may feature in the increase in overdose mortality rate year on year from 2009, as has also been reported in the USA. These are areas which require further research. The number of moderate to severe cases of opioid poisoning, as handled by WAPIC, 2007–2017, which serves as a measure of morbidity, differs markedly in ranking compared with overdose mortality. Tramadol was the highest, with a rate per 100,000 grams OME dispensed of 3.9, followed by buprenorphine, tapentadol, oxycodone, morphine, fentanyl and hydromorphone. A statistically significant decline in the rate of cases per 100,000 grams OME dispensed was detected for buprenorphine at 17%, on the other hand a significant 11% increase was detected for oxycodone. Similarly, oxycodone had a 34% greater change over time in moderate and severe poisonings than buprenorphine. Data from the US records a lower risk of major medical effect or hospitalisation, with the exception of hydromorphone, than that of Western Australia [ 14 ]. The rate of major medical effect or hospitalisation per 100,000 grams OME dispensed in the US is as follows; hydromorphone (1.28, 7.67), oxycodone (0.28, 1.66), morphine (0.21, 1.01), tramadol (0.06, 0.32) and tapentadol (0.04, 0.26) [ 14 ]. This is compared with the average moderate to severe toxicity for Western Australia; tramadol (3.9), buprenorphine (3.5), tapentadol (3.3), oxycodone (2.6), morphine (2.0), hydromorphone (1.6) and fentanyl (1.3). New treatment episodes commenced for opioid addiction in Western Australia between 2015 and 2017, a measure of abuse, was highest for morphine (418), followed by oxycodone (380) and lowest for hydromorphone and tapentadol (“nil or extremely low”). The average rate of commencement of a treatment episode, in Western Australia, per 100,000 grams OME dispensed was highest for morphine (160.1) followed by buprenorphine (122.6), oxycodone (60.2), fentanyl (26.7), tramadol (9.6) and lowest for tapentadol and hydromorphone. This rate remains consistent over the study period, with clear linear trends observed. Calls received by WAIPC between 2007 and 2017, for WA calls only, where the intent of the opioid poisoning was classified as intentional abuse numbered 74 over an 11-year period. This data needs to be approached with a degree of scepticism given the small number of calls. The Western Australian data records a higher average rate of intentional abuse, than that of the US data [ 27 ] with the exception of tapentadol and hydromorphone. The US data, from October 2011 to June 2016 records the following number of calls to a poison information centre per 100,000 units dispensed, where the intent was recorded as abuse; hydromorphone (0.062) morphine (0.052), oxycodone (0.036), tapentadol (0.028) and tramadol (0.022). In comparison, for Western Australia the following average number of calls per 100,000g OME were calculated; fentanyl (0.8), morphine (0.7) oxycodone (0.5), buprenorphine (0.4), tramadol (0.3), hydromorphone (0.0) and tapentadol (0.0). The ranking is broadly similar, with the exception of hydromorphone which is the highest for the US, and equal lowest for Australia. 7. Conclusions Based upon this paper the following conclusions can be made: The rates of overdose mortality, morbidity and abuse differ according to the opioid dispensed, even once the confounding factors of availability and strength have been accounted for. The risk of overdose mortality is highest for morphine followed by oxycodone, tramadol, fentanyl, buprenorphine, hydromorphone and tapentadol. The risk of morbidity has increased over time for oxycodone and decreased for buprenorphine, other morbidity data is inconclusive, with conflicting comparisons between Australian data, and compared with US data. No conclusions can be drawn regarding the comparative risk of morbidity of prescription opioids based upon this data. The average rate of abuse is highest for morphine, buprenorphine, oxycodone and fentanyl and lowest for tramadol, tapentadol and hydromorphone in Western Australia, however due to a lack of data, no significant comparisons between opioids can be made. Further research is needed to gather more data, particularly on the morbidity and abuse of common prescription opioids to obtain statistically significant comparisons between the opioids. Abbreviations National Coronial Information System (NCIS), Western Australian Poisons Information Centre (WAPIC), Western Australian Mental Health Commission (WAMHC), Oral Morphine Equivalent (OME), Central nervous system activity (CNS), Pharmeceutical Benefits Scheme (PBS). Declarations Funding Pharmaceutical sales data for all opioid medications sold in Australia was provided via a third-party request through Seqirus Australia, the manufacturers of Palexia. Statistical analysis was completed by Sally Burrows, Statistician, Royal Perth Hospital Research Foundation, which provides limited, in-kind support to research projects whereby Royal Perth Hospital is a beneficiary of the research. Nil direct funding was received for this research. Conflicts of interest/Competing interests SA Schug was a member of the international and the Australian Advisory Board for tapentadol. His employer UWA, and since his retirement in October 2019, has received consulting fees, speaking honoraria and/or travel grants from the manufacturers of tapentadol (Grunenthal, bioCSL and Seqirus) in the last 5 years. JS Channell has received speaking honoraria from Sequirus, the manufacturers of tapentadol, in the last 5 years. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Full publication independence was maintained at all times in the research and writing of this paper. Consent for publication, not applicable. Author contributions All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Jessie Channell and Stephan Schug. The first draft of the manuscript was written by Jessie Channell and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Corresponding author is Jessie Channell. Availability of data and material The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. Ethics approval The research utilised anonymous data, available by simple request, with nil interaction with the individuals, ethics was thus not required as per University of Western Australian guidelines at the time of commencement of the research project. References Chrzanowska A, Man N, Sutherland R, Degenhardt L, Peacock A. Trends in drug-induced deaths in Australia, 1997–2019. Drug trends bulletin series Sydney: National Drug and Alcohol Research Centre, UNSW Sydney. 2021. Australian Institute of Health and Welfare. Opioid harm in Australia and comparisons between Australia and Canada. Canberra: AIHW; 2018. Karanges EA, Blanch B, Buckley NA, Pearson SA. Twenty-five years of prescription opioid use in Australia: a whole‐of‐population analysis using pharmaceutical claims. Br J Clin Pharmacol. 2016;82(1):255–67. Whiteford HA, Degenhardt L, Rehm J, Baxter AJ, Ferrari AJ, Erskine HE, et al. Global burden of disease attributable to mental and substance use disorders: findings from the Global Burden of Disease Study 2010. The Lancet. 2013;382(9904):1575–86. Degenhardt L, Charlson F, Ferrari A, Santomauro D, Erskine H, Mantilla-Herrara A, et al. The global burden of disease attributable to alcohol and drug use in 195 countries and territories, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. The Lancet Psychiatry. 2018;5(12):987–1012. Roxburgh A, Hall WD, Dobbins T, Gisev N, Burns L, Pearson S, et al. Trends in heroin and pharmaceutical opioid overdose deaths in Australia. Drug Alcohol Depend. 2017;179:291–8. National Institute on Drug Abuse. Overdose Death Rates. In: overdone-data.xls, editor.: National Institute on Drug Abuse; 2018. Raffa RB. On subclasses of opioid analgesics. Curr Med Res Opin. 2014;30(12):2579–84. Atkinson TJ, Fudin J, Pandula A, Mirza M. Medication pain management in the elderly: Unique and underutilized analgesic treatment options. Clin Ther. 2013;35(11):1669–89. Ordonez Gallego A, Gonzalez Baron M Fau - Espinosa Arranz E, Espinosa Arranz E. Oxycodone: a pharmacological and clinical review. Clin Transl Oncol. 2007;9(5):298–307. Ventura L, Carvalho F, Dinis-Oliveira RJ. Opioids in the Frame of New Psychoactive Substances Network: A Complex Pharmacological and Toxicological Issue. Curr Mol Pharmacol. 2017;04:04. Pathan H, Williams J. Basic opioid pharmacology: an update. British journal of pain. 2012;6(1):11–6. National Center for Biotechnology Information. Hydromorphone [Available from: https://pubchem.ncbi.nlm.nih.gov/compound/5284570 . Murphy DL, Lebin JA, Severtson SG, Olsen HA, Dasgupta N, Dart RC. Comparative Rates of Mortality and Serious Adverse Effects Among Commonly Prescribed Opioid Analgesics. Drug Saf. 2018:1–9. Dart RC, Surratt HL, Cicero TJ, Parrino MW, Severtson SG, Bucher-Bartelson B, et al. Trends in opioid analgesic abuse and mortality in the United States. N Engl J Med. 2015;372(3):241–8. Australian Institute of Health and Welfare. Non-medical use of pharmaceuticals: trends, harms and treatment, 2006-07 to 2015-16. Canberra: AIHW; 2017. Contract No.: Cat. no. HSE 195. National Coronial Information System. Explanatory Notes Melbourne: National Coronial Information System; [Available from: http://www.ncis.org.au/about-the-data/explanatory-notes/ . Neate SL, Bugeja LC, Jelinek GA, Spooner HM, Ding L, Ranson DL. Non-reporting of reportable deaths to the coroner: when in doubt, report. The Medical journal of Australia. 2013;199(6):402. Department of Health. WA Poisons Information Centre: Government of Western Australia; [Available from: http://www.scgh.health.wa.gov.au/OurServices/WAPIC/ . Persson HE, Sjöberg GK, Haines JA, De Garbino JP. Poisoning Severity Score. Grading of Acute Poisoning. Journal of Toxicology: Clinical Toxicology. 1998;36(3):205–13. Mental Health Commission. Our services Perth: Government of Western Australia; [Available from: https://www.mhc.wa.gov.au/about-us/our-services/ . Sequirus Australia. Our Products: Sequirus Australia; 2018 [Available from: https://www.seqirus.com.au/s1/cs/aucb/1196562673365/page/1199979032915/ProductFinder.htm . World Health Organisation. INTOX Definitions [Internet]. WHO; 2000 [Available from: https://www.who.int/ipcs/poisons/definitions_en.pdf . Center for Drug Evaluation and Research (CDER). Assessment of Abuse Potential of Drugs Guidance for Industry. In: Food and Drug Administration, editor. Maryland, USA2017. Roxburgh A, Pilgrim JL, Hall WD, Burns L, Degenhardt L. Accurate identification of opioid overdose deaths using coronial data. Forensic Sci Int. 2018;287:40–6. IMS Health. Australian Pharmaceutical Index: IMS Plus workshop manual. Sydney: IMS Health Australia; 2009. Vosburg SK, Severtson SG, Dart RC, Cicero TJ, Kurtz SP, Parrino MW, et al. Assessment of Tapentadol API Abuse Liability With the Researched Abuse, Diversion and Addiction-Related Surveillance System. J Pain. 2018;19(4):439–53. Nielsen S, Degenhardt L, Hoban B, Gisev N. A synthesis of oral morphine equivalents (OME) for opioid utilisation studies. Pharmacoepidemiology and drug safety. 2016;25(6):733–7. eTG complete. Therapeutic guidelines. 2002. Additional Declarations Competing interest reported. Funding Pharmaceutical sales data for all opioid medications sold in Australia was provided via a third-party request through Seqirus Australia, the manufacturers of Palexia. Statistical analysis was completed by Sally Burrows, Statistician, Royal Perth Hospital Research Foundation, which provides limited, in-kind support to research projects whereby Royal Perth Hospital is a beneficiary of the research. Nil direct funding was received for this research. Conflicts of interest/Competing interests SA Schug was a member of the international and the Australian Advisory Board for tapentadol. His employer UWA, and since his retirement in October 2019, has received consulting fees, speaking honoraria and/or travel grants from the manufacturers of tapentadol (Grunenthal, bioCSL and Seqirus) in the last 5 years. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Full publication independence was maintained at all times in the research and writing of this paper. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4269986","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":304169654,"identity":"018bba73-a9e7-4959-a448-1d51c652cf8a","order_by":0,"name":"Jessie Channell","email":"data:image/png;base64,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","orcid":"","institution":"The University of Western Australia","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Jessie","middleName":"","lastName":"Channell","suffix":""},{"id":304169655,"identity":"d02cf1a5-bdc5-49f6-bc4e-4376ab5bd2e3","order_by":1,"name":"Stephan Schug","email":"","orcid":"","institution":"The University of Western Australia","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Stephan","middleName":"","lastName":"Schug","suffix":""}],"badges":[],"createdAt":"2024-04-15 13:15:01","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4269986/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4269986/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57427465,"identity":"609e7221-d82b-4b7c-8710-93011010f4c3","added_by":"auto","created_at":"2024-05-30 14:33:52","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":79935,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eOpioid overdose mortality per 100,000 grams OME dispensed, 2000 – 2015. Note: Tapentadol was first dispensed in Australia in 2013.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4269986/v1/5f0db38833c7057957f6c6a7.png"},{"id":57427464,"identity":"1c8e400a-16b7-428e-81a7-854108f53502","added_by":"auto","created_at":"2024-05-30 14:33:52","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":27841,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eComparative overdose mortality compared with morphine for the period 01/07/2000 to 12/12/2015. Circle represents the IRR of the opioid compared with morphine, Vertical bars represent the 95%CI.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4269986/v1/7561ba27944d2069e16965c3.png"},{"id":57427466,"identity":"32341665-14ec-4b5c-be17-5b134f5a3fd3","added_by":"auto","created_at":"2024-05-30 14:33:52","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":130368,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eModerate and severe opioid poisoning cases, WA only, per 100,000 grams OME dispensed, 2007-2017\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4269986/v1/38e3431f7f588efc390e66c0.png"},{"id":57427468,"identity":"a9ac144d-cf6f-4de3-9862-72e8d55327ea","added_by":"auto","created_at":"2024-05-30 14:33:52","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":66774,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eRate of new commencement of opioid addiction treatment by WAMHC, WA, 2015 – 2017, per 100,000 grams OME dispensed\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4269986/v1/c59d7c0576b7ec90fb69580c.png"},{"id":57427467,"identity":"6e01530f-a4fc-4ec8-82bd-7d1f92a5cc72","added_by":"auto","created_at":"2024-05-30 14:33:52","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":121731,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eIntentional abuse of prescription opioids as handled by WAPIC, WA only, per 100,000 grams OME dispensed, 2007-2017\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-4269986/v1/0232ea762ae281bb90e8220f.png"},{"id":59309256,"identity":"deffe5df-20f9-4d5c-ade9-ccdfb7a624d4","added_by":"auto","created_at":"2024-06-29 06:18:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1467911,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4269986/v1/b9858de8-02fe-4c0d-bcb9-f6aafa8b1027.pdf"}],"financialInterests":"Competing interest reported. Funding \nPharmaceutical sales data for all opioid medications sold in Australia was provided via a third-party request through Seqirus Australia, the manufacturers of Palexia. Statistical analysis was completed by Sally Burrows, Statistician, Royal Perth Hospital Research Foundation, which provides limited, in-kind support to research projects whereby Royal Perth Hospital is a beneficiary of the research. Nil direct funding was received for this research. \nConflicts of interest/Competing interests \nSA Schug was a member of the international and the Australian Advisory Board for tapentadol. His employer UWA, and since his retirement in October 2019, has received consulting fees, speaking honoraria and/or travel grants from the manufacturers of tapentadol (Grunenthal, bioCSL and Seqirus) in the last 5 years. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Full publication independence was maintained at all times in the research and writing of this paper.","formattedTitle":"\u003cp\u003eComparative Overdose Mortality, Morbidity and Abuse of Common Prescription Opioids\u003c/p\u003e","fulltext":[{"header":"Key Points","content":"\u003cp\u003e\u003cstrong\u003eThe risk of overdose mortality amongst common prescription opioids is highest for morphine followed by oxycodone, tramadol, fentanyl, buprenorphine, hydromorphone and tapentadol. The risk of morbidity has increased over time for oxycodone and decreased for buprenorphine, other morbidity data is inconclusive. The average rate of abuse is highest for morphine, buprenorphine, oxycodone and fentanyl and lowest for tramadol, tapentadol and hydromorphone in Western Australia, however due to a lack of data, no significant comparisons between opioids can be made. \u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"1. Introduction","content":"\u003cp\u003ePrescription opioid use continues to be of great concern to the health of Australians, with 56% of all opioid related deaths attributed to pharmaceutical opioids only in 2019 [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This is set against a backdrop of ever increasing use of prescription opioids with 3.1\u0026nbsp;million Australians dispensed opioid prescriptions in 2016-17 [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. In 2019, opioid analgesics were the fourth most common group of pharmaceuticals used for non-medical purposes behind cannabis, cocaine and ecstasy. Within Australia, 2.7% of the population aged 14 and over reported recently using prescription opioids for non-medical purposes. Promisingly, this rate has reduced from 3.6% in 2016. However, misuse of prescription opioids has the highest contribution to the global burden of disease amongst illegal drugs [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThere were 4,963 deaths in Australia due to opioid poisoning excluding heroin for the period 2001\u0026ndash;2012 [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. This represents an increase from 21.9 deaths per million population in 2001 to 36.2 in 2012.\u003c/p\u003e \u003cp\u003eThe term \u0026lsquo;prescription opioids\u0026rsquo; encompasses several opioids with varying mechanisms of action [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Buprenorphine has its effects on the classical opioid receptors, being a partial agonist at the \u0026micro; opioid receptor and an antagonist at the ĸ (kappa)-receptor [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Oxycodone exhibits agonist activity on the \u0026micro;- (mu), ĸ- and δ- (delta) opioid receptors [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. The efficacy of tapentadol is believed to be due to \u0026micro;-opioid receptor agonist activity and inhibition of noradrenaline reuptake resulting in increased noradrenaline concentrations [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Tramadol, a phenylpiperidine analogue of codeine is thought to work via the same activity as tapendadol, with the added effect of serotonin reuptake modulation [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Fentanyl, a synthetic opioid has \u0026micro;-opioid receptor agonist activity [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Morphine is considered to be predominately a \u0026micro;-opioid receptor agonist, but also has some degree of agonistic efficacy on the ĸ- and δ-opioid receptors [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Hydromorphone, a semi synthetic opioid selectively binds the \u0026micro;-opioid receptor to provide an agonistic effect [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eWith the varying mechanism of action, it therefore follows that overdose mortality, morbidity and abuse between these prescription opioids may also differ. Differing rates of overdose mortality, morbidity and abuse have been established in the USA [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e, \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e], and to a lesser degree in Australia [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eUnderstanding of each medications\u0026rsquo; overdose mortality, morbidity and abuse potential is necessary to make an informed choice as to which medication(s) reflect the lowest risk to patients. This study aims to evaluate the overdose mortality, morbidity and abuse of buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol.\u003c/p\u003e"},{"header":"2. Objectives","content":"\u003cp\u003e \u003col\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTo compare overdose mortality attributable to buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTo compare morbidity attributable to buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003cspan\u003e \u003cli\u003e \u003cp\u003eTo compare abuse of buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol.\u003c/p\u003e \u003c/li\u003e \u003c/span\u003e \u003c/ol\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eHypothesis\u003c/strong\u003e \u003cp\u003eA significant difference exists in the overdose mortality, morbidity and abuse of buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol once availability and strength are accounted for.\u003c/p\u003e \u003c/p\u003e"},{"header":"3. Methods","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e3.1. Study Design\u003c/h2\u003e \u003cp\u003eThis retrospective observational study utilised several sources to assess the overdose mortality, morbidity and abuse rates of buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol.\u003c/p\u003e \u003cp\u003eOverdose mortality: National Coronial Information System (NCIS) \u0026ndash; deaths, Australia wide data, 2000\u0026ndash;2017\u003c/p\u003e \u003cp\u003eMorbidity: Western Australian Poisons Information Centre (WAPIC), Western Australian data, 2007\u0026ndash;2017.\u003c/p\u003e \u003cp\u003eAbuse: Western Australian Mental Health Commission (WAMHC), 2015\u0026ndash;2017 and Western Australian Poisons Information Centre (WAPIC), 2007\u0026ndash;2017.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Data Sources\u003c/h2\u003e \u003cp\u003eNational Coronial Information System\u003c/p\u003e \u003cp\u003eData provided: overdose mortality\u003c/p\u003e \u003cp\u003ePopulation: Australia\u003c/p\u003e \u003cp\u003eThe NCIS is a database containing information on deaths reported to a Coroner in Australia or New Zealand [\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Deaths are required to be investigated and reported to the Coroner which \u0026ldquo;appear unexpected, unnatural or violent or have resulted directly or indirectly from an accident or injury, or are related to a medical procedure\u0026rdquo; [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Data was extracted by conducting a search of closed NCIS cases from 01/07/2000 to 31/12/2015 by NCIS research officers to identify those where primary opioid toxicity was the mechanism of death. QLD data was only available from 01/01/2001 onwards. The opioid fatalities represent the number of instances the drug was judged as contributing to a death, not the total number of deaths, unless otherwise stated.\u003c/p\u003e \u003cp\u003eWestern Australian Poisons Information Centre\u003c/p\u003e \u003cp\u003eData provided: morbidity and abuse\u003c/p\u003e \u003cp\u003ePopulation: Western Australia\u003c/p\u003e \u003cp\u003eIn Australia four poison information centres, located in Western Australia, New South Wales, Victoria and Queensland, run the Poisons Information hotline. The hotline is a free, nationwide, 24-hour service for health professionals and the public. The specialist trained staff, provide risk assessment and management information for all types of poisonings, recording the case information in a database [\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The WAIPC receives calls predominantly from members of the public and health professionals in Western Australia, South Australia and the Northern Territory. There is a rotation system between the four poisons information centres, which cover calls for after-hours. Due to a lack of a centralised database and shared after-hours scheduling (A-M Lynch 2018, personal communication), the WAIPC database contains a mixture of records of poisoning events from around Australia, however most calls originating in Western Australia are received by WAPIC. The WAPIC database was provided for the dates 2007 to 2017.\u003c/p\u003e \u003cp\u003eMorbidity data extracted from the WAPIC database include cases of poisoning involving prescription opioids whereby the poisoning severity score was moderate to severe [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Abuse data extracted from the WAIPC database includes calls made to WAPIC regarding prescription opioid poisoning, whereby the intention of the individual poisoned was recorded as \u0026ldquo;Intentional: Abuse\u0026rdquo;. The number of cases reflect the number of single or multiple drug toxicity events. The opioid each poisoning case was attributed to for this paper was based upon the assessment of the WAPIC personnel.\u003c/p\u003e \u003cp\u003eWestern Australian Mental Health Commission\u003c/p\u003e \u003cp\u003eData provided: abuse\u003c/p\u003e \u003cp\u003ePopulation: Western Australia\u003c/p\u003e \u003cp\u003eThe WAMHC funds the provision of drug and alcohol support services and programs to the community. In Western Australia they are the only provider of publicly funded services which include community based and residential rehabilitation programs [\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. The number of new cases whereby a prescription opioid was the primary drug of concern was provided for the period 2015 to 2017. In cases of polysubstance abuse, the case was attributed to the main drug of abuse.\u003c/p\u003e \u003cp\u003eIQVIA Opioid Sales Data\u003c/p\u003e \u003cp\u003eData provided: pharmaceutical dispensation\u003c/p\u003e \u003cp\u003ePopulation: Australia\u003c/p\u003e \u003cp\u003ePharmaceutical sales data for all opioid medications sold in Australia was provided via a third-party request through Seqirus Australia, the manufacturers of Palexia [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e], for the period 2000\u0026ndash;2017. Data was provided as number of packs sold for each brand and pack size per state per month across retail and hospitals. The number of grams per pack was calculated and double-checked by a scientist with a background in pharmacy. Oral Morphine Equivalent (OME) for each route of administration of each opioid and was used to calculate the OME for individual opioids. For a patch route of administration, the delivery rate per hour was used to calculate the total opioid delivered over the suggested life of the patch. This is the method used by the National Drug and Alcohol Research Centre, Australia [N.Gisev 2019, personal communication].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Definitions\u003c/h2\u003e \u003cp\u003ePoisoning Severity Score: A standardized scale for grading the severity of poisoning [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. The following scores may be given: NONE (0) - No symptoms or signs related to poisoning; MINOR (1) - Mild, transient and spontaneously resolving symptoms; MODERATE (2) - Pronounced or prolonged symptoms; SEVERE (3) - Severe or life-threatening symptoms; FATAL (4) \u0026ndash; Death [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eToxicity intent of \u0026ldquo;Intentional: Abuse\u0026rdquo;: defined by WAPIC according to the WHO as a deliberate exposure to an agent on which the person is dependent, or in order to achieve a euphoriant or psychotropic effect. Unintentional misuse differs from intentional misuse in that the exposure was unplanned or not foreseen by the patient [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eAbuse potential: Products with abuse potential contain substances that have central nervous system activity (CNS) and produce a change in mood such as euphoria, hallucinations, and effects consistent with CNS depressants or stimulants [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Analysis\u003c/h2\u003e \u003cp\u003eOpioids selected for analysis include buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol. These were selected due to their prevalence as common choices for prescription opioid analgesic medication in Australia. Methadone was not included in the study as it was unable to be isolated from the NCIS overdose mortality data provided. All cases where exposure to one or more of these opioids resulted in death or moderate to severe morbidity were included for analysis of opioid toxicity. All cases where abuse of one of these opioids was noted was included for analysis of opioid abuse. No distinction was made in this study between formulation (e.g. immediate or extended release, abuse-deterrent), method of administration, reason for prescription (chronic vs acute pain) or the presence of a prescription due to lack of available information.\u003c/p\u003e \u003cp\u003eStatistical analysis of overdose mortality and morbidity data was completed using negative binomial regression with 100,000 grams OME dispensed as an exposure variable. OME, an assessment of opioid potency, was calculated using the conversion factors listed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eSeparate regression modelling assessed overdose mortality by; a) change over time owing to all opioids combined; b) change over time within each opioid; and c) comparative overdose mortality to the reference opioid morphine. Morbidity was modelled by; a) change over time within each opioid; and b) change over time comparing opioids. Regression modelling of abuse data was not completed owing to the small amount of data available at the time. For the analyses, incidence rate ratio (IRR) changes according to the variable. For opioid the IRR represents the difference in rates between an opioid and the reference opioid, expressed as a %. For time, IRR represents the change in rate of each increment year.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eOral morphine equivalents (OME) conversion factors for commonly prescribed opioids.\u003c/span\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMolecule\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eRoute of administration\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOME Conversion Factor to convert to mg/day [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eBuprenorphine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParenteral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e75 mg/day [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatch\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.2 mcg/hr [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBuccal/Sublingual\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38.8 mg/day [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFentanyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePatch\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.7 mcg/hr [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBuccal/Sublingual\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e.1 mcg/day [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eHydromorphone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParenteral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.5 mg/day [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTablet or Lozenge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5 mg/day [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eMorphine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParenteral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 mg/day [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTablet or Lozenge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 mg/day [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eOxycodone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParenteral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e3 mg/day [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTablet or Lozenge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5 mg/day [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSuppository\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5 mg/day [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTapentadol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTablet or Lozenge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.4 mg/day [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eTramadol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eParenteral\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.33 mg/day [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTablet or Lozenge\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.2 mg/day [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e]\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"4. Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e4.1. Overdose mortality\u003c/h2\u003e \u003cp\u003eAnalysis of the seven opioids combined found a 7% increase in overdose mortality each year between 01/07/2000 and 12/12/2015 (IRR\u0026thinsp;=\u0026thinsp;1.07 95%CI:1.05, 1.09, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Amongst the seven opioids analysed, morphine was identified as the leading cause of absolute mortality and relative mortality per 100,000 grams OME dispensed (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e, Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Tapentadol was associated with the lowest average mortality per 100,000 grams OME dispensed. Testing for change over time within each opioid detected nil significant change for buprenorphine and tapentadol. However, for all the other opioids, a significant increase in rates of death for each yearly increment was detected; hydromorphone 37%; fentanyl 33%; tramadol 6%; morphine 5%; and oxycodone 4%.\u003c/p\u003e \u003cp\u003eTo avoid the risk of false positives through a high number of comparisons, morphine was selected as the reference opioid to compare all other opioids to. After adjusting for variation in overdose mortality rates over time, analysis found all other opioids had a significant lower rate of death. Oxycodone had the least comparative decrease in overdose mortality, at 69% lower (IRR\u0026thinsp;=\u0026thinsp;0.31, 95%CI: 0.25, 0.39, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), tramadol at 78% (IRR\u0026thinsp;=\u0026thinsp;0.22, 95%CI: 0.17, 0.27, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), fentanyl at 84% (IRR\u0026thinsp;=\u0026thinsp;0.16, 95%CI: 0.12, 0.20, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), buprenorphine at 87% (IRR\u0026thinsp;=\u0026thinsp;0.13, 95%CI: 0.09, 0.18, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), hydromorphone at 91% (IRR\u0026thinsp;=\u0026thinsp;0.09, 95%CI: 0.06, 0.13, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and tapentadol at 96% lower (IRR\u0026thinsp;=\u0026thinsp;0.04, 95%CI: 0.02, 0.11, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eRelative rates of Australian overdose mortality data for commonly prescribed opioid analgesics, 01 July 2000\u0026ndash;2015 (QLD from 01 January 2001).\u003c/span\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOpioid\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAbsolute overdose mortality\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTotal grams dispensed\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAverage overdose mortality per 100,000g dispensed, OME\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIRR, change over time within each opioid\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% CI, change over time within each opioid\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep value, change over time within each opioid\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBuprenorphine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e136\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70 025\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.88\u0026ndash;1.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.151\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFentanyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e547\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e114 507\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.33\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.27\u0026ndash;1.40\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHydromorphone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e66\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e409 092\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.21\u0026ndash;1.55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorphine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e3644\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e19 416 258\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e16.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.05\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.03\u0026ndash;1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxycodone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e1851\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e21 199 522\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e5.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.03\u0026ndash;1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTapentadol*\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1 375 118\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.13\u0026ndash;2.72\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.502\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTramadol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e855\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e109 178 842\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.06\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.03\u0026ndash;1.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e*Tapentadol data is calculated for the shortened date range of 2013\u0026ndash;2015, as tapentadol was first dispensed in Australia in 2013.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eAustralian overdose mortality, absolute, for commonly prescribed opioid analgesics by year 01 July 2000\u0026ndash;2015 (QLD from 01 January 2001). To protect the identity of the individuals, where deaths are less than 4, they have been recorded as \u0026lt;\u0026thinsp;4.\u003c/span\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDEATHS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2000\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2001\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2002\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2003\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2004\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2005\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2006\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2007\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBuprenorphine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFentanyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHydromorphone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorphine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e133\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e208\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e200\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e192\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e221\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e233\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e183\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e213\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxycodone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e27\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e36\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e44\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e59\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e96\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTapentadol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTramadol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e32\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e37\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e45\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e38\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e50\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e477\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e396\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e380\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e418\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e444\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e454\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e329\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e \u003cp\u003e494\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"No\" id=\"Taba\" border=\"1\"\u003e \u003ccolgroup cols=\"9\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDEATHS\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2008\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2009\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2010\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003e2011\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2012\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003e2013\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2014\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e \u003cp\u003e2015\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBuprenorphine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e12\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e17\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e26\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFentanyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e31\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e55\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e77\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e91\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e121\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e136\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHydromorphone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e10\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e20\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorphine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e247\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e276\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e243\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e199\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e219\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e310\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e313\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxycodone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e104\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e154\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e177\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e200\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e224\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e271\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e244\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTapentadol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTramadol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e46\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e67\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e56\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e79\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e89\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e107\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e117\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOther\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e608\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e665\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e637\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e643\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e665\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e656\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c8\"\u003e \u003cp\u003e781\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c9\"\u003e \u003cp\u003e812\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e4.2. Morbidity\u003c/h2\u003e \u003cp\u003eThe number of moderate and severe opioid poisonings cases in WA, handled by the WAPIC between 2007 and 2017 in regards to statistical analysis is low and varies markedly each year (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). As a result, there are few statistically significant results.\u003c/p\u003e \u003cp\u003eThe average number of moderate and severe poisoning cases per 100,000 grams OME dispensed is highest for tramadol, with 3.9 cases and lowest for fentanyl with 1.3 (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). A significant 17% decline in the rate of cases was detected for buprenorphine over time (IRR\u0026thinsp;=\u0026thinsp;0.83, 95%CI: 0.72, 0.95, p\u0026thinsp;=\u0026thinsp;0.008) and for oxycodone a significant 11% increase in cases per year (IRR1.11, 95%CI: 1.02,1.21, p\u0026thinsp;=\u0026thinsp;0.02). No significant changes over time were detected for the remaining opioids (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). A comparison of all opioids against the others in terms of pattern over time (interaction IRRs) was completed, one significant result was achieved for the 21 comparisons made with multiple testing correction applied; Oxycodone has a 34% greater change over time in moderate and severe poisonings than buprenorphine (IRR\u0026thinsp;=\u0026thinsp;1.34, 95%CI: 1.14, 1.58, p\u0026thinsp;=\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab4\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 4\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eModerate and severe opioid poisoning cases, WA, 2007\u0026ndash;2017\u003c/span\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOpioid\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eModerate poisoning cases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSevere poisoning cases\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAverage moderate and severe poisoning cases per 100,000g OME dispensed\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eIRR, change over time within each opioid\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003e95% CI, change over time within each opioid\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003ep value, change over time within each opioid\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBuprenorphine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.83\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.72\u0026ndash;0.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFentanyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.04\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.86\u0026ndash;1.25\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.706\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHydromorphone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e1.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.66\u0026ndash;1.22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.504\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorphine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.97\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.85\u0026ndash;1.09\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.576\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxycodone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e47\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e2.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.11\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e1.02\u0026ndash;1.21\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.022\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTapentadol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.56\u0026ndash;1.81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.985\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTramadol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e92\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.94\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.88\u0026ndash;1.01\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.091\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e4.3. Abuse\u003c/h2\u003e \u003cp\u003eFor the period 2015\u0026ndash;2017, the number of inpatient and outpatient treatment episodes commenced in Western Australia, where the primary drug of abuse was a prescription opioid, was highest for morphine, followed by oxycodone and buprenorphine (Table\u0026nbsp;\u003cspan refid=\"Tab4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). Tapentadol and Hydromorphone are not individually recorded but are grouped under \u0026lsquo;other opioids\u0026rsquo; in the WAMHC database as the rates are nil, or extremely low [R. O\u0026rsquo;Regan 2018, personal communication]. Treatment episodes per 100,000 grams OME dispensed are highest for morphine.\u003c/p\u003e \u003cp\u003eCalls received by WAPIC between 2007 and 2017 where the intent of the individual was abuse of opioids, was greatest for morphine (1.3) and least for hydromorphone (0.0) and tapentadol (0.0), per 100,000 grams OME dispensed (Table\u0026nbsp;\u003cspan refid=\"Tab5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Fentanyl has increased since 2012, to now record the highest average for 2017 (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). Nil statistical modelling was attempted for either sources of abuse data owing to the small amount of data.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab5\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 5\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eRate of new commencement of opioid addiction treatment by WAMHC, 2015\u0026ndash;2017.\u003c/span\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrimary drug of abuse\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTreatment episodes commenced\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eTreatment episodes per 100,000g OME dispensed\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBuprenorphine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e343\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e122.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFentanyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e64\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e26.7\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorphine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e363\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e139.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxycodone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e380\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e60.2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTramadol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e81\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e9.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab6\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 6\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cspan type=\"SmallCaps\" class=\"SmallCaps\" name=\"Emphasis\"\u003eIntentional abuse of prescription opioids as handled by WAPIC, WA only, 2007\u0026ndash;2017\u003c/span\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOpioid\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCases handled by WAPIC with abuse intent\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eCases handled by WAPIC with abuse intent per 100,000g OME dispensed\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBuprenorphine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFentanyl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.6\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHydromorphone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMorphine\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e16\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOxycodone\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e23\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTapentadol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTramadol\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e22\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"5. Limitations","content":"\u003cp\u003eThe conclusions in this paper must be regarded with limitations in mind. Screening for each of the listed opioids was not routinely performed until recently, with the date of implementation differing from state to state. Previously the opioids tested for was at the discretion of the coroner. Each death due to opioid toxicity is the judgement of the coroner. Differing coroners may attribute the cause of death differently and as such the overdose mortality data may be an under- or over-estimate of the true number. This is especially difficult when differentiating between a death due to heroin or morphine toxicity, or a combination of both. In cases where the individual has died suddenly after administration of heroin, the metabolite of heroin 6-MAM will not be produced. In these cases, the death will be attributed to morphine, unless the history points to a heroin-related death (e.g. needle in situ). It is therefore likely that some cases were incorrectly attributed to morphine related fatalities, resulting in an over-estimation of morphine related fatalities. A recent paper cites 25% of the deaths attributed to morphine were in fact due to heroin as a result of their further investigation [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe formulation of the opioids and the source of the opioids (diverted/prescribed/illicit manufacture) was unable to be determined due to limitations in the source date. Additionally, confounding factors regarding patient demographic were unable to be determined owing to the lack of detail in the source information.\u003c/p\u003e \u003cp\u003eThe poisons information centre data was limited as the proportion of WAPIC data capture of Western Australian opioid poisonings is only anecdotally known. Additionally, the quality of the information in the WAPIC database relies heavily upon the expertise of the toxicologist entering the data. The temporal relationship between the data captured and reality also differs. Each call reflects the information given by the caller at a discrete moment in time. The severity of poisonings however, vary over time, and the information captured in the database is unlikely to represent the greatest severity experienced by the individual, which this analysis assumes.\u003c/p\u003e \u003cp\u003eThe intent of callers is not recorded for many cases of opioid poisoning. Thus, the absolute number is likely an underestimation. Furthermore, these instances of abuse intent reflect only a small subset of the population in that they are also currently experiencing symptoms of opioid poisoning. It is only useful as a comparison between the opioids and is not reflective of the amount of abuse in the community. The comparison may be further limited in that opioids with fewer instances of poisoning have a higher likelihood of being an underestimation, whereas opioids which more readily induce side-effects are likely to be over-represented in the data.\u003c/p\u003e \u003cp\u003eThe relative rates of prescription opioid abuse requiring drug rehabilitation services in Western Australia is an underestimate as whilst the WAMHC is the sole public provider of these services, a small number of private providers also provide drug rehabilitation services in Western Australia.\u003c/p\u003e \u003cp\u003eIQVIA data is estimated to cover over 94% of all pharmaceutical sales nationally [\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] making it a robust index. This analysis however assumes that 100% of all opioids available in the community are reflected in the data. No estimate for illegally imported or manufactured opioids is available for Australia.\u003c/p\u003e \u003cp\u003eThe data and trends presented in this paper cannot be assumed to reflect the situation today. Nevertheless, insights which are relevant for today can be drawn from the data presented in this paper as the formulations and regulatory environments have not changed since the most recent data from this paper.\u003c/p\u003e"},{"header":"6. Discussion","content":"\u003cp\u003eThis retrospective observational study presents a high-level overview of the comparative overdose mortality, morbidity and abuse of buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol in Australia and Western Australia. This study was restricted to data sources which were accessible and allowed for differentiation between opioids. This has resulted in a mixed collection of study populations, time periods and geographical locations. WA specific data cannot be assumed to reflect the Australia-wide data. Nevertheless, this paper which combines Australian data on the comparative overdose mortality, morbidity and abuse of seven common prescription opioids is the largest comparison to date.\u003c/p\u003e \u003cp\u003eThe comparative overdose mortality, morbidity and abuse of common prescription opioids shows a mixed picture in Australia. Overall, there was a statistically significant increase of 7% in overdose mortality each year for all analysed opioids combined. This result is similar to that reported by Roxburgh et al [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e] at 6%, who analysed a smaller number of prescription opioids and for an earlier time period. Of the opioids, morphine recorded the highest absolute overdose mortality, highest comparative overdose mortality per 100,000 grams OME dispensed, and the fourth highest increase in overdose mortality each year, at 5%. Important to note is that mortalities attributed to morphine may be an overestimation (Section 5) and some may be due to heroin toxicity [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Oxycodone was the second highest overdose mortality, at 69% lower than morphine, with a yearly increase of 4%. This was followed by tramadol at 78% lower with a yearly increase of 6%, fentanyl at 84% lower with a yearly increase of 33%, buprenorphine 87% lower, hydromorphone 91% lower with 37% yearly increase and finally tapentadol with the lowest overdose mortality at 96% lower than morphine. Statistical significance was achieved for each of the above results. The large swings in overdose mortality per 100,000 grams OME for buprenorphine are due to one death in 2001 and three deaths in 2004 during which only small amounts of buprenorphine were sold (2001: 2414 grams per OME, 2004: 2058 grams per OME), approximately 0.002% of yearly sales in 2017.\u003c/p\u003e \u003cp\u003eThe underlying reason for the difference in the rate of overdose mortality between common prescription opioids has not been thoroughly researched. A 2018 paper [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e] proposes that the potency of the opioid accounts for 96% of the difference in serious adverse side effects. However, considering the variation in rate of overdose mortality per 100,000 grams OME dispensed, which corrects for potency, and the availability of the opioid in the community, it would follow that other causes of the difference exist. Assuming the overdose mortality and dispensation data is a true reflection of reality, a possible explanation could be the inherent difference in the pharmacokinetics of each opioid and their unique effect upon the individual in terms of risk of overdose mortality, morbidity and abuse potential. Illegally produced opioids, not captured in the dispensation data could also account for the difference in rates of overdose mortality. However, this is unlikely as the difference between the opioids are generally consistent over time. This points to an inherent difference in the pharmacokinetics rather than a difference in availability, which would be expected to result in a frequent change of overdose mortality which is not the case. Anecdotally, illegal Fentanyl, or riskier use, may feature in the increase in overdose mortality rate year on year from 2009, as has also been reported in the USA. These are areas which require further research.\u003c/p\u003e \u003cp\u003eThe number of moderate to severe cases of opioid poisoning, as handled by WAPIC, 2007\u0026ndash;2017, which serves as a measure of morbidity, differs markedly in ranking compared with overdose mortality. Tramadol was the highest, with a rate per 100,000 grams OME dispensed of 3.9, followed by buprenorphine, tapentadol, oxycodone, morphine, fentanyl and hydromorphone. A statistically significant decline in the rate of cases per 100,000 grams OME dispensed was detected for buprenorphine at 17%, on the other hand a significant 11% increase was detected for oxycodone. Similarly, oxycodone had a 34% greater change over time in moderate and severe poisonings than buprenorphine.\u003c/p\u003e \u003cp\u003eData from the US records a lower risk of major medical effect or hospitalisation, with the exception of hydromorphone, than that of Western Australia [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. The rate of major medical effect or hospitalisation per 100,000 grams OME dispensed in the US is as follows; hydromorphone (1.28, 7.67), oxycodone (0.28, 1.66), morphine (0.21, 1.01), tramadol (0.06, 0.32) and tapentadol (0.04, 0.26) [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. This is compared with the average moderate to severe toxicity for Western Australia; tramadol (3.9), buprenorphine (3.5), tapentadol (3.3), oxycodone (2.6), morphine (2.0), hydromorphone (1.6) and fentanyl (1.3).\u003c/p\u003e \u003cp\u003eNew treatment episodes commenced for opioid addiction in Western Australia between 2015 and 2017, a measure of abuse, was highest for morphine (418), followed by oxycodone (380) and lowest for hydromorphone and tapentadol (\u0026ldquo;nil or extremely low\u0026rdquo;). The average rate of commencement of a treatment episode, in Western Australia, per 100,000 grams OME dispensed was highest for morphine (160.1) followed by buprenorphine (122.6), oxycodone (60.2), fentanyl (26.7), tramadol (9.6) and lowest for tapentadol and hydromorphone. This rate remains consistent over the study period, with clear linear trends observed.\u003c/p\u003e \u003cp\u003eCalls received by WAIPC between 2007 and 2017, for WA calls only, where the intent of the opioid poisoning was classified as intentional abuse numbered 74 over an 11-year period. This data needs to be approached with a degree of scepticism given the small number of calls. The Western Australian data records a higher average rate of intentional abuse, than that of the US data [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e] with the exception of tapentadol and hydromorphone. The US data, from October 2011 to June 2016 records the following number of calls to a poison information centre per 100,000 units dispensed, where the intent was recorded as abuse; hydromorphone (0.062) morphine (0.052), oxycodone (0.036), tapentadol (0.028) and tramadol (0.022). In comparison, for Western Australia the following average number of calls per 100,000g OME were calculated; fentanyl (0.8), morphine (0.7) oxycodone (0.5), buprenorphine (0.4), tramadol (0.3), hydromorphone (0.0) and tapentadol (0.0). The ranking is broadly similar, with the exception of hydromorphone which is the highest for the US, and equal lowest for Australia.\u003c/p\u003e"},{"header":"7. Conclusions","content":"\u003cp\u003eBased upon this paper the following conclusions can be made:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eThe rates of overdose mortality, morbidity and abuse differ according to the opioid dispensed, even once the confounding factors of availability and strength have been accounted for.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe risk of overdose mortality is highest for morphine followed by oxycodone, tramadol, fentanyl, buprenorphine, hydromorphone and tapentadol.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe risk of morbidity has increased over time for oxycodone and decreased for buprenorphine, other morbidity data is inconclusive, with conflicting comparisons between Australian data, and compared with US data. No conclusions can be drawn regarding the comparative risk of morbidity of prescription opioids based upon this data.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eThe average rate of abuse is highest for morphine, buprenorphine, oxycodone and fentanyl and lowest for tramadol, tapentadol and hydromorphone in Western Australia, however due to a lack of data, no significant comparisons between opioids can be made.\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eFurther research is needed to gather more data, particularly on the morbidity and abuse of common prescription opioids to obtain statistically significant comparisons between the opioids.\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eNational Coronial Information System (NCIS),\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWestern Australian Poisons Information Centre (WAPIC),\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWestern Australian Mental Health Commission (WAMHC),\u003c/p\u003e\n\u003cp\u003eOral Morphine Equivalent (OME),\u003c/p\u003e\n\u003cp\u003eCentral nervous system activity (CNS),\u003c/p\u003e\n\u003cp\u003ePharmeceutical Benefits Scheme (PBS).\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePharmaceutical sales data for all opioid medications sold in Australia was provided via a third-party request through Seqirus Australia, the manufacturers of Palexia. Statistical analysis was completed by Sally Burrows, Statistician, Royal Perth Hospital Research Foundation, which provides limited, in-kind support to research projects whereby Royal Perth Hospital is a beneficiary of the research. Nil direct funding was received for this research.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflicts of interest/Competing interests\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSA Schug was a member of the international and the Australian Advisory Board for tapentadol. His employer UWA, and since his retirement in October 2019, has received consulting fees, speaking honoraria and/or travel grants from the manufacturers of tapentadol (Grunenthal, bioCSL and Seqirus) in the last 5 years. JS Channell has received speaking honoraria from Sequirus, the manufacturers of tapentadol, in the last 5 years. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. Full publication independence was maintained at all times in the research and writing of this paper.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent for publication, not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Jessie Channell and Stephan Schug. The first draft of the manuscript was written by Jessie Channell and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Corresponding author is Jessie Channell.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and material\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe research utilised anonymous data, available by simple request, with nil interaction with the individuals, ethics was thus not required as per University of Western Australian guidelines at the time of commencement of the research project.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eChrzanowska A, Man N, Sutherland R, Degenhardt L, Peacock A. Trends in drug-induced deaths in Australia, 1997\u0026ndash;2019. 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N Engl J Med. 2015;372(3):241\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eAustralian Institute of Health and Welfare. Non-medical use of pharmaceuticals: trends, harms and treatment, 2006-07 to 2015-16. Canberra: AIHW; 2017. Contract No.: Cat. no. HSE 195.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNational Coronial Information System. Explanatory Notes Melbourne: National Coronial Information System; [Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.ncis.org.au/about-the-data/explanatory-notes/\u003c/span\u003e\u003cspan address=\"http://www.ncis.org.au/about-the-data/explanatory-notes/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNeate SL, Bugeja LC, Jelinek GA, Spooner HM, Ding L, Ranson DL. Non-reporting of reportable deaths to the coroner: when in doubt, report. The Medical journal of Australia. 2013;199(6):402.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDepartment of Health. WA Poisons Information Centre: Government of Western Australia; [Available from: \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.scgh.health.wa.gov.au/OurServices/WAPIC/\u003c/span\u003e\u003cspan address=\"http://www.scgh.health.wa.gov.au/OurServices/WAPIC/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003ePersson HE, Sj\u0026ouml;berg GK, Haines JA, De Garbino JP. Poisoning Severity Score. Grading of Acute Poisoning. Journal of Toxicology: Clinical Toxicology. 1998;36(3):205\u0026ndash;13.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMental Health Commission. 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Sydney: IMS Health Australia; 2009.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eVosburg SK, Severtson SG, Dart RC, Cicero TJ, Kurtz SP, Parrino MW, et al. Assessment of Tapentadol API Abuse Liability With the Researched Abuse, Diversion and Addiction-Related Surveillance System. J Pain. 2018;19(4):439\u0026ndash;53.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eNielsen S, Degenhardt L, Hoban B, Gisev N. A synthesis of oral morphine equivalents (OME) for opioid utilisation studies. Pharmacoepidemiology and drug safety. 2016;25(6):733\u0026ndash;7.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eeTG complete. Therapeutic guidelines. 2002.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-4269986/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4269986/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e: assess the overdose mortality of buprenorphine, fentanyl, hydromorphone, morphine, oxycodone, tapentadol and tramadol in Australia and the morbidity and abuse rates in Western Australia.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDesign\u003c/strong\u003e: Retrospective observational study.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSetting\u003c/strong\u003e: Australian and/or Western Australian data from the following sources; National Coronial Information System (NCIS), Western Australian Poisons Information Centre (WAPIC), Western Australian Mental Health Commission (WAMHC).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMain outcome measures\u003c/strong\u003e: Overdose mortality (deaths attributed to opioid toxicity by the coroner), morbidity (calls to WAPIC regarding moderate to severe opioid toxicity) and abuse (number of new opioid abuse WAMHC cases and calls to WAPIC where the opioid toxicity was related to abuse) of prescription opioids, per 100,000 grams oral morphine equivalent dispensed.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: The overall risk of overdose mortality per prescription opioid dispensed increased by 7% over the study period. The risk of mortality, with morphine as the reference opioid, in order from highest to lowest mortality is; oxycodone 69% lower; tramadol 78%; fentanyl 84%; buprenorphine 87%; hydromorphone 91%; and tapentadol at 96% lower. Analysis of morbidity data found a significant 17% decline in the rate of cases detected for buprenorphine and a significant 11% increase in cases for oxycodone. Abuse data was insufficient to achieve statistical significance.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: The rates of overdose mortality, morbidity and abuse differ according to the opioid dispensed even once availability and opioid strength is accounted for. These differences may be due to the inherent difference in the pharmacokinetics of each opioid and their unique effect upon the individual.\u003c/p\u003e","manuscriptTitle":"Comparative Overdose Mortality, Morbidity and Abuse of Common Prescription Opioids","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-05-30 14:33:48","doi":"10.21203/rs.3.rs-4269986/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"08548b12-e3ba-46aa-8ce2-43d690d80462","owner":[],"postedDate":"May 30th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-06-29T06:10:08+00:00","versionOfRecord":[],"versionCreatedAt":"2024-05-30 14:33:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4269986","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4269986","identity":"rs-4269986","version":["v1"]},"buildId":"7rjqhiLT3MXkJMwkYKINL","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}