Eur J Clin Pharmacol (2014) 70:197–204 DOI 10.1007/s00228-013-1594-5
PHARMACOEPIDEMIOLOGY AND PRESCRIPTION
Factors associated with pregabalin dispensing at higher than the approved maximum dose Robert Bodén & Björn Wettermark & Lena Brandt & Helle Kieler
Received: 28 May 2013 / Accepted: 23 September 2013 / Published online: 19 October 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose Concerns have been raised about the abuse potential of pregabalin. Therefore, the aim of our study was to characterize patients dispensed pregabalin at higher than the maximum allowed dose in a cohort study based on data extracted from Swedish national registers. Methods All patients dispensed at least three prescriptions of pregabalin between July 2006 and December 2009 were included (n =48,550). The daily dose was defined as the amount of pregabalin dispensed divided by the number of days between the second and third dispensings. Associations between sociodemographic and clinical variables and dispensing pregabalin at a dose exceeding the maximum daily allowed dose (600 mg) were investigated in multivariate regression models. Results Of the patients dispensed pregabalin during the study period, 8.5 % were dispensed a dose that exceeded the maximum daily allowed dose. A previous addictive disorder drug treatment or diagnosis was present in 20 and 31 % of patients dispensed pregabalin within and exceeding the recommended dose range, respectively. Our analysis revealed that those patients at increased risk of being dispensed pregabalin at higher than the maximum allowed dose were male [adjusted odds ratio (aOR) 1.40, 95 % confidence interval (CI) 1.31– 1.49], were between 18 and 29 years of age compared with those aged ≥65 years (aOR 1.62, 95 % CI 1.45–1.82), had a low income (aOR 1.24, 95 % CI 1.10–1.40), had epilepsy compared with no diagnosis (aOR 1.41, 95 % CI 1.10–1.81), R. Bodén : B. Wettermark : L. Brandt : H. Kieler Centre for Pharmacoepidemiology at the Department of Medicine, Karolinska Institutet, Stockholm, Sweden R. Bodén (*) Unit of Psychiatry, Department of Neuroscience, Uppsala University, Uppsala 751 85, Sweden e-mail: [email protected]
had a previous substance use disorder treatment or diagnosis (aOR 1.41, 95 % CI 1.31–1.52) or had previously been dispensed high doses of drugs with abuse potential (aOR 1.77, 95 % CI 1.62–1.94). Conclusion Based on our results we conclude that patients at a high risk of addiction and patients with epilepsy are more likely to be dispensed pregabalin at higher than the maximum approved daily dose. Keywords Pregabalin . Abuse . Generalized anxiety disorder . Pharmacoepidemiology . Neuropathic pain . Epilepsy
Introduction Pregabalin was introduced in 2004 and has been marketed as a new pharmacological approach to treat common disorders such as neuropathic pain and generalized anxiety disorder (GAD), and as adjunctive treatment of partial-onset seizures, all of which are now approved indications in Europe [1, 2]. In the USA, pregabalin is approved for epilepsy, fibromyalgia and neuropathic pain associated with diabetes, herpes or spinal injury [3]. Pregabalin is structurally related to gammaaminobutyric acid (GABA) but does not bind to GABA (A), GABA (B) or other benzodiazepine receptors [4]. When introduced on the market, pregabalin’s potential for abuse and dependence was thought to be small [5, 6], and pregabalin has even been suggested as a treatment for alcohol and benzodiazepine dependence [7, 8]. The Food and Drug Administration in the USA considers the potential for abuse and dependence to be low and has labeled pregabalin as a schedule V controlled drug [3]. However, case reports of adverse drug reactions, recreational misuse and dependence have recently emerged and raised concerns regarding pregabalin’s potential for abuse and addiction [9–15]. In 2010 the potential for
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pregabalin abuse and a call for caution in patients with a history of substance abuse was added to the EU summary of product characteristics [2]. To our knowledge, there are to date no population-based studies available to confirm or refute these observations. Thus, in this study, our aim was to determine the characteristics of patients dispensed pregabalin that exceeds the maximum approved dose.
Methods This was an observational cohort study based on data extracted from Swedish national health and population registers. Four registers were linked by using the Swedish personal identification numbers (PIN) [16]: (1) data on dispensed drugs from the Swedish Prescribed Drug Register [17]; (2) data on diagnoses from in- and out-patient care in hospitals from the National Patient Register [18]; (3) data on patients who were deceased from the National Cause of Death Register [19]; (4) socioeconomic data from Statistics Sweden on patient education, income and country of birth [20]. The Prescribed Drug Register contains patient-level data on dispensed medicines for the entire Swedish population from 1 July 2005 onwards.
Table 1 Definitions of drugs with an abuse potential, addictive disorder drugs, substance use disorders and approved indications for pregabalin
a
Classification of drugs according to the Anatomical Therapeutic Chemical (ATC) classification of the World Health Organization (WHO)
b
Classification of disorders/ diseases according to WHO’s International Classification of Diseases, update 10 (ICD-10)
Drugs/disorders/approved indications Drugs with potential for abusea Benzodiazepines Weak opioids Strong opioids Psychostimulants Addictive disorder drugsa Acamprosate Naltrexone Disulfiram Methadone Buprenorphine Substance use disordersb Approved indications for pregabalinb Epilepsy Generalized anxiety disorder Neuropathic pain related diagnoses: Neuropathies
Cerebrovascular disease sequelae Mechanical neuropathies Unspecified pain
More specifically, it contains information on the dispensed drug (product, quantity and price), the prescriber and the dates of prescription and dispensing. However, the register does not cover prescriptions that have not yet been dispensed. All drugs are classified according to the World Health Organization Anatomical Therapeutic Chemical (ATC) classification and the register is updated monthly. From the register we obtained information on filled prescriptions for pregabalin (ATC code N03AX16). We also obtained information on the use of other drugs with a potential for abuse and dependence, as well as drugs prescribed for addictive disorders (Table 1). Information on diagnoses recorded in hospitals between 2002 and 2009 was collected from the National Patient Register. This register includes all diagnoses recorded in Swedish hospitals, both after inpatient care and specialized outpatient visits. The WHO’s International Classification of Diseases, update 10 (ICD-10) codes have been used for coding of diagnoses since 1997. All incident users aged >12 years who filled at least three prescriptions of pregabalin from 1 July 2006 through to 31 December 2009 were identified using the Prescribed Drug Register and included in the study. To be defined as an incident user no pregabalin should have been dispensed within 1 year prior to the inclusion period, i.e. from 1 July 2005
ATC/ICD-10 code
N05B and N05C N02AA59, N02AX02, N02AX06 or N02AC04 N02A (except those defined as weak opioids) N06B N07BB03 N07BB04 N07BB01 N07BC02 N02AE01 F11-F19 or Z71.4-5 G40 F41.1 G35.9, G50.0, G50.1, G51.0, G53.0, G54.4, G54.6, G55.0, G55.1, G56.0, G56.2, G56.4, G56.9, G57.0, G57.1, G57.8, G57.9, G58.0, G58.7, G58.8, G62.9, G63.2, G82.1, G95.0, G95.2, G95.8, G97.9. I69.1, I69.3 M48.0, M50.1, M53.0, M53.1 M54.1, M54.3, M54.4, M79, M79.2, and M89.0 R52
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through 30 June 2006. The study was approved by the regional ethical committee at Karolinska Institutet in Stockholm, Sweden. We obtained information on diagnoses reflecting the approved indications in the EU: epilepsy, GAD and neuropathic pain. As neuropathic pain is not a well-defined entity, we included all diagnoses that may be associated with this condition (Table 1). Educational attainment was classified into three categories, representing distinct levels in the Swedish educational system: primary, secondary and university level. Low educational level was equivalent to ≤9 years at primary school; medium educational level, as 10–12 years at secondary school; high educational level, as >12 years of education. Country of birth was classified as Sweden, other Nordic countries, Europe (excluding the Nordic countries) and the rest of the world (excluding Europe). Income was classified in quartiles representing the quartiles of the distribution of the income of the Swedish population. Type of prescriber was categorized by workplace as primary care clinic, somatic hospital clinic, psychiatric or addiction clinic and other. History of substance use disorders included diagnoses of mental or behavioral disorders related to alcohol or drug use, or dispensings for addictive disorder drug treatment. Only diagnoses and dispensings prior to the initiation of pregabalin were included (Table 1). Previous high-dose users of drugs with a potential for abuse and dependence included all individuals who had been dispensed >2 defined daily doses (DDDs) per day of benzodiazepines, weak opioids, strong opioids or psychostimulants. The dispensing should have occurred during a 12-month period prior to the first dispensing of pregabalin. The median DDDs for drugs with abuse potential in the time periods 6–12 months before and 6–12 months after the initiation of pregabalin treatment were calculated for all patients with at least two prescriptions of these drugs. The daily dose for pregabalin was calculated using information from the second and third dispensing only. The amount of dispensed drug from the second dispensing was divided by the number of days in the interval between the second and third dispensing. According to the label, the maximum dose of pregabalin is 600 mg daily, which is equivalent to two DDDs. Filling of prescriptions equating to a dose above the two DDD was used as a proxy or indicator for potential misuse of pregabalin. Statistical methods Numbers and proportions were used to describe the study cohort characteristics for patients within or above the recommended dose range, according to their estimated DDDs per day of pregabalin. Using univariate and multivariate logistic regression models, we studied associations between sociodemographic and clinical variables and the filling of prescriptions that resulted in the patient being dispensed pregabalin at higher than the maximum allowed dose. In each multivariate model
199
all factors listed in Table 1 were included. Statistical analysis was performed using SAS software ver. 9.2 (SAS Institute Inc., Cary, NC).
Results We identified 48,550 patients who were dispensed pregabalin at least three times during the study period. Of those, 4,130 (8.5 %) had an estimated daily dosage that exceeded the maximum approved dose. The sociodemographic and clinical characteristics of the cohort are described in Table 2. More females than males were treated with pregabalin (61.4 vs. 38.6 %), but among those treated with doses that exceeded the maximum recommended dose, the sex difference was attenuated (51.9 vs. 48.1 %, respectively). The majority of patients treated with pregabalin were between 30 and 64 years of age, and prescriptions that exceeded the maximum recommended dose were more common among young adults. Among patients with no record of an approved indication for pregabalin, 8.3 % were dispensed dosages that exceeded the maximum approved dose; the corresponding numbers for patients with approved indications were 12.3, 8.9 and 9.2 % for epilepsy, neuropathic pain and GAD, respectively, and for those with more than one approved diagnosis, 13 %. There were only minor differences in the distribution of the type of prescriber between those who were prescribed doses within the recommended range and those who were prescribed doses exceeding it. Twenty percent of patients treated with a dose below the maximum dose had a previous substance use disorder or had been treated previously with addictive disorder drugs; the corresponding figure for patients receiving above the maximum dose was 30.5 %. Among those treated with a dose lower than the maximum dose, 9.3 % had been treated with >2 DDDs/day of drugs with an abuse potential 1 year prior to the first dispensing of pregabalin; the corresponding proportion for those receiving a dose exceeding the maximum dose was 17 %. Sociodemographic and clinical factors investigated for an association the dispensing of pregabalin at doses exceeding the maximum daily dose are shown in Table 3. Male sex, low income, having epilepsy or neuropathic pain diagnoses and/or several of the approved diagnoses or having a history of addiction or more than 2 DDDs/day of drugs with abuse potential were all associated with an increased likelihood of being dispensed pregabalin at a dose exceeding the maximum recommended dose. The age stratum including young adulthood (18–29 years) was most strongly associated with dispensing that exceeded the maximum recommended dose. Educational level and country of birth were not associated with an increased likelihood of being dispensed pregabalin at a dose exceeding 600 mg per day. As illustrated in Fig. 1, the proportions of patients dispensed drugs with abuse potential
200 Table 2 Sociodemograpic and clinical factors by estimated daily dose of pregabalin within or above the recommended dose range
Eur J Clin Pharmacol (2014) 70:197–204
Patients dispensed ≤600 mg/day (n =44,420; 91.5 %)
Patients dispensed >600 mg/day (n =4,130; 8.5 %)
N
%
N
%
17,162 27,258
38.6 61.4
1,985 2,145
48.1 51.9
158 4,314
0.4 9.7
10 532
0.2 12.9
9,968 16,352 13,628
22.4 36.8 30.7
1,092 1,575 921
26.4 38.1 22.3
15,542 19,819 9,059
35.0 44.6 20.4
1,388 1,913 829
33.6 46.3 20.1
14,266 17,583 7,591 4,980
32.1 39.6 17.1 11.2
1,444 1,587 678 421
35.0 38.4 16.4 10.2
37,760 1,900 2,531 2,229
85.0 4.3 5.7 5.0
3,518 182 219 211
85.2 4.4 5.3 5.1
None 33,185 74.7 2,992 Epilepsy 536 1.2 75 Neuropathic pain 9,113 20.5 892 GAD 1,371 3.1 139 More than one 215 0.5 32 Prescriber workplace Primary care clinic 13,691 30.8 1,254 Somatic hospital clinic 13,272 29.9 1,265 Psychiatric or addiction clinic 14,196 32.0 1,287 Other 3,252 7.3 322 Previous addictive disorder diagnosisb or addictive disorder drugsc No 35,349 79.6 2,870 Yes 9,071 20.4 1,260 Addictive diagnosis 7,109 16.0 1,078 Addictive disorder drugsc 4,163 9.4 523 >2 DDD/day of drugs with abuse potential 12 months prior to receiving pregabalin None 40,293 90.7 3,429 Anyd,e,f,g 4,127 9.3 701 Benzodiazepinesd 2,787 6.3 420
72.4 1.8 21.6 3.4 0.8
Sociodemograpic and clinical factors
Sex Male Female Age (years) 12–17 18–29 30–44 45–64 ≥65 Educational level Low (≤9 years) Medium (10–12 years) High (>12 years) Income in quartiles of population 1st (lowest) 2nd 3rd 4th (highest) Country of birth Sweden Other Nordic countries Other European countries Non-European countries Approved indication for pregabalina
DDD,Defined daily dose; GAD, generalized anxiety disorder a
Approved indication in Europe during the study period
b ICD-10 code F11-F19 or Z71.4-5 c
Acamprosate, naltrexone, disulfiram, buprenorphine or methadone
d Anxiolytics and hypnotics/ sedatives e f
Codeine, tramadol, tapentadol
All opioids than those defined as weak opioids
Weak opioidse Strong opioidsf Psychostimulants
627 887 176
1.4 2.0 0.4
128 174 53
30.4 30.6 31.2 7.8 69.5 30.5 26.1 12.7 83.0 17.0 10.2 3.1 4.2 1.3
Eur J Clin Pharmacol (2014) 70:197–204 Table 3 Odds ratios and 95 % confidence intervals of being dispensed pregabalin at a dose that exceeds the maximum daily recommended dose (>600 mg) for social and clinical factors.
Sociodemograpic and clinical factors
Sex Male Female Age (years) 1–17 18–29 30–44 45–64 ≥65 Educational level Low (≤9 years) Medium (10–12 years) High (>12 years) Income in quartiles 1st (lowest) 2nd 3rd 4th (highest) Country of birth Sweden Other Nordic countries Other European countries Non-European countries Approved indication for pregabalin None Epilepsy Neuropathic pain GAD
OR, Odds ratio; CI, confidence interval a
All variables in the table are included in the multivariate analyses
b
See Table 1 for definitions
c
Refer to Table 1 for drug definitions
201
Univariate analysis OR (95 % CI)
Multivariate analysisa OR (95 % CI)
1.47 (1.38–1.57) Reference=1
1.40 (1.31–1.49)
0.94 (0.49–1.78) 1.83 (1.63–2.04) 1.62 (1.48–1.78) 1.43 (1.31–1.55) Reference=1
0.92 (0.48–1.76) 1.62 (1.45–1.82) 1.50 (1.36–1.66) 1.33 (1.21–1.45)
Reference=1 1.08 (1.01–1.16) 1.03 (0.94–1.12) 1.20 (1.07–1.34) 1.07 (0.96–1.19) 1.06 (0.93–1.20) Reference=1 Reference=1 1.03 (0.88–1.20) 0.93 (0.81–1.07) 1.02 (0.88–1.18) Reference=1 1.55 (1.22–1.98) 1.09 (1.00–1.17) 1.12 (0.94–1.34)
More than one 1.65 (1.14–2.40) Previous addictive disorder diagnosis or addictive disorder drugsb No Reference=1 Yes 1.71 (1.6–1.84) >2 DDD/day of drugs with abuse potential 12 months prior to pregabalinc None reference=1 Any 2.00 (1.83–2.18)
12 months before and after the initiation of pregabalin treatment was similar. Moreover, the median DDDs of the dispensed drugs with abuse potential were similar in the time periods 16–12 months before and 6–12 months after the initiation of pregabalin treatment (Table 4).
Discussion In this large population-based study of all first-time pregabalin users in Sweden, we found that 8.5 % were dispensed a dose
1.07 (0.97–1.18) 1.03 (0.96–1.11) 1.24 (1.10–1.40) 1.11 (0.99–1.25) 1.07 (0.94–1.21)
1.06 (0.91–1.25) 0.97 (0.84–1.12) 0.95 (0.82–1.11)
1.41 (1.10–1.81) 1.17 (1.08–1.27) 1.02 (0.85–1.22) 1.53 (1.05–2.23)
1.41 (1.31–1.52)
1.77 (1.62–1.94)
of pregabalin that exceeded the maximum recommended daily dose of 600 mg. Dispensing a dose that exceeded the maximum dose was more likely to occur in young adult males and in those with a low income. A previous substance use disorder and having used large amounts of other drugs with abuse potential were also associated with the use of doses that exceeded the maximum dose. In addition, patients with epilepsy or with several of the approved indications for pregabalin treatment were more prone to being dispensed doses that exceeded the maximum dose, when compared with those without an approved indication.
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Fig. 1 Proportion of patients being dispensed above or below two defined daily doses (DDD) of drugs with abuse potential 12 months before and after pregabalin initiation. Bdz Benzodiazepines
Having a history of addiction was associated with the dispensing of pregabalin at a dose that exceeded the maximum dose irregardless of how the addiction was assessed, i.e. whether addiction was defined by diagnosis, addictionspecific treatment or by high dose dispensing of drugs with addiction liability. Being a young adult, being male and having a low income was also associated with high doses of pregabalin. Male sex and low socioeconomic status are known risk factors for substance use disorders [21]. Considering that pregabalin has been proposed as a treatment for alcohol and benzodiazepine dependence, our findings of individuals at risk for addiction have an increased risk of being dispensed high doses of pregabalin might suggest the off-label prescribing of pregabalin for substance use disorders [7, 8]. Nevertheless, if pregabalin is being used successfully for the treatment of benzodiazepine dependence we would have expected to observe a decrease in the use of these drug after the initiation of pregabalin treatment—and this was not the case. Although we did not assess individual changes in the high dose consumption of drugs with an addiction potential before and after pregabalin initiation, there were only minimal changes in the proportion of patients prescribed benzodiazepines and in the median dose 1 year before and 1 year after pregabalin initiation. This is an ecological comparison, but it nevertheless Table 4 Defined daily doses of drugs with abuse potential 6–12 months before and 6–12 months after initiation of pregabalin treatment
a
Refer to Table 1 for drug definitions
Drugs
suggests that pregabalin seems to have been a supplement to the benzodiazepines rather than a replacement of them, a finding that is discordant with that reported in a Norwegian claims data study [22]. In the Norwegian study 15–29 % of individuals had stopped using benzodiazepines after pregabalin initiation although a direct comparison is hampered by the fact that we also included hypnotics. If being dispensed large amounts of pregabalin is a phenomenon related to tolerance and dependence, recreational misuse/abuse or selling to others or a lack of efficacy or effectiveness within the recommended dose range is not possible to disentangle based on the available data in our study. Previous studies of abuse and dependence mainly comprise case reports and case series [9–14]. Dispensing of a drug is not equal to ingestion of that drug and, therefore, we do not know if the drugs assessed in this study were used regularly, were hoarded or had been used by someone other than the patient they were dispensed to. It should be pointed out that we assessed the estimated daily amount of pregabalin between the second and third dispensing. Thus, if the dispensing of pregabalin at a dose exceeding the maximum recommended dose was due to tolerance it occurred early in the course of treatment. On the other hand, a previous long-term study of pregabalin treatment for epilepsy did not find any evidence for tolerance [23]. Another explanation for over-the-maximum dose dispensing of pregabalin could be recreational misuse/ abuse or selling to others, although the use of single doses of 1.5–6 g of pregabalin has been reported [10, 13, 15]. Patients with epilepsy and with more than one of the approved diagnoses were more likely to be dispensed pregabalin at a dose that exceeded the maximum dose. One explanation is that epilepsy treatment alone and comorbidity with neuropathic pain and GAD might require higher doses to be effective [23]. In a pooled analysis of studies on pregabalin for painful diabetic peripheral neuropathy, the authors observed that patients receiving the highest dose of 600 mg were those for whom the drug had the best effect and who showed the highest persistence [24]. Thus, the recommended dose of pregabalin might not be adequate in all patients. We have previously reported that the average dose of pregabalin was highest in patients with epilepsy (321 mg/day), followed by those with GAD (275 mg/day) and neuropathic pain (244 mg/day), and lowest in patients without any recorded indicated diagnosis
Initiation of pregabalin treatment 6–12 months before
Benzodiazepinea Opiates Psychostimulants
6-12 months after
n
Median
Quartiles
n
Median
Quartiles
1,593 1,155 47
0.88 0.50 1.32
0.43; 1.39 0.23; 0.97 0.82; 2.26
1,634 1,210 83
0.93 0.51 1.24
0.48; 1.44 0.25; 1.05 0.25; 1.05
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(230 mg/day) [25]. It should, however, be noted that there were only minor differences in the distribution of type of prescriber by level of prescribed dose. The main strength of the study is the national coverage of all prescribed drugs dispensed in Sweden and therefore recorded in the Prescribed Drug Register [26]. We were also able to assess a broad set of sociodemographic and clinical factors by using information collected in the other health registers and in the population register with national coverage; thus, our study represents a non-selected population. Accordingly, the generalizability of the study results should be high. Moreover, the diagnoses in the National Patient Register are generally accurate, and they have been found to have high validity [18]. It should, however, be noted that we did not have information on diagnoses from primary care as such national data are not available. Nevertheless, we observed that the percentage of patients dispensed pregabalin at doses that exceeded the maximum recommended dose was lowest in the group of patients with no recorded diagnosis and highest among those with epilepsy and more than one approved indication. To estimate the daily dose we used information from the second and third dispensing. The rationale for using information only from these dispensings was that more than one dispensing would be needed to estimate the daily dose, and it seemed important to assess regular users and not include those in need of an initial dose titration. Our aim was to capture incident users and, therefore, we applied a 1-year observation period before inclusion, during which those included in the study should not have been dispensed pregabalin. However, some of those included in the study might not be true first-time users as they could have filled a prescription before information on dispensing were available in the Prescribed Drug Register (1 July 2005). For these patients, the assessment of dose would include dispensings occurring after the third dispensing, but as dose titration generally takes place when the patient is started on pregabalin, we believe that including these patients did not affect our results. Moreover, as pregabalin was introduced the year prior to the start of the study period we feel safe in assuming that most patients were probably incident users [25].There is no generally accepted definition of high doses of drugs, which might possess a risk for abuse, but as the recommended maximum dose of 600 mg equals two DDDs, we chose to define high dose use of drugs with abuse potential accordingly. In conclusion, dispensing pregabalin at a dose that exceeded the maximum recommended daily dose, i.e. 600 mg, was evident in 8.5 % of all patients dispensed pregabalin in our analysis. This was more likely in patients with a history and risk factors for addiction, which prompts the need for continued monitoring and surveillance for signals of abuse and for further assessment of the abuse potential of this drug.
203 Conflict of Interest The study was independently developed from a project initiated and partially funded by Pfizer, Sweden. Pfizer had no further role in the study design, in the collection, analysis and interpretation of data, in the writing of the report nor in the decision to submit the paper for publication. The authors declare no personal potential conflicts of interest.
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PHARMACOEPIDEMIOLOGY AND PRESCRIPTION
Factors associated with pregabalin dispensing at higher than the approved maximum dose Robert Bodén & Björn Wettermark & Lena Brandt & Helle Kieler
Received: 28 May 2013 / Accepted: 23 September 2013 / Published online: 19 October 2013 # Springer-Verlag Berlin Heidelberg 2013
Abstract Purpose Concerns have been raised about the abuse potential of pregabalin. Therefore, the aim of our study was to characterize patients dispensed pregabalin at higher than the maximum allowed dose in a cohort study based on data extracted from Swedish national registers. Methods All patients dispensed at least three prescriptions of pregabalin between July 2006 and December 2009 were included (n =48,550). The daily dose was defined as the amount of pregabalin dispensed divided by the number of days between the second and third dispensings. Associations between sociodemographic and clinical variables and dispensing pregabalin at a dose exceeding the maximum daily allowed dose (600 mg) were investigated in multivariate regression models. Results Of the patients dispensed pregabalin during the study period, 8.5 % were dispensed a dose that exceeded the maximum daily allowed dose. A previous addictive disorder drug treatment or diagnosis was present in 20 and 31 % of patients dispensed pregabalin within and exceeding the recommended dose range, respectively. Our analysis revealed that those patients at increased risk of being dispensed pregabalin at higher than the maximum allowed dose were male [adjusted odds ratio (aOR) 1.40, 95 % confidence interval (CI) 1.31– 1.49], were between 18 and 29 years of age compared with those aged ≥65 years (aOR 1.62, 95 % CI 1.45–1.82), had a low income (aOR 1.24, 95 % CI 1.10–1.40), had epilepsy compared with no diagnosis (aOR 1.41, 95 % CI 1.10–1.81), R. Bodén : B. Wettermark : L. Brandt : H. Kieler Centre for Pharmacoepidemiology at the Department of Medicine, Karolinska Institutet, Stockholm, Sweden R. Bodén (*) Unit of Psychiatry, Department of Neuroscience, Uppsala University, Uppsala 751 85, Sweden e-mail: [email protected]
had a previous substance use disorder treatment or diagnosis (aOR 1.41, 95 % CI 1.31–1.52) or had previously been dispensed high doses of drugs with abuse potential (aOR 1.77, 95 % CI 1.62–1.94). Conclusion Based on our results we conclude that patients at a high risk of addiction and patients with epilepsy are more likely to be dispensed pregabalin at higher than the maximum approved daily dose. Keywords Pregabalin . Abuse . Generalized anxiety disorder . Pharmacoepidemiology . Neuropathic pain . Epilepsy
Introduction Pregabalin was introduced in 2004 and has been marketed as a new pharmacological approach to treat common disorders such as neuropathic pain and generalized anxiety disorder (GAD), and as adjunctive treatment of partial-onset seizures, all of which are now approved indications in Europe [1, 2]. In the USA, pregabalin is approved for epilepsy, fibromyalgia and neuropathic pain associated with diabetes, herpes or spinal injury [3]. Pregabalin is structurally related to gammaaminobutyric acid (GABA) but does not bind to GABA (A), GABA (B) or other benzodiazepine receptors [4]. When introduced on the market, pregabalin’s potential for abuse and dependence was thought to be small [5, 6], and pregabalin has even been suggested as a treatment for alcohol and benzodiazepine dependence [7, 8]. The Food and Drug Administration in the USA considers the potential for abuse and dependence to be low and has labeled pregabalin as a schedule V controlled drug [3]. However, case reports of adverse drug reactions, recreational misuse and dependence have recently emerged and raised concerns regarding pregabalin’s potential for abuse and addiction [9–15]. In 2010 the potential for
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pregabalin abuse and a call for caution in patients with a history of substance abuse was added to the EU summary of product characteristics [2]. To our knowledge, there are to date no population-based studies available to confirm or refute these observations. Thus, in this study, our aim was to determine the characteristics of patients dispensed pregabalin that exceeds the maximum approved dose.
Methods This was an observational cohort study based on data extracted from Swedish national health and population registers. Four registers were linked by using the Swedish personal identification numbers (PIN) [16]: (1) data on dispensed drugs from the Swedish Prescribed Drug Register [17]; (2) data on diagnoses from in- and out-patient care in hospitals from the National Patient Register [18]; (3) data on patients who were deceased from the National Cause of Death Register [19]; (4) socioeconomic data from Statistics Sweden on patient education, income and country of birth [20]. The Prescribed Drug Register contains patient-level data on dispensed medicines for the entire Swedish population from 1 July 2005 onwards.
Table 1 Definitions of drugs with an abuse potential, addictive disorder drugs, substance use disorders and approved indications for pregabalin
a
Classification of drugs according to the Anatomical Therapeutic Chemical (ATC) classification of the World Health Organization (WHO)
b
Classification of disorders/ diseases according to WHO’s International Classification of Diseases, update 10 (ICD-10)
Drugs/disorders/approved indications Drugs with potential for abusea Benzodiazepines Weak opioids Strong opioids Psychostimulants Addictive disorder drugsa Acamprosate Naltrexone Disulfiram Methadone Buprenorphine Substance use disordersb Approved indications for pregabalinb Epilepsy Generalized anxiety disorder Neuropathic pain related diagnoses: Neuropathies
Cerebrovascular disease sequelae Mechanical neuropathies Unspecified pain
More specifically, it contains information on the dispensed drug (product, quantity and price), the prescriber and the dates of prescription and dispensing. However, the register does not cover prescriptions that have not yet been dispensed. All drugs are classified according to the World Health Organization Anatomical Therapeutic Chemical (ATC) classification and the register is updated monthly. From the register we obtained information on filled prescriptions for pregabalin (ATC code N03AX16). We also obtained information on the use of other drugs with a potential for abuse and dependence, as well as drugs prescribed for addictive disorders (Table 1). Information on diagnoses recorded in hospitals between 2002 and 2009 was collected from the National Patient Register. This register includes all diagnoses recorded in Swedish hospitals, both after inpatient care and specialized outpatient visits. The WHO’s International Classification of Diseases, update 10 (ICD-10) codes have been used for coding of diagnoses since 1997. All incident users aged >12 years who filled at least three prescriptions of pregabalin from 1 July 2006 through to 31 December 2009 were identified using the Prescribed Drug Register and included in the study. To be defined as an incident user no pregabalin should have been dispensed within 1 year prior to the inclusion period, i.e. from 1 July 2005
ATC/ICD-10 code
N05B and N05C N02AA59, N02AX02, N02AX06 or N02AC04 N02A (except those defined as weak opioids) N06B N07BB03 N07BB04 N07BB01 N07BC02 N02AE01 F11-F19 or Z71.4-5 G40 F41.1 G35.9, G50.0, G50.1, G51.0, G53.0, G54.4, G54.6, G55.0, G55.1, G56.0, G56.2, G56.4, G56.9, G57.0, G57.1, G57.8, G57.9, G58.0, G58.7, G58.8, G62.9, G63.2, G82.1, G95.0, G95.2, G95.8, G97.9. I69.1, I69.3 M48.0, M50.1, M53.0, M53.1 M54.1, M54.3, M54.4, M79, M79.2, and M89.0 R52
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through 30 June 2006. The study was approved by the regional ethical committee at Karolinska Institutet in Stockholm, Sweden. We obtained information on diagnoses reflecting the approved indications in the EU: epilepsy, GAD and neuropathic pain. As neuropathic pain is not a well-defined entity, we included all diagnoses that may be associated with this condition (Table 1). Educational attainment was classified into three categories, representing distinct levels in the Swedish educational system: primary, secondary and university level. Low educational level was equivalent to ≤9 years at primary school; medium educational level, as 10–12 years at secondary school; high educational level, as >12 years of education. Country of birth was classified as Sweden, other Nordic countries, Europe (excluding the Nordic countries) and the rest of the world (excluding Europe). Income was classified in quartiles representing the quartiles of the distribution of the income of the Swedish population. Type of prescriber was categorized by workplace as primary care clinic, somatic hospital clinic, psychiatric or addiction clinic and other. History of substance use disorders included diagnoses of mental or behavioral disorders related to alcohol or drug use, or dispensings for addictive disorder drug treatment. Only diagnoses and dispensings prior to the initiation of pregabalin were included (Table 1). Previous high-dose users of drugs with a potential for abuse and dependence included all individuals who had been dispensed >2 defined daily doses (DDDs) per day of benzodiazepines, weak opioids, strong opioids or psychostimulants. The dispensing should have occurred during a 12-month period prior to the first dispensing of pregabalin. The median DDDs for drugs with abuse potential in the time periods 6–12 months before and 6–12 months after the initiation of pregabalin treatment were calculated for all patients with at least two prescriptions of these drugs. The daily dose for pregabalin was calculated using information from the second and third dispensing only. The amount of dispensed drug from the second dispensing was divided by the number of days in the interval between the second and third dispensing. According to the label, the maximum dose of pregabalin is 600 mg daily, which is equivalent to two DDDs. Filling of prescriptions equating to a dose above the two DDD was used as a proxy or indicator for potential misuse of pregabalin. Statistical methods Numbers and proportions were used to describe the study cohort characteristics for patients within or above the recommended dose range, according to their estimated DDDs per day of pregabalin. Using univariate and multivariate logistic regression models, we studied associations between sociodemographic and clinical variables and the filling of prescriptions that resulted in the patient being dispensed pregabalin at higher than the maximum allowed dose. In each multivariate model
199
all factors listed in Table 1 were included. Statistical analysis was performed using SAS software ver. 9.2 (SAS Institute Inc., Cary, NC).
Results We identified 48,550 patients who were dispensed pregabalin at least three times during the study period. Of those, 4,130 (8.5 %) had an estimated daily dosage that exceeded the maximum approved dose. The sociodemographic and clinical characteristics of the cohort are described in Table 2. More females than males were treated with pregabalin (61.4 vs. 38.6 %), but among those treated with doses that exceeded the maximum recommended dose, the sex difference was attenuated (51.9 vs. 48.1 %, respectively). The majority of patients treated with pregabalin were between 30 and 64 years of age, and prescriptions that exceeded the maximum recommended dose were more common among young adults. Among patients with no record of an approved indication for pregabalin, 8.3 % were dispensed dosages that exceeded the maximum approved dose; the corresponding numbers for patients with approved indications were 12.3, 8.9 and 9.2 % for epilepsy, neuropathic pain and GAD, respectively, and for those with more than one approved diagnosis, 13 %. There were only minor differences in the distribution of the type of prescriber between those who were prescribed doses within the recommended range and those who were prescribed doses exceeding it. Twenty percent of patients treated with a dose below the maximum dose had a previous substance use disorder or had been treated previously with addictive disorder drugs; the corresponding figure for patients receiving above the maximum dose was 30.5 %. Among those treated with a dose lower than the maximum dose, 9.3 % had been treated with >2 DDDs/day of drugs with an abuse potential 1 year prior to the first dispensing of pregabalin; the corresponding proportion for those receiving a dose exceeding the maximum dose was 17 %. Sociodemographic and clinical factors investigated for an association the dispensing of pregabalin at doses exceeding the maximum daily dose are shown in Table 3. Male sex, low income, having epilepsy or neuropathic pain diagnoses and/or several of the approved diagnoses or having a history of addiction or more than 2 DDDs/day of drugs with abuse potential were all associated with an increased likelihood of being dispensed pregabalin at a dose exceeding the maximum recommended dose. The age stratum including young adulthood (18–29 years) was most strongly associated with dispensing that exceeded the maximum recommended dose. Educational level and country of birth were not associated with an increased likelihood of being dispensed pregabalin at a dose exceeding 600 mg per day. As illustrated in Fig. 1, the proportions of patients dispensed drugs with abuse potential
200 Table 2 Sociodemograpic and clinical factors by estimated daily dose of pregabalin within or above the recommended dose range
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Patients dispensed ≤600 mg/day (n =44,420; 91.5 %)
Patients dispensed >600 mg/day (n =4,130; 8.5 %)
N
%
N
%
17,162 27,258
38.6 61.4
1,985 2,145
48.1 51.9
158 4,314
0.4 9.7
10 532
0.2 12.9
9,968 16,352 13,628
22.4 36.8 30.7
1,092 1,575 921
26.4 38.1 22.3
15,542 19,819 9,059
35.0 44.6 20.4
1,388 1,913 829
33.6 46.3 20.1
14,266 17,583 7,591 4,980
32.1 39.6 17.1 11.2
1,444 1,587 678 421
35.0 38.4 16.4 10.2
37,760 1,900 2,531 2,229
85.0 4.3 5.7 5.0
3,518 182 219 211
85.2 4.4 5.3 5.1
None 33,185 74.7 2,992 Epilepsy 536 1.2 75 Neuropathic pain 9,113 20.5 892 GAD 1,371 3.1 139 More than one 215 0.5 32 Prescriber workplace Primary care clinic 13,691 30.8 1,254 Somatic hospital clinic 13,272 29.9 1,265 Psychiatric or addiction clinic 14,196 32.0 1,287 Other 3,252 7.3 322 Previous addictive disorder diagnosisb or addictive disorder drugsc No 35,349 79.6 2,870 Yes 9,071 20.4 1,260 Addictive diagnosis 7,109 16.0 1,078 Addictive disorder drugsc 4,163 9.4 523 >2 DDD/day of drugs with abuse potential 12 months prior to receiving pregabalin None 40,293 90.7 3,429 Anyd,e,f,g 4,127 9.3 701 Benzodiazepinesd 2,787 6.3 420
72.4 1.8 21.6 3.4 0.8
Sociodemograpic and clinical factors
Sex Male Female Age (years) 12–17 18–29 30–44 45–64 ≥65 Educational level Low (≤9 years) Medium (10–12 years) High (>12 years) Income in quartiles of population 1st (lowest) 2nd 3rd 4th (highest) Country of birth Sweden Other Nordic countries Other European countries Non-European countries Approved indication for pregabalina
DDD,Defined daily dose; GAD, generalized anxiety disorder a
Approved indication in Europe during the study period
b ICD-10 code F11-F19 or Z71.4-5 c
Acamprosate, naltrexone, disulfiram, buprenorphine or methadone
d Anxiolytics and hypnotics/ sedatives e f
Codeine, tramadol, tapentadol
All opioids than those defined as weak opioids
Weak opioidse Strong opioidsf Psychostimulants
627 887 176
1.4 2.0 0.4
128 174 53
30.4 30.6 31.2 7.8 69.5 30.5 26.1 12.7 83.0 17.0 10.2 3.1 4.2 1.3
Eur J Clin Pharmacol (2014) 70:197–204 Table 3 Odds ratios and 95 % confidence intervals of being dispensed pregabalin at a dose that exceeds the maximum daily recommended dose (>600 mg) for social and clinical factors.
Sociodemograpic and clinical factors
Sex Male Female Age (years) 1–17 18–29 30–44 45–64 ≥65 Educational level Low (≤9 years) Medium (10–12 years) High (>12 years) Income in quartiles 1st (lowest) 2nd 3rd 4th (highest) Country of birth Sweden Other Nordic countries Other European countries Non-European countries Approved indication for pregabalin None Epilepsy Neuropathic pain GAD
OR, Odds ratio; CI, confidence interval a
All variables in the table are included in the multivariate analyses
b
See Table 1 for definitions
c
Refer to Table 1 for drug definitions
201
Univariate analysis OR (95 % CI)
Multivariate analysisa OR (95 % CI)
1.47 (1.38–1.57) Reference=1
1.40 (1.31–1.49)
0.94 (0.49–1.78) 1.83 (1.63–2.04) 1.62 (1.48–1.78) 1.43 (1.31–1.55) Reference=1
0.92 (0.48–1.76) 1.62 (1.45–1.82) 1.50 (1.36–1.66) 1.33 (1.21–1.45)
Reference=1 1.08 (1.01–1.16) 1.03 (0.94–1.12) 1.20 (1.07–1.34) 1.07 (0.96–1.19) 1.06 (0.93–1.20) Reference=1 Reference=1 1.03 (0.88–1.20) 0.93 (0.81–1.07) 1.02 (0.88–1.18) Reference=1 1.55 (1.22–1.98) 1.09 (1.00–1.17) 1.12 (0.94–1.34)
More than one 1.65 (1.14–2.40) Previous addictive disorder diagnosis or addictive disorder drugsb No Reference=1 Yes 1.71 (1.6–1.84) >2 DDD/day of drugs with abuse potential 12 months prior to pregabalinc None reference=1 Any 2.00 (1.83–2.18)
12 months before and after the initiation of pregabalin treatment was similar. Moreover, the median DDDs of the dispensed drugs with abuse potential were similar in the time periods 16–12 months before and 6–12 months after the initiation of pregabalin treatment (Table 4).
Discussion In this large population-based study of all first-time pregabalin users in Sweden, we found that 8.5 % were dispensed a dose
1.07 (0.97–1.18) 1.03 (0.96–1.11) 1.24 (1.10–1.40) 1.11 (0.99–1.25) 1.07 (0.94–1.21)
1.06 (0.91–1.25) 0.97 (0.84–1.12) 0.95 (0.82–1.11)
1.41 (1.10–1.81) 1.17 (1.08–1.27) 1.02 (0.85–1.22) 1.53 (1.05–2.23)
1.41 (1.31–1.52)
1.77 (1.62–1.94)
of pregabalin that exceeded the maximum recommended daily dose of 600 mg. Dispensing a dose that exceeded the maximum dose was more likely to occur in young adult males and in those with a low income. A previous substance use disorder and having used large amounts of other drugs with abuse potential were also associated with the use of doses that exceeded the maximum dose. In addition, patients with epilepsy or with several of the approved indications for pregabalin treatment were more prone to being dispensed doses that exceeded the maximum dose, when compared with those without an approved indication.
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Fig. 1 Proportion of patients being dispensed above or below two defined daily doses (DDD) of drugs with abuse potential 12 months before and after pregabalin initiation. Bdz Benzodiazepines
Having a history of addiction was associated with the dispensing of pregabalin at a dose that exceeded the maximum dose irregardless of how the addiction was assessed, i.e. whether addiction was defined by diagnosis, addictionspecific treatment or by high dose dispensing of drugs with addiction liability. Being a young adult, being male and having a low income was also associated with high doses of pregabalin. Male sex and low socioeconomic status are known risk factors for substance use disorders [21]. Considering that pregabalin has been proposed as a treatment for alcohol and benzodiazepine dependence, our findings of individuals at risk for addiction have an increased risk of being dispensed high doses of pregabalin might suggest the off-label prescribing of pregabalin for substance use disorders [7, 8]. Nevertheless, if pregabalin is being used successfully for the treatment of benzodiazepine dependence we would have expected to observe a decrease in the use of these drug after the initiation of pregabalin treatment—and this was not the case. Although we did not assess individual changes in the high dose consumption of drugs with an addiction potential before and after pregabalin initiation, there were only minimal changes in the proportion of patients prescribed benzodiazepines and in the median dose 1 year before and 1 year after pregabalin initiation. This is an ecological comparison, but it nevertheless Table 4 Defined daily doses of drugs with abuse potential 6–12 months before and 6–12 months after initiation of pregabalin treatment
a
Refer to Table 1 for drug definitions
Drugs
suggests that pregabalin seems to have been a supplement to the benzodiazepines rather than a replacement of them, a finding that is discordant with that reported in a Norwegian claims data study [22]. In the Norwegian study 15–29 % of individuals had stopped using benzodiazepines after pregabalin initiation although a direct comparison is hampered by the fact that we also included hypnotics. If being dispensed large amounts of pregabalin is a phenomenon related to tolerance and dependence, recreational misuse/abuse or selling to others or a lack of efficacy or effectiveness within the recommended dose range is not possible to disentangle based on the available data in our study. Previous studies of abuse and dependence mainly comprise case reports and case series [9–14]. Dispensing of a drug is not equal to ingestion of that drug and, therefore, we do not know if the drugs assessed in this study were used regularly, were hoarded or had been used by someone other than the patient they were dispensed to. It should be pointed out that we assessed the estimated daily amount of pregabalin between the second and third dispensing. Thus, if the dispensing of pregabalin at a dose exceeding the maximum recommended dose was due to tolerance it occurred early in the course of treatment. On the other hand, a previous long-term study of pregabalin treatment for epilepsy did not find any evidence for tolerance [23]. Another explanation for over-the-maximum dose dispensing of pregabalin could be recreational misuse/ abuse or selling to others, although the use of single doses of 1.5–6 g of pregabalin has been reported [10, 13, 15]. Patients with epilepsy and with more than one of the approved diagnoses were more likely to be dispensed pregabalin at a dose that exceeded the maximum dose. One explanation is that epilepsy treatment alone and comorbidity with neuropathic pain and GAD might require higher doses to be effective [23]. In a pooled analysis of studies on pregabalin for painful diabetic peripheral neuropathy, the authors observed that patients receiving the highest dose of 600 mg were those for whom the drug had the best effect and who showed the highest persistence [24]. Thus, the recommended dose of pregabalin might not be adequate in all patients. We have previously reported that the average dose of pregabalin was highest in patients with epilepsy (321 mg/day), followed by those with GAD (275 mg/day) and neuropathic pain (244 mg/day), and lowest in patients without any recorded indicated diagnosis
Initiation of pregabalin treatment 6–12 months before
Benzodiazepinea Opiates Psychostimulants
6-12 months after
n
Median
Quartiles
n
Median
Quartiles
1,593 1,155 47
0.88 0.50 1.32
0.43; 1.39 0.23; 0.97 0.82; 2.26
1,634 1,210 83
0.93 0.51 1.24
0.48; 1.44 0.25; 1.05 0.25; 1.05
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(230 mg/day) [25]. It should, however, be noted that there were only minor differences in the distribution of type of prescriber by level of prescribed dose. The main strength of the study is the national coverage of all prescribed drugs dispensed in Sweden and therefore recorded in the Prescribed Drug Register [26]. We were also able to assess a broad set of sociodemographic and clinical factors by using information collected in the other health registers and in the population register with national coverage; thus, our study represents a non-selected population. Accordingly, the generalizability of the study results should be high. Moreover, the diagnoses in the National Patient Register are generally accurate, and they have been found to have high validity [18]. It should, however, be noted that we did not have information on diagnoses from primary care as such national data are not available. Nevertheless, we observed that the percentage of patients dispensed pregabalin at doses that exceeded the maximum recommended dose was lowest in the group of patients with no recorded diagnosis and highest among those with epilepsy and more than one approved indication. To estimate the daily dose we used information from the second and third dispensing. The rationale for using information only from these dispensings was that more than one dispensing would be needed to estimate the daily dose, and it seemed important to assess regular users and not include those in need of an initial dose titration. Our aim was to capture incident users and, therefore, we applied a 1-year observation period before inclusion, during which those included in the study should not have been dispensed pregabalin. However, some of those included in the study might not be true first-time users as they could have filled a prescription before information on dispensing were available in the Prescribed Drug Register (1 July 2005). For these patients, the assessment of dose would include dispensings occurring after the third dispensing, but as dose titration generally takes place when the patient is started on pregabalin, we believe that including these patients did not affect our results. Moreover, as pregabalin was introduced the year prior to the start of the study period we feel safe in assuming that most patients were probably incident users [25].There is no generally accepted definition of high doses of drugs, which might possess a risk for abuse, but as the recommended maximum dose of 600 mg equals two DDDs, we chose to define high dose use of drugs with abuse potential accordingly. In conclusion, dispensing pregabalin at a dose that exceeded the maximum recommended daily dose, i.e. 600 mg, was evident in 8.5 % of all patients dispensed pregabalin in our analysis. This was more likely in patients with a history and risk factors for addiction, which prompts the need for continued monitoring and surveillance for signals of abuse and for further assessment of the abuse potential of this drug.
203 Conflict of Interest The study was independently developed from a project initiated and partially funded by Pfizer, Sweden. Pfizer had no further role in the study design, in the collection, analysis and interpretation of data, in the writing of the report nor in the decision to submit the paper for publication. The authors declare no personal potential conflicts of interest.
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