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National trends in alcohol pharmacotherapy: Findings from an Australian claims database
Drug and Alcohol Dependence 166 (2016) 254–257
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Short communication
National trends in alcohol pharmacotherapy: Findings from an Australian claims database Kirsten C. Morley a,∗ , Warren Logge b , Sallie-Anne Pearson c , Andrew Baillie b , Paul S. Haber a,d a
NHMRC Centre for Excellence in Mental Health and Substance Use, Sydney Medical School, The University of Sydney, NSW 2006, Australia NHMRC Centre for Excellence in Mental Health and Substance Use, Macquarie University, NSW 2109, Australia c Centre for Big Data Research in Health, UNSW, 2052, Australia d Drug Health Services, Royal Prince Alfred Hospital, Camperdown, 2050 NSW, Australia b
a r t i c l e
i n f o
Article history: Received 29 April 2016 Received in revised form 21 June 2016 Accepted 23 June 2016 Available online 29 June 2016 Keywords: Naltrexone Acamprosate Alcohol dependence Pharmacotherapy Prescription
a b s t r a c t Background: Although the efficacy of alcohol pharmacotherapy has been widely investigated, little is known about real-world prescription patterns. Population-based dispensing data can provide an understanding of prescription patterns and characteristics of treatment in nonexperimental settings. Methods: A retrospective cohort study of patients (aged 15–84) treated with acamprosate or naltrexone between July 2009 and June 2013 was conducted using dispensing claims from the Australian Pharmaceutical benefits Scheme Database. Only individuals with prescriptions from September 2009 onwards were included. Results: We identified 61,904 individuals (40% female, 32% in 35–44 age bracket,) with a total number of 198,247 dispensings. There were 23,452 naltrexone-treated and 38,452 acamprosate-treated patients. For naltrexone, 42% of initial dispenses were followed by a second dispense with only 25% receiving at least 3 months of treatment. For acamprosate, 28% of dispenses were followed by a third dispense with only 15% receiving at least 3 months of treatment. Patients in older age groups were more likely to be dispensed a repeat script than those in younger age groups (e.g., for the 75–84 vs 15–24 age bracket OR’s = 2.27 and 2.98 for naltrexone and acamprosate respectively). Conclusion: Current national guidelines in Australia recommend alcohol pharmacotherapy for a minimum period of 3 months yet only 15–25% are receive this duration of treatment. Naltrexone-treated patients were more likely to return for a second and third dispense than acamprosate-treated patients. Prevalence and prescribing patterns change with age. Crown Copyright © 2016 Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction World-wide, harmful use of alcohol is responsible for 5.9% of all deaths and is a causal factor in more than 200 disease and injury conditions (WHO, 2015). In Australia, alcohol misuse accounts for an annual economic burden estimated at $30 billion including harms to drinkers and harms to others (Laslett et al., 2010) and is a major cause of drug-related death, twice that of tobacco when expressed as potential years of life lost (Collins and Lapsley, 2008). Alcohol-use disorders are highly prevalent in Australia yet fewer than one-third of those affected will seek treatment (Teesson et al., 2010).
∗ Corresponding author. E-mail address: [email protected] (K.C. Morley).
Acamprosate and naltrexone are the most commonly used ‘anti-craving’ pharmacotherapies for the treatment of alcohol dependence internationally. Since 2000, the Australian government has subsidised treatment with acamprosate and naltrexone on the Pharmaceutical Benefits Scheme (PBS), establishing a continuing clinical role for these medicines. National treatment guidelines recommend naltrexone and acamprosate as first-line therapy with at least a 90 day treatment period (Morley et al., 2009). Naltrexone is an orally active non-specific opioid antagonist with a moderate, but statistically reliable effect in reducing heavy drinking, as demonstrated in meta-analyses of randomised controlled trials (RCTs; Jonas et al., 2014; Rösner et al., 2010). Acamprosate is a synthetic GABA analogue thought to restore N-methyl-d-aspartate (NMDA) receptor tone following increased neuronal hyperexcitability during alcohol withdrawal (Rammes et al., 2001) and, while not consistently observed (e.g., Anton et al., 2006; Chick et al., 2000; Morley et al., 2006), meta-analyses of pooled RCT data sug-
http://dx.doi.org/10.1016/j.drugalcdep.2016.06.027 0376-8716/Crown Copyright © 2016 Published by Elsevier Ireland Ltd. All rights reserved.
K.C. Morley et al. / Drug and Alcohol Dependence 166 (2016) 254–257
gest some efficacy for controlling alcohol consumption (Jonas et al., 2014). However, while randomised controlled trials have high internal validity whereby group differences can be causally linked to treatment, it is not guaranteed that treatments will be as effective in other contexts such as those found in clinical practice (Buri et al., 2007). Compliance with medicines prescribed to treat substance abuse is recognised as a challenge (Kranzler et al., 1996). Between 25–50% of subjects enrolled in many clinical trials for alcohol dependence fail to complete the 12 weeks of recommended therapy, with most dropouts taking place within the first 6 weeks. Adherence with naltrexone has been found to be associated with improved treatment effect (Volpicelli et al., 1997) suggesting that naltrexone is an active agent whereby good compliance is central to effectiveness. Thus, given low adherence to treatment in general in this population the benefits of alcohol pharmacotherapy in realworld clinical practice have been questioned (Bouza et al., 2004). Indeed, a retrospective analysis of paid health insurance claims in the United States for naltrexone indicated that most patients do not complete a full course of treatment (Harris and Thomas, 2004). The aim of the current study was thus to characterise patterns and costs of alcohol pharmacotherapy in Australia. We conducted a population-based evaluation of the ‘anti-craving’ alcohol pharmacotherapies, naltrexone and acamprosate, dispensed in Australia between 2009 and 2013. Information regarding pharmacotherapy dispensing rates, adherence rate and prevalence of usage can provide insight into real-world clinical practice.
2. Methods We conducted a restrospective cohort study of all patients dispensed acamprosate and/or naltrexone under the PBS between July 2009 and May 2013. The Australian PBS is a government medicine reimbursement system subsidising a range of prescribed medicines (Mellish et al., 2015). For medicines costing more than the relevant beneficiary co-payment, additional costs are paid by the government. The Department of Human Services maintains a database of all PBS-subsidised claims, amounting to approximately 280 million dispensings a year. The dispensing of a PBS medicine is only not recorded in the database if the government does not contribute to the cost of the medicine. Acamprosate and naltrexone are above the general beneficiary co-payment threshold such that the claims database represents a complete capture of the total population prescribed acamprosate or naltrexone in the Australian community (and private hospitals) under the PBS. Both medications are dispensed in a 30 day supply package. We extracted data for naltrexone and acamprosate dispenses, date of supply, gender and age group. The Australian Government, Department of Human Services External Request Committee granted data access approval. To allow for consistency in our database, we included a two month wash out period which excluded prescription data from the first two months of our cohort window. This prevented the inclusion of patients that may have been receiving medications on a continual basis before the period of observation. The index dispense for each patient was the first original prescription of either acamprosate or naltrexone that appeared in the dataset for that period. A treatment episode was defined as the period between the index dispense and the estimated end date of the last prescription calculated as 31 days from that last dispense date. We calculated the rate of a second and a third dispense (3 months treatment duration) from the index dispense date, defined as a dispensing for the same medication within 31 days from the estimated end date of the previous prescription. Thus, a gap of 31 days between the end of a prescription and the beginning of the following one was allowed (60 days since date of prescription). If
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Table 1 Number of patients with at least one index dispense for alcohol pharmacotherapy in Australia, 2009–2013 for gender and age.
Total Gender, % (n) Male Female Age, % (n) 15–24 25–34 35–44 45–54 55–64 65–74 75–84
Naltrexone
Acamprosate
23452
38452
OR (95% CI)
59 (13823) 41 (9629)
60 (23241) 40 (15211)
0.94 (0.91–0.97)**
4 (104) 20 (4725) 32 (7386) 26 (5973) 14 (3197) 4 (997) 1 (13)
4 (1538) 19 (7175) 31 (11727) 26 (10157) 15 (5651) 5 (1911) 1 (293)
1.01 (0.09–0.13)*** 1.01 (1.06–1.15)*** 1.05 (1.01–1.09)* 0.95 (0.92–0.99)* 0.92 (0.87–0.96)** 0.85 (0.79–0.92)*** 0.07 (0.04–0.13)***
Notes: The index dispense was the first original prescription of either acamprosate or naltrexone that appeared in the dataset for that period (to prevent including patients receiving medications on a continual basis before the period of observation we excluded prescriptions before September 2009). OR = Odds ratio for naltrexone versus acamprosate, CI = confidence interval. * p < 0.01. ** p < 0.001. *** p < 0.0001.
more than one 30 day supply was dispensed simultaneously to the same individual it was considered to be a repeat (only a small number of cases). The median days on medication was computed as the duration between the index date and the estimated end date of the last prescription. Concurrent use was defined as a co-dispense for the alternative alcohol pharmacotherapy within 31 days from the estimated end date of the last prescription. Switching was defined as the absence of a refill prescription for naltrexone or acamprosate in addition to a dispensing for the alternate alcohol pharmacotherapy more than 31 days since the estimated end date of the last prescription. Descriptive statistics were used to determine sociodemographics (age group, gender) and prescription patterns (frequency and patterns of dispensing, concurrent use and switching). Chi-squared tests were employed to examine the association between categorical variables and prescription pattern. All data were analysed using SPSS 22.0 and all tests were two tailed with a significance level at P < 0.05.
3. Results A total of 61,904 individuals and 198,247 dispensed scripts were included in the analysis (2009–2013). The number of individuals dispensed alcohol pharmacotherapy over a representative 12 month period (2011–2012) was 23, 206, or 23.21 per 1000. Dispense patterns are depicted in Tables 1 and 2. For naltrexone, we identified 73,024 dispenses and 23,452 patients with a median of 2 dispenses per patient and a median treatment duration of 1 month. In terms of repeat dispenses, 42% (9934) of index dispenses were followed by a second dispense and 25% (5764) were followed by a third dispense. Thus, 57% of naltrexone-treated patients completed only one month of treatment. For acamprosate, we identified 125,223 dispenses and 38,452 patients with a median of 1 dispense per patient and a median treatment duration of 1 month. In terms of repeat dispenses, whereby 28% (10,839) of index dispenses were followed by a second dispense and 15% (5666) followed up with a third dispense. Thus, 72% of acamprosate-treated patients completed only one month of treatment. Naltrexone users were more likely to return for a second dispense than acamprosate users (OR = 1.86, 1 2 = 1294.68, p < 0.0001, 95% CI: 1.80–1.93) and also more likely to return for three dispenses (OR = 1.89, 95% CI: 1.81–1.97, p < 0.0001).
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K.C. Morley et al. / Drug and Alcohol Dependence 166 (2016) 254–257
Table 2 Patterns of alcohol pharmacotherapy dispensing in Australia, 2009–2013.
Median days (mean) 2nd dispense, % (n) 3rd dispense, % (n)
Naltrexone (N = 23,452)
Acamprosate (N = 38,452)
OR (95% CI)
30 (72.03) 42 (9934) 25 (5764)
30 (54.66) 28 (10839) 15 (5666)
1.86 (1.80–1.93)* 1.89 (1.81–1.97)**
Notes: To prevent inclusion of patients receiving medications on a continual basis before the period of observation we excluded prescriptions before September 2009. OR = Odds ratio for naltrexone versus acamprosate, CI = confidence interval. * Odds ratio of at least a second dispense, p < 0.0001. ** Odds ratio of at least three dispenses (3 months of treatment), p < 0.0001.
For naltrexone-treated patients, there were 59% (13,823) males and 41% (9629) females and for acamprosate-treated patients, there were 60% (23,241) males and 40% (15211) females. These rates were significantly different between the two medications (1 2 = 13.64, p < 0.001). For naltrexone, males were less likely to return for a second script compared to females (OR = 0.93, 1 2 = 6.69, p < 0.01, 95% CI: 0.89–0.98) whereas this was not the case for acamprosate (OR = 0.96, 1 2 = 2.29, p = 0.13, 95% CI: 0.92–1.01). The highest number of dispenses occurred in the 35–44 age bracket (32%) with almost 60% of all dispenses occurring between the ages of 35–55 (see Table 1). There were significant differences in the rate of dispenses between naltrexone and acamprosate for each age bracket (1 2 > 6.78, p’s < 0.01). For both medications, the odds of returning for at least a second dispense increased with age group, with significant differences between each age bracket and the 15–24 age bracket (1 2 ’s > 8.9, p’s < 0.003). The odds of returning for a second script in each age bracket compared to the 15–24 age bracket for naltrexone were: 75–84 OR = 2.27 (95%CI: 1.58–3.27); 65–74 OR = 2.35 (95%CI: 1.96–2.81); 55–64 OR = 1.76 (95%CI: 1.52–2.04); 45–54 OR = 1.57 (95%CI 1.37–1.81); 35–44 OR = 1.42 (95%CI 1.23–1.62); 25–34 OR = 1.26 (95%CI: 1.10–1.46). For acamprosate: 75–84 OR = 2.98 (95%CI: 2.29–3.88); 65–74 OR = 2.85 (95%CI: 2.44–3.33); 55–64 OR = 2.09 (95%CI: 1.82–2.40); 45–54 OR = 1.68 (95%CI: 1.47–1.92); 35–44 OR = 1.43 (95%CI: 1.25–1.63); 25–34 OR = 1.23 (95%CI: 1.07–1.41). Overall, 16% (8480) of individuals received dispenses for both acamprosate and naltrexone at any point during the four year time period as either a co-dispense, a switch or following a lengthy separation. Co-dispensing for acamprosate and naltrexone occurred at a rate of 6% (3591). Switching from naltrexone to acamprosate or vice versa after a treatment episode occurred at a rate of 4% (2540). Patients were more likely to switch from acamprosate to naltrexone (60%) than from naltrexone to acamprosate (40%) (OR = 2.22, 1 2 = 196.85, p < 0.0001, 95% CI: 1.99–2.48). 4. Discussion This study utilised a large, representative database containing information on every alcohol pharmacotherapy prescription dispensed in Australia over 2009–2013. A total of 61,904 individuals were identified, with 23,206 or 23.21 per 1000 annually (as per 2011–2012 representation), suggesting a 72% increase in the raw number of individuals receiving alcohol pharmacotherapy over the decade since an early estimate in 2001 of 13.50 patients per 1000 (Doran et al., 2003). Given a 3.9% prevalence rate for alcohol dependence (Teesson et al., 2010), we estimate that approximately 2.7–3% of individuals with alcohol dependence in Australia are being prescribed alcohol pharmacotherapy. This is despite 80% presenting to a general practitioner each year (Proudfoot and Teesson, 2009). The hesitancy of physicians to prescribe alcohol pharmacotherapies has also been noted in the USA and thought to stem from beliefs regarding limited efficacy (Mark et al., 2003a, 2003b). The rate of returning for a second dispense was 42% and 28% for naltrexone and acamprosate respectively. For a third dispense, the rates were 25% and 10% for naltrexone and acamprosate respec-
tively. These figures are particularly concerning given the national guidelines recommend a treatment duration of 3 months or 3 dispenses (Morley et al., 2009). In addition, these adherence rates are low compared with the one-month persistence rate of 62–70% reported for antidepressants (Bauer et al., 2013; Sawada et al., 2009). Treatment adherence according to recommendations is a recognised concern for all medications that preclude the full benefits of pharmacotherapy, with up to 50% of patients not taking medications as prescribed (Brown and Bussell, 2011). Naltrexone-treated individuals were significantly more likely than acamprosate-treated individuals to return for a second dispense. It is possible this difference is related to enhanced efficacy. Although meta-analyses of pooled international studies indicate similar efficacy rates for the two medications (Jonas et al., 2014), head to head trials of the two medications generally find a superior effect of naltrexone (Anton et al., 2006; Morley et al., 2006). Given that people with alcohol dependence are known to have high drop-out rates from treatment (McNeely and Sherman, 2011), it is also possible that complex dosing regimens and/or side effects may interfere with adherence to a greater degree than the general population. Acamprosate treatment requires dosing of two tablets three times per day (6 tables per day) compared to naltrexone dosing of 1 tablet per day. This may explain why fewer acamprosate prescriptions are repeated relative to naltrexone. Minimizing the frequency of dosing has been shown to improve adherence (Schroeder et al., 2004) whereby each additional daily dose results in a 10% decrease in adherence (Osterberg and Blaschke, 2005). Combining acamprosate and naltrexone (co-dispensing) or switching between them occurred at a rate of 6% and 4% respectively. There is evidence showing enhanced efficacy for the combination of acamprosate and naltrexone (Kiefer et al., 2003; Kiefer and Wiedemann, 2004) however this was not replicated in the large COMBINE trial with high naltrexone dose (Anton et al., 2006). Naltrexone administration has been shown to increase the plasma levels of acamprosate and the combined dose, although with increased side effects, is behaviourally and pharmacologically safe (Johnson et al., 2003). Nonetheless, this pattern of usage does not seem to have been widely translated into practice. While there were significant gender differences in the rate and pattern of dispensing for naltrexone versus acamprosate, the clinical significance of these differences is likely to be negligible. Dispensing of alcohol pharmacotherapy mainly occurred in the age ranges of 35–54 years with the highest dispense rate occurring between 35 and 44. This mirrors the average age range in alcohol treatment trials in Australia (Morley et al., 2014, 2016) and is also consistent with the finding that people suffering from alcohol dependence, on average, do not seek treatment for at least 14 years (Chapman et al., 2015). For both medications, the odds of returning for a second dispense increased with age. These findings are consistent with other areas of medicine where the risk of nonpersistence to chronic medication decreases with increasing age (Yeaw et al., 2009). Given both the overall low dispense rate and the low but differing adherence rates between alcohol pharmacotherapies, solutions to enhance increased medication adherence and to subsequently
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improve the treatment of alcohol use disorders may require a varied approach. It is likely that a multitude of factors lead to poor medication uptake and/or adherence such as those that are patient-based (cognitive function, ambivalence), clinician-based (communication, knowledge, treatment preferences), medicationbased (complex regimens, adverse effects, limited efficacy) and system-based (access to care) (for review see Brown and Bussell, 2011). One of the main limitations of the PBS dataset is that it underestimates whole of population use which may have slightly impacted on the overall dispensing rate for these medications in Australia (Mellish et al., 2015). It is possible, for example, that these medications could be dispensed without the government subsidy however these cases would be rare given the cost to the individual would be 25 times greater. In addition, the database does not capture prescribing in some public hospital inpatient settings where there is no government arrangement. Finally, as we have no context in which the medications were prescribed (e.g., some patients may reduce their dosing due to side effects and therefore require less dispenses), this analysis does not provide an accurate study of medication compliance but is a descriptive analysis of how these anti-craving agents are dispensed in nonexperimental community settings. In summary, we used a large epidemiological database to analyse dispensation rates of alcohol pharmacotherapy to individuals in Australia. The adherence rate is higher for naltrexone relative to acamprosate treatment and for older age groups. In spite of guidelines, the rate of pharmacotherapy use and adherence rate remains low. Role of funding source This study was supported by the NHMRC CRE in Mental Health and Substance Use (K.M. A.B. P.H.) and the NHMRC CRE in Medicines and Ageing (S.P.). Conflict of interest No Conflict declared. Contributors K.M. made contributions to the concept and design of the study, performed the analysis and wrote the manuscript. W.L. performed the data extraction and made contributions to analysis. S.A.P. made contributions to the design of the study and advice regarding data extraction and analysis. A.B. made contributions to the concept and design of the study. pH made contributions to the concept and design of the study. All authors read and approved the final manuscript. References Anton, R.F., O’Malley, S.S., Ciraulo, D.A., Cisler, R.A., Couper, D., Donovan, D.M., Gastfriend, D.R., Hosking, J.D., Johnson, B.A., LoCastro, J.S., Longabaugh, R., Mason, B.J., et al., 2006. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA 295, 2003–2017. Bauer, A.M., Schillinger, D., Parker, M.M., Katon, W., Adler, N., Adams, A.S., Moffett, H.H., Karter, A.J., 2013. Health literacy and antidepressant medication adherence among adults with diabetes: the diabetes study of Northern California (DISTANCE). J. Gen. Intern. Med. 28, 1181–1187. Bouza, C., Angeles, M., Munoz, A., Amate, J.M., 2004. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 99, 811–828. Brown, M.T., Bussell, J.K., 2011. Medication adherence: WHO cares? Mayo Clin. Proc. 86, 304–314. Buri, C., Moggi, F., Giovanoli, A., Strik, W., 2007. Prescription procedures in medication for relapse prevention after inpatient treatment for alcohol use disorders in Switzerland. Alcohol Alcohol. 42, 333–339.
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Drug and Alcohol Dependence journal homepage: www.elsevier.com/locate/drugalcdep
Short communication
National trends in alcohol pharmacotherapy: Findings from an Australian claims database Kirsten C. Morley a,∗ , Warren Logge b , Sallie-Anne Pearson c , Andrew Baillie b , Paul S. Haber a,d a
NHMRC Centre for Excellence in Mental Health and Substance Use, Sydney Medical School, The University of Sydney, NSW 2006, Australia NHMRC Centre for Excellence in Mental Health and Substance Use, Macquarie University, NSW 2109, Australia c Centre for Big Data Research in Health, UNSW, 2052, Australia d Drug Health Services, Royal Prince Alfred Hospital, Camperdown, 2050 NSW, Australia b
a r t i c l e
i n f o
Article history: Received 29 April 2016 Received in revised form 21 June 2016 Accepted 23 June 2016 Available online 29 June 2016 Keywords: Naltrexone Acamprosate Alcohol dependence Pharmacotherapy Prescription
a b s t r a c t Background: Although the efficacy of alcohol pharmacotherapy has been widely investigated, little is known about real-world prescription patterns. Population-based dispensing data can provide an understanding of prescription patterns and characteristics of treatment in nonexperimental settings. Methods: A retrospective cohort study of patients (aged 15–84) treated with acamprosate or naltrexone between July 2009 and June 2013 was conducted using dispensing claims from the Australian Pharmaceutical benefits Scheme Database. Only individuals with prescriptions from September 2009 onwards were included. Results: We identified 61,904 individuals (40% female, 32% in 35–44 age bracket,) with a total number of 198,247 dispensings. There were 23,452 naltrexone-treated and 38,452 acamprosate-treated patients. For naltrexone, 42% of initial dispenses were followed by a second dispense with only 25% receiving at least 3 months of treatment. For acamprosate, 28% of dispenses were followed by a third dispense with only 15% receiving at least 3 months of treatment. Patients in older age groups were more likely to be dispensed a repeat script than those in younger age groups (e.g., for the 75–84 vs 15–24 age bracket OR’s = 2.27 and 2.98 for naltrexone and acamprosate respectively). Conclusion: Current national guidelines in Australia recommend alcohol pharmacotherapy for a minimum period of 3 months yet only 15–25% are receive this duration of treatment. Naltrexone-treated patients were more likely to return for a second and third dispense than acamprosate-treated patients. Prevalence and prescribing patterns change with age. Crown Copyright © 2016 Published by Elsevier Ireland Ltd. All rights reserved.
1. Introduction World-wide, harmful use of alcohol is responsible for 5.9% of all deaths and is a causal factor in more than 200 disease and injury conditions (WHO, 2015). In Australia, alcohol misuse accounts for an annual economic burden estimated at $30 billion including harms to drinkers and harms to others (Laslett et al., 2010) and is a major cause of drug-related death, twice that of tobacco when expressed as potential years of life lost (Collins and Lapsley, 2008). Alcohol-use disorders are highly prevalent in Australia yet fewer than one-third of those affected will seek treatment (Teesson et al., 2010).
∗ Corresponding author. E-mail address: [email protected] (K.C. Morley).
Acamprosate and naltrexone are the most commonly used ‘anti-craving’ pharmacotherapies for the treatment of alcohol dependence internationally. Since 2000, the Australian government has subsidised treatment with acamprosate and naltrexone on the Pharmaceutical Benefits Scheme (PBS), establishing a continuing clinical role for these medicines. National treatment guidelines recommend naltrexone and acamprosate as first-line therapy with at least a 90 day treatment period (Morley et al., 2009). Naltrexone is an orally active non-specific opioid antagonist with a moderate, but statistically reliable effect in reducing heavy drinking, as demonstrated in meta-analyses of randomised controlled trials (RCTs; Jonas et al., 2014; Rösner et al., 2010). Acamprosate is a synthetic GABA analogue thought to restore N-methyl-d-aspartate (NMDA) receptor tone following increased neuronal hyperexcitability during alcohol withdrawal (Rammes et al., 2001) and, while not consistently observed (e.g., Anton et al., 2006; Chick et al., 2000; Morley et al., 2006), meta-analyses of pooled RCT data sug-
http://dx.doi.org/10.1016/j.drugalcdep.2016.06.027 0376-8716/Crown Copyright © 2016 Published by Elsevier Ireland Ltd. All rights reserved.
K.C. Morley et al. / Drug and Alcohol Dependence 166 (2016) 254–257
gest some efficacy for controlling alcohol consumption (Jonas et al., 2014). However, while randomised controlled trials have high internal validity whereby group differences can be causally linked to treatment, it is not guaranteed that treatments will be as effective in other contexts such as those found in clinical practice (Buri et al., 2007). Compliance with medicines prescribed to treat substance abuse is recognised as a challenge (Kranzler et al., 1996). Between 25–50% of subjects enrolled in many clinical trials for alcohol dependence fail to complete the 12 weeks of recommended therapy, with most dropouts taking place within the first 6 weeks. Adherence with naltrexone has been found to be associated with improved treatment effect (Volpicelli et al., 1997) suggesting that naltrexone is an active agent whereby good compliance is central to effectiveness. Thus, given low adherence to treatment in general in this population the benefits of alcohol pharmacotherapy in realworld clinical practice have been questioned (Bouza et al., 2004). Indeed, a retrospective analysis of paid health insurance claims in the United States for naltrexone indicated that most patients do not complete a full course of treatment (Harris and Thomas, 2004). The aim of the current study was thus to characterise patterns and costs of alcohol pharmacotherapy in Australia. We conducted a population-based evaluation of the ‘anti-craving’ alcohol pharmacotherapies, naltrexone and acamprosate, dispensed in Australia between 2009 and 2013. Information regarding pharmacotherapy dispensing rates, adherence rate and prevalence of usage can provide insight into real-world clinical practice.
2. Methods We conducted a restrospective cohort study of all patients dispensed acamprosate and/or naltrexone under the PBS between July 2009 and May 2013. The Australian PBS is a government medicine reimbursement system subsidising a range of prescribed medicines (Mellish et al., 2015). For medicines costing more than the relevant beneficiary co-payment, additional costs are paid by the government. The Department of Human Services maintains a database of all PBS-subsidised claims, amounting to approximately 280 million dispensings a year. The dispensing of a PBS medicine is only not recorded in the database if the government does not contribute to the cost of the medicine. Acamprosate and naltrexone are above the general beneficiary co-payment threshold such that the claims database represents a complete capture of the total population prescribed acamprosate or naltrexone in the Australian community (and private hospitals) under the PBS. Both medications are dispensed in a 30 day supply package. We extracted data for naltrexone and acamprosate dispenses, date of supply, gender and age group. The Australian Government, Department of Human Services External Request Committee granted data access approval. To allow for consistency in our database, we included a two month wash out period which excluded prescription data from the first two months of our cohort window. This prevented the inclusion of patients that may have been receiving medications on a continual basis before the period of observation. The index dispense for each patient was the first original prescription of either acamprosate or naltrexone that appeared in the dataset for that period. A treatment episode was defined as the period between the index dispense and the estimated end date of the last prescription calculated as 31 days from that last dispense date. We calculated the rate of a second and a third dispense (3 months treatment duration) from the index dispense date, defined as a dispensing for the same medication within 31 days from the estimated end date of the previous prescription. Thus, a gap of 31 days between the end of a prescription and the beginning of the following one was allowed (60 days since date of prescription). If
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Table 1 Number of patients with at least one index dispense for alcohol pharmacotherapy in Australia, 2009–2013 for gender and age.
Total Gender, % (n) Male Female Age, % (n) 15–24 25–34 35–44 45–54 55–64 65–74 75–84
Naltrexone
Acamprosate
23452
38452
OR (95% CI)
59 (13823) 41 (9629)
60 (23241) 40 (15211)
0.94 (0.91–0.97)**
4 (104) 20 (4725) 32 (7386) 26 (5973) 14 (3197) 4 (997) 1 (13)
4 (1538) 19 (7175) 31 (11727) 26 (10157) 15 (5651) 5 (1911) 1 (293)
1.01 (0.09–0.13)*** 1.01 (1.06–1.15)*** 1.05 (1.01–1.09)* 0.95 (0.92–0.99)* 0.92 (0.87–0.96)** 0.85 (0.79–0.92)*** 0.07 (0.04–0.13)***
Notes: The index dispense was the first original prescription of either acamprosate or naltrexone that appeared in the dataset for that period (to prevent including patients receiving medications on a continual basis before the period of observation we excluded prescriptions before September 2009). OR = Odds ratio for naltrexone versus acamprosate, CI = confidence interval. * p < 0.01. ** p < 0.001. *** p < 0.0001.
more than one 30 day supply was dispensed simultaneously to the same individual it was considered to be a repeat (only a small number of cases). The median days on medication was computed as the duration between the index date and the estimated end date of the last prescription. Concurrent use was defined as a co-dispense for the alternative alcohol pharmacotherapy within 31 days from the estimated end date of the last prescription. Switching was defined as the absence of a refill prescription for naltrexone or acamprosate in addition to a dispensing for the alternate alcohol pharmacotherapy more than 31 days since the estimated end date of the last prescription. Descriptive statistics were used to determine sociodemographics (age group, gender) and prescription patterns (frequency and patterns of dispensing, concurrent use and switching). Chi-squared tests were employed to examine the association between categorical variables and prescription pattern. All data were analysed using SPSS 22.0 and all tests were two tailed with a significance level at P < 0.05.
3. Results A total of 61,904 individuals and 198,247 dispensed scripts were included in the analysis (2009–2013). The number of individuals dispensed alcohol pharmacotherapy over a representative 12 month period (2011–2012) was 23, 206, or 23.21 per 1000. Dispense patterns are depicted in Tables 1 and 2. For naltrexone, we identified 73,024 dispenses and 23,452 patients with a median of 2 dispenses per patient and a median treatment duration of 1 month. In terms of repeat dispenses, 42% (9934) of index dispenses were followed by a second dispense and 25% (5764) were followed by a third dispense. Thus, 57% of naltrexone-treated patients completed only one month of treatment. For acamprosate, we identified 125,223 dispenses and 38,452 patients with a median of 1 dispense per patient and a median treatment duration of 1 month. In terms of repeat dispenses, whereby 28% (10,839) of index dispenses were followed by a second dispense and 15% (5666) followed up with a third dispense. Thus, 72% of acamprosate-treated patients completed only one month of treatment. Naltrexone users were more likely to return for a second dispense than acamprosate users (OR = 1.86, 1 2 = 1294.68, p < 0.0001, 95% CI: 1.80–1.93) and also more likely to return for three dispenses (OR = 1.89, 95% CI: 1.81–1.97, p < 0.0001).
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Table 2 Patterns of alcohol pharmacotherapy dispensing in Australia, 2009–2013.
Median days (mean) 2nd dispense, % (n) 3rd dispense, % (n)
Naltrexone (N = 23,452)
Acamprosate (N = 38,452)
OR (95% CI)
30 (72.03) 42 (9934) 25 (5764)
30 (54.66) 28 (10839) 15 (5666)
1.86 (1.80–1.93)* 1.89 (1.81–1.97)**
Notes: To prevent inclusion of patients receiving medications on a continual basis before the period of observation we excluded prescriptions before September 2009. OR = Odds ratio for naltrexone versus acamprosate, CI = confidence interval. * Odds ratio of at least a second dispense, p < 0.0001. ** Odds ratio of at least three dispenses (3 months of treatment), p < 0.0001.
For naltrexone-treated patients, there were 59% (13,823) males and 41% (9629) females and for acamprosate-treated patients, there were 60% (23,241) males and 40% (15211) females. These rates were significantly different between the two medications (1 2 = 13.64, p < 0.001). For naltrexone, males were less likely to return for a second script compared to females (OR = 0.93, 1 2 = 6.69, p < 0.01, 95% CI: 0.89–0.98) whereas this was not the case for acamprosate (OR = 0.96, 1 2 = 2.29, p = 0.13, 95% CI: 0.92–1.01). The highest number of dispenses occurred in the 35–44 age bracket (32%) with almost 60% of all dispenses occurring between the ages of 35–55 (see Table 1). There were significant differences in the rate of dispenses between naltrexone and acamprosate for each age bracket (1 2 > 6.78, p’s < 0.01). For both medications, the odds of returning for at least a second dispense increased with age group, with significant differences between each age bracket and the 15–24 age bracket (1 2 ’s > 8.9, p’s < 0.003). The odds of returning for a second script in each age bracket compared to the 15–24 age bracket for naltrexone were: 75–84 OR = 2.27 (95%CI: 1.58–3.27); 65–74 OR = 2.35 (95%CI: 1.96–2.81); 55–64 OR = 1.76 (95%CI: 1.52–2.04); 45–54 OR = 1.57 (95%CI 1.37–1.81); 35–44 OR = 1.42 (95%CI 1.23–1.62); 25–34 OR = 1.26 (95%CI: 1.10–1.46). For acamprosate: 75–84 OR = 2.98 (95%CI: 2.29–3.88); 65–74 OR = 2.85 (95%CI: 2.44–3.33); 55–64 OR = 2.09 (95%CI: 1.82–2.40); 45–54 OR = 1.68 (95%CI: 1.47–1.92); 35–44 OR = 1.43 (95%CI: 1.25–1.63); 25–34 OR = 1.23 (95%CI: 1.07–1.41). Overall, 16% (8480) of individuals received dispenses for both acamprosate and naltrexone at any point during the four year time period as either a co-dispense, a switch or following a lengthy separation. Co-dispensing for acamprosate and naltrexone occurred at a rate of 6% (3591). Switching from naltrexone to acamprosate or vice versa after a treatment episode occurred at a rate of 4% (2540). Patients were more likely to switch from acamprosate to naltrexone (60%) than from naltrexone to acamprosate (40%) (OR = 2.22, 1 2 = 196.85, p < 0.0001, 95% CI: 1.99–2.48). 4. Discussion This study utilised a large, representative database containing information on every alcohol pharmacotherapy prescription dispensed in Australia over 2009–2013. A total of 61,904 individuals were identified, with 23,206 or 23.21 per 1000 annually (as per 2011–2012 representation), suggesting a 72% increase in the raw number of individuals receiving alcohol pharmacotherapy over the decade since an early estimate in 2001 of 13.50 patients per 1000 (Doran et al., 2003). Given a 3.9% prevalence rate for alcohol dependence (Teesson et al., 2010), we estimate that approximately 2.7–3% of individuals with alcohol dependence in Australia are being prescribed alcohol pharmacotherapy. This is despite 80% presenting to a general practitioner each year (Proudfoot and Teesson, 2009). The hesitancy of physicians to prescribe alcohol pharmacotherapies has also been noted in the USA and thought to stem from beliefs regarding limited efficacy (Mark et al., 2003a, 2003b). The rate of returning for a second dispense was 42% and 28% for naltrexone and acamprosate respectively. For a third dispense, the rates were 25% and 10% for naltrexone and acamprosate respec-
tively. These figures are particularly concerning given the national guidelines recommend a treatment duration of 3 months or 3 dispenses (Morley et al., 2009). In addition, these adherence rates are low compared with the one-month persistence rate of 62–70% reported for antidepressants (Bauer et al., 2013; Sawada et al., 2009). Treatment adherence according to recommendations is a recognised concern for all medications that preclude the full benefits of pharmacotherapy, with up to 50% of patients not taking medications as prescribed (Brown and Bussell, 2011). Naltrexone-treated individuals were significantly more likely than acamprosate-treated individuals to return for a second dispense. It is possible this difference is related to enhanced efficacy. Although meta-analyses of pooled international studies indicate similar efficacy rates for the two medications (Jonas et al., 2014), head to head trials of the two medications generally find a superior effect of naltrexone (Anton et al., 2006; Morley et al., 2006). Given that people with alcohol dependence are known to have high drop-out rates from treatment (McNeely and Sherman, 2011), it is also possible that complex dosing regimens and/or side effects may interfere with adherence to a greater degree than the general population. Acamprosate treatment requires dosing of two tablets three times per day (6 tables per day) compared to naltrexone dosing of 1 tablet per day. This may explain why fewer acamprosate prescriptions are repeated relative to naltrexone. Minimizing the frequency of dosing has been shown to improve adherence (Schroeder et al., 2004) whereby each additional daily dose results in a 10% decrease in adherence (Osterberg and Blaschke, 2005). Combining acamprosate and naltrexone (co-dispensing) or switching between them occurred at a rate of 6% and 4% respectively. There is evidence showing enhanced efficacy for the combination of acamprosate and naltrexone (Kiefer et al., 2003; Kiefer and Wiedemann, 2004) however this was not replicated in the large COMBINE trial with high naltrexone dose (Anton et al., 2006). Naltrexone administration has been shown to increase the plasma levels of acamprosate and the combined dose, although with increased side effects, is behaviourally and pharmacologically safe (Johnson et al., 2003). Nonetheless, this pattern of usage does not seem to have been widely translated into practice. While there were significant gender differences in the rate and pattern of dispensing for naltrexone versus acamprosate, the clinical significance of these differences is likely to be negligible. Dispensing of alcohol pharmacotherapy mainly occurred in the age ranges of 35–54 years with the highest dispense rate occurring between 35 and 44. This mirrors the average age range in alcohol treatment trials in Australia (Morley et al., 2014, 2016) and is also consistent with the finding that people suffering from alcohol dependence, on average, do not seek treatment for at least 14 years (Chapman et al., 2015). For both medications, the odds of returning for a second dispense increased with age. These findings are consistent with other areas of medicine where the risk of nonpersistence to chronic medication decreases with increasing age (Yeaw et al., 2009). Given both the overall low dispense rate and the low but differing adherence rates between alcohol pharmacotherapies, solutions to enhance increased medication adherence and to subsequently
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improve the treatment of alcohol use disorders may require a varied approach. It is likely that a multitude of factors lead to poor medication uptake and/or adherence such as those that are patient-based (cognitive function, ambivalence), clinician-based (communication, knowledge, treatment preferences), medicationbased (complex regimens, adverse effects, limited efficacy) and system-based (access to care) (for review see Brown and Bussell, 2011). One of the main limitations of the PBS dataset is that it underestimates whole of population use which may have slightly impacted on the overall dispensing rate for these medications in Australia (Mellish et al., 2015). It is possible, for example, that these medications could be dispensed without the government subsidy however these cases would be rare given the cost to the individual would be 25 times greater. In addition, the database does not capture prescribing in some public hospital inpatient settings where there is no government arrangement. Finally, as we have no context in which the medications were prescribed (e.g., some patients may reduce their dosing due to side effects and therefore require less dispenses), this analysis does not provide an accurate study of medication compliance but is a descriptive analysis of how these anti-craving agents are dispensed in nonexperimental community settings. In summary, we used a large epidemiological database to analyse dispensation rates of alcohol pharmacotherapy to individuals in Australia. The adherence rate is higher for naltrexone relative to acamprosate treatment and for older age groups. In spite of guidelines, the rate of pharmacotherapy use and adherence rate remains low. Role of funding source This study was supported by the NHMRC CRE in Mental Health and Substance Use (K.M. A.B. P.H.) and the NHMRC CRE in Medicines and Ageing (S.P.). Conflict of interest No Conflict declared. Contributors K.M. made contributions to the concept and design of the study, performed the analysis and wrote the manuscript. W.L. performed the data extraction and made contributions to analysis. S.A.P. made contributions to the design of the study and advice regarding data extraction and analysis. A.B. made contributions to the concept and design of the study. pH made contributions to the concept and design of the study. All authors read and approved the final manuscript. References Anton, R.F., O’Malley, S.S., Ciraulo, D.A., Cisler, R.A., Couper, D., Donovan, D.M., Gastfriend, D.R., Hosking, J.D., Johnson, B.A., LoCastro, J.S., Longabaugh, R., Mason, B.J., et al., 2006. Combined pharmacotherapies and behavioral interventions for alcohol dependence: the COMBINE study: a randomized controlled trial. JAMA 295, 2003–2017. Bauer, A.M., Schillinger, D., Parker, M.M., Katon, W., Adler, N., Adams, A.S., Moffett, H.H., Karter, A.J., 2013. Health literacy and antidepressant medication adherence among adults with diabetes: the diabetes study of Northern California (DISTANCE). J. Gen. Intern. Med. 28, 1181–1187. Bouza, C., Angeles, M., Munoz, A., Amate, J.M., 2004. Efficacy and safety of naltrexone and acamprosate in the treatment of alcohol dependence: a systematic review. Addiction 99, 811–828. Brown, M.T., Bussell, J.K., 2011. Medication adherence: WHO cares? Mayo Clin. Proc. 86, 304–314. Buri, C., Moggi, F., Giovanoli, A., Strik, W., 2007. Prescription procedures in medication for relapse prevention after inpatient treatment for alcohol use disorders in Switzerland. Alcohol Alcohol. 42, 333–339.
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