Carisoprodol use and abuse in Norway. A pharmacoepidemiological study

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1 British Journal of Clinical Pharmacology DOI: /j x Carisoprodol use and abuse in Norway. A pharmacoepidemiological study Jørgen G. Bramness, 1 Kari Furu, 1 Anders Engeland, 1,2 & Svetlana Skurtveit 1,3 1 Department of Pharmacoepidemiology, Division of Epidemiology, Norwegian Institute of Public Health, Oslo, 2 Department of Public Health and Primary Health Care, Section of Epidemiology and Medical Statistics, University of Bergen, Bergen and 3 Department of Pharmacy, University of Tromsø, Tromsø, Norway What is already known about this subject Carisoprodol was developed to create a drug with less abuse potential than meprobamate. Case reports have established carisoprodol as a drug of abuse, but no systematic studies have been published about the extent of abuse. What this study adds A large number of patients used more carisoprodol than recommended. High use of carisoprodol was associated with high use of benzodiazepines and opiates. Compared with other medicinal drugs, carisoprodol showed many prescription database signals of being a potential drug of abuse. Correspondence Jørgen G. Bramness MD, PhD, Senior researcher, Department of Pharmacoepidemiology, Norwegian Institute of Public Health, PO Box 4404 Nydalen, NO-0403 Oslo, Norway. Tel.: Fax: jorgen.bramness@fhi.no... Keywords carisoprodol, meprobamate, pharmacoepidemiology, prescription drug abuse... Received 15 June 2006 Accepted 3 November 2006 Published OnlineEarly 12 February 2007 Aim Carisoprodol was developed to create a drug with less potential for abuse than meprobamate. However, case reports have established carisoprodol as a drug of abuse. This paper explores the extent of potential abuse of this drug in Norway. Methods The Norwegian Prescription Database contains information on prescription drugs dispensed to individuals in Norway. Patients can be followed over time. High levels of carisoprodol use could indicate use for pleasurable effects or development of tolerance. Concomitant use of other potential drugs of abuse was also studied. We studied drug-seeking behaviour by looking at patients who received carisoprodol from many different pharmacies and doctors or from high-prescribing doctors. Carisoprodol was compared with a series of other medicinal drugs with or without known potential for abuse. Results Some Norwegian women (2.4%) and men (1.3%) 18 years old received carisoprodol at least once in Prescribing of carisoprodol was skewed. As many as 32% of the patients received more than 15 defined daily doses (DDDs) of carisoprodol and > patients (15%) received 75 DDDs in High users of carisoprodol also received more benzodiazepines and opioids. Few patients used three or more doctors for prescriptions, but carisoprodol-abusing patients more often received their prescription from high-prescribing doctors. Conclusions Carisoprodol was widely used and the skewedness in use indicated that it is a potential drug of abuse. A large number of patients used more carisoprodol than recommended in the guidelines. The high level of use and abuse of carisoprodol should be of concern in Norway. Br J Clin Pharmacol 64: The Authors Journal compilation 2007 Blackwell Publishing Ltd

2 Carisoprodol use and abuse in Norway Introduction The centrally acting muscle relaxant carisoprodol has been on the market for >40 years [1]. It has been tried for various muscular skeletal disorders [2 4], pain symptoms [5, 6] and spasmodic conditions. Currently, the drug is recommended in Norway only for acute lower back pain [7, 8]. The drug is approved for short-term use only (up to 1 week) and only in doses of up to 350 mg taken three times daily and once at bedtime. Use of carisoprodol, in the doses seen in the clinical studies of the drug, can cause dizziness, drowsiness, nausea and sometimes psychomotor impairment [3, 4, 9]. Adverse reactions that may appear only in higher doses or with long-term use, such as drug abuse, drug dependence and drug toxicity, are difficult to study in controlled clinical experimental studies. Carisoprodol is metabolized to meprobamate [10]. Meprobamate is a barbiturate-like drug [11] with welldocumented extensive abuse [12, 13]. Carisoprodol was developed to reduce abuse [1] and an early report claimed that it had no addictive potential [14]. However, case reports have subsequently been published on the abuse and dependence of carisoprodol [15]. Two reports have found high concentrations of carisoprodol in the blood of drug-impaired drivers [16, 17], cases that could be viewed as carisoprodol abuse [18]. The Drug Abuse Warning Network (DAWN) in the USA has seen an increase in the number of admissions to emergency departments that involve carisoprodol over recent years [19]. Even though these reports cause concern about the extent of carisoprodol abuse, no systematic studies have been published. The aim of the present study was to explore the potential abuse of carisoprodol in Norway by investigating prescriptions given to individual patients. Materials and methods Prescription database Data were drawn from the Norwegian Prescription Database (NorPD) covering the entire country (4.6 million inhabitants). From 1 January 2004 all pharmacies in Norway were obliged by law every month to submit electronic data on all prescriptions to the Norwegian Institute of Public Health. The NorPD contains information on all prescription drugs, whether or not reimbursed, dispensed at Norwegian pharmacies to individual patients who live outside institutions [20]. The data collected are: patients unique identifiers (encrypted), gender, age, place of residence, prescribers unique identifiers (encrypted), the date of dispensing and drug information [brand name, package size, number of packages, anatomical therapeutic chemical code (ATC-code), defined daily dose (DDD) and price]. The indication for prescribing is not recorded. Data on age- and gender-specific population figures were taken from Statistics Norway. Study population In Norway, carisoprodol is approved for the treatment of acute lower back pain. The DDD for carisoprodol is set internationally to 1400 mg (350 mg four times daily) [21]. During 2004 a total of DDDs of carisoprodol were dispensed in Norway. Of these, the following amounts were excluded from further study: DDDs (1.5%) dispensed to institutions; DDDs (0.4%) supplied to doctors own practices; DDDs (%) dispensed to patients without person identifiers; 5793 DDDs (0.1%) prescribed by doctors without person identifiers; and 4012 DDDs (0.1%) dispensed to 119 patients <18 years old. The remaining DDDs (96.6%) were dispensed to patients 18 years old and were included in the further investigation. Five different groups of carisoprodol users were defined depending on the patient s use of carisoprodol, benzodiazepines and opioids. These were: (i) therapeutic use of carisoprodol, (ii) pseudo-therapeutic long-term use of carisoprodol [22], (iii) pure carisoprodol abuse, (iv) patients with anxiety or benzodiazepine abusers using carisoprodol and high doses of benzodiazepines, and (v) pain patients or opioid abusers with concomitant use of carisoprodol and high level of use of opioids. Specific definitions of the five groups are given in Table 1. Measured parameters One-year period prevalence of use was measured as the number of individuals who had received at least one prescription for carisoprodol in 2004 per 100 inhabitants in 1-year age groups. We studied several parameters from the prescription database that could indicate abuse of carisoprodol. The high level of use of carisoprodol was studied by looking at the total amount (in DDDs) of carisoprodol prescribed during As carisoprodol is indicated for the treatment of acute lower back pain and should be used for only 1 2 weeks [7, 23], high users were those patients who received >15 DDDs during the year. Maximum therapeutic intensity was studied in order to discriminate between patients with a pseudo-therapeutic long-term use of carisoprodol (low intensity over a long time) and carisoprodol abusers (high intensity over different lengths of time). The number of DDDs for each Br J Clin Pharmacol 64:2 211

3 J. G. Bramness et al. Table 1 The patients ( 18 years old) who received at least one prescription for carisoprodol characterized according to their use of carisoprodol, benzodiazepines and opioids (Norwegian Prescription Database 2004) Group Carisoprodol use Definition criteria Opioid and benzodiazepine use Therapeutic use of carisoprodol <15 DDDs in 2004 <100 DDDs year -1 of both Pseudo-therapeutic long-term use of <2 DDDs day -1 in any prescription, <100 DDDs year -1 of both carisoprodol but 15 DDDs in 2004 Carisoprodol abuse 2 DDDs day -1 in any prescription <100 DDDs year -1 of both Anxiety patient/benzodiazepine abuser Any amount <100 DDDs/year opioids, 100 DDDs year -1 benzodiazepines Pain patient/opioid abuser Any amount 100 DDDs year -1 opioids, any amount of benzodiazepines prescription for every patient who received two or more prescriptions was determined by dividing the amount of carisoprodol in each prescription by the number of days until the next prescription. If a patient received more than one prescription in a single day, these were added and divided by the number of days to the next prescription. The prescription yielding the highest number of DDDs per day for each patient was used to describe maximum therapeutic intensity for each patient. Doctor shopping, or visiting many doctors to obtain prescriptions for carisoprodol, could be an indicator of drug-seeking behaviour and drug dependence [24]. The number of doctors used to obtain prescriptions for carisoprodol, and whether the patient had used more than three doctors for such prescriptions, were noted. The Norwegian system of designated family doctors is an obstacle for patients visiting and obtaining prescriptions from different doctors. Thus, we also investigated whether the patient had obtained a prescription from a doctor who might be known for high prescribing (highprescribing doctor). These doctors were defined as the highest prescribers of opioids or benzodiazepines generally to all Norwegian patients. During 2004, prescriptions for opioids (ATC code N02AA) and benzodiazepine anxiolytics (N05BA) and hypnotics (N05CD) were registered at the NorPD. These were prescribed by doctors. Of these doctors, 1% (n = 197) prescribed almost 20% of these potential abuse drugs (in DDDs) and were classified as highprescribing doctors. Patients who received at least one prescription from this group were noted. Concomitant use of potential drugs of abuse, such as benzodiazepines and opioids, may also indicate drug abuse. The amount of benzodiazepine anxiolytics (ATC code N05BA) and hypnotics (N05CD) and opioids (N02AA) dispensed to carisoprodol users during 2004 was calculated. The patients who received >100 DDDs of opioids or 100 DDDs of benzodiazepines during 2004 were considered to be high users of these drugs. Comparison drugs We compared the possible drug abuse parameters used on carisoprodol with five other drugs (Table 3). Codeine combinations are commonly prescribed drugs for moderate to severe pain in Norway, but are also a known drug of abuse. Diazepam has several uses, but is also involved in harmful use. Medicinal drugs without a known abuse potential included were esomeprazol (proton pump inhibitor), metformin (oral glucose-reducing drug) and salbutamol (b 2 -adrenergic agonist for inhalation). In certain cases, a skew in the prescribing of a drug could indicate abuse [25]. A Lorenz curve illustrates a cumulative distribution of use ranking the highest users first. A Lorenz curve was constructed for each drug to illustrate the distribution in prescribing. The high figure for the 1% from a Lorenz curve was noted for each of the studied drugs. Results Use of carisoprodol Age- and gender-specific prevalence related to the total Norwegian population aged 18 years ( individuals) is shown in Figure 1. In 2004, women (2.4% of the female population) and men (1.3%) received at least one prescription. The female users were older (mean 49 vs. 47 years) and received a larger mean amount of carisoprodol than men (mean 49 vs. 39 DDDs). Of the carisoprodol users, 62% fulfilled our criteria for therapeutic use. Pseudo-therapeutic long :2 Br J Clin Pharmacol

4 Carisoprodol use and abuse in Norway Prevalence (%) Age (years) Figure 1 Age- and gender-specific prevalence (%) of patients aged 18 years receiving at least one prescription for carisoprodol (Norwegian Prescription Database 2004). Male ( ), female ( ) term use involved 16%, whereas only 1% of patients were characterized as pure carisoprodol abusers. Of the patients, 8% had a high concomitant use of benzodiazepines and were considered to be either patients with anxiety or abusers of benzodiazepines, whereas 14% were considered to be primary opioid abusers (Table 2). The therapeutic carisoprodol users received only 12% of the total amount of carisoprodol dispensed in 2004, whereas the primary opioid abusers received as much as 48% of the total amount of carisoprodol. High level of use of carisoprodol Of the patients receiving at least one prescription for carisoprodol, (32%) received 15 DDDs of carisoprodol in 2004, whereas patients (14%) received 75 DDDs. Among patients receiving high prescriptions, 4280 (5%) received at least one prescription that could supply them with >2 DDDs day -1 until the next prescription, whereas 2048 patients (2%) received at least one prescription that could supply them with >5 DDDs day -1 until the next prescription. Doctor shopping Most patients received their carisoprodol prescriptions from one doctor (74 305; 89%). The number for two doctors was 7602 (9%), for three 1377 (2%) and for more than three doctors 429 (0.6%). The number of carisoprodol-prescribing doctors visited rose with increasing amounts of carisoprodol dispensed, and to some extent with the concomitant use of benzodiazepines and opioids (Table 2). The number of patients receiving their prescription from high-prescribing doctors was 7834 (9%). This number increased with the amount of carisoprodol dispensed, and even more with the concomitant use of other prescription drugs of abuse (Table 2). Concomitant use with other potential drugs of abuse The user groups were defined also according to their use of benzodiazepines and opioids (Table 1). Table 2 confirms that the anxiety patients were subscribed a substantial amount of benzodiazepines, while the pain patients were prescribed a great deal of both benzodiazepines and opioids. Comparison drugs The Lorenz curves for all the studied drugs are shown in Figure 2. Table 3 shows the data for the comparison drugs. In addition to the data given for the carisoprodol user groups (Table 2), Table 3 presents the Lorenz curve 1% parameter for each drug. Parameters on Lorenz 1%, visiting more than three prescribers and receiving prescriptions from the highest-prescribing doctors were drug abuse parameters that separated drugs of abuse from medicinal drugs without abuse potential. Carisoprodol had the highest figure for Lorenz 1%, but was surpassed by diazepam for the two other measures. Neither maximum therapeutic intensity nor doctor or pharmacy shopping seemed to differ between potential drugs of abuse and drugs without such potential. Discussion Carisoprodol was used in higher doses than recommended. The use of carisoprodol was more skewed than that of the other drugs studied. The majority of patients used the drug in a recommended manner, but most of the carisoprodol was dispensed to patients who used more than recommended and used it together with large amounts of benzodiazepines and opioids. The use of more than three prescribers or visiting high-prescribing doctors were more prevalent for the potential drugs of abuse, including carisoprodol. An advantage of the present investigation was the absence of selection and information bias. The NorPD includes all prescriptions for carisoprodol from all Norwegian doctors to the entire population over 1 year. A potential weakness is that the NorPD does not include information on diagnosis or severity of conditions and we do not know if the drugs dispensed are ingested. Our research aim can still be validly addressed within the database. Br J Clin Pharmacol 64:2 213

5 J. G. Bramness et al. Table 2 Pharmacoepidemiological data on drug use, drug abuse parameters and concomitant use of benzodiazepines and opioids for the different groups of carisoprodol users Age (years) mean (SD) Drug user characteristics Drug abuse parameters Other prescriptions Female, Carisoprodol (DDDs year -1 ), Share from GPs* (%) Max. therapeutic intensity (highest prescription: DDDs day -1 ), Number of pharmacies, Number of prescribers, More than 3 prescribers, n (%) From 1% highest prescribers, n (%) Benzodiazepines (DDDs year -1 ), Opioids (DDDs year -1 ), Therapeutic use of carisoprodol Pseudo-therapeutic long-term use of carisoprodol (61.8) (15.8) Carisoprodol abuse 815 (1.0) Anxiety patient/benzodiazepine abuser Pain patient/ opioid abuser 6546 (7.8) (13.6) 47.3 (14.0) 49.2 (13.3) 44.6 (12.4) 53.1 (15.0) 49.7 (13.3) (61.7) (68.6) 530 (65.0) 4563 (69.7) 7783 (68.4) 8.8 (3.0) 57.9 (54.4) (228.1) 84.2 (123.5) (226.8) (0.3) (5.8) (3.1) (5.1) (0.2) (0.8) (0.2) (0.9) 1.4 (0.8) 0.0 (0.0) 129 (1.0) 37 (4.5) 69 () 228 (2.0) 1875 (3.6) 991 (7.5) 88 (10.8) 1657 (25.3) 3223 (28.3) 3.3 (11.9) 8.4 (19.6) 13.4 (24.9) (472.7) (615.1) 6.6 (14.3) 14.8 (23.8) 17.1 (25.5) 16.0 (25.0) (397.5) Data are given as mean (standard deviation) or as number (percentage of total number in group) (Norwegian Prescription Database 2004). *General practitioners (GPs) were specialists of family medicine. Doctors could be practising as GPs for some years without being specialists in family medicine. The number of defined daily doses (DDDs) of carisoprodol in all prescriptions for each patient receiving at least two prescriptions for carisoprodol was divided by the number of days before the next prescription. If a patient received two prescriptions for carisoprodol on the same day the number of DDDs on these two prescriptions were added and divided by the number of days before the next prescription. The highest DDD per day for each patient was recorded. The doctors were characterized according to how much of the total amount of benzodiazepines or opioids they prescribed. The highest prescribing doctors were the 1% of the doctors who had prescribed most of these drugs :2 Br J Clin Pharmacol

6 Carisoprodol use and abuse in Norway Percentile of drug volume Carisoprodol Codeine combinations 20 Diazepam Esomeprazole 10 Metformin Salbutamol Percentile of users Figure 2 Lorenz curves for the drugs carisoprodol ( ), codeine combinations ( ), diazepam ( ), esomeprazole ( ), metformin ( ) and salbutamol ( ). The graph shows the proportion of drug use that is accounted for by the percentiles of drug users, ranked according to their drug use in 2004 Drug abuse and dependence are clinical diagnoses. Although the NorPD database contains no diagnosis, two measures could be deduced that resembled criteria for drug dependence [24]: first, if the drug was taken in larger amounts or over a longer period of time than intended (indicating tolerance or drug taking for pleasurable effects) or, second, if a great deal of time was spent on activities necessary to obtain the substance (drug-seeking behaviour), which could include visiting several doctors to obtain prescriptions for the drug ( doctor shopping ). The other criteria required for a diagnosis of drug abuse and dependence are related more to clinical and social consequences of drug use and could not be extracted from our database. Norwegian patients all have a designated general practitioner and show high doctor fidelity. The low frequency of visiting multiple doctors for prescriptions of carisoprodol and other potential drugs of abuse confirmed this, even if the figures were higher than for drugs without known abuse potential. We therefore studied the prevalence of prescriptions from high-prescribing doctors as an alternative to doctor shopping. Indeed, many high users of carisoprodol and other drugs of abuse received their prescriptions from these doctors. High users will, however, produce high prescribers. Our definition of high prescribers was based on drugs other than carisoprodol and this may have reduced, but not eliminated, the problem. The limit for high level of use of carisoprodol was set arbitrarily. Other strategies have been used when trying to set criteria for abuse of prescription drugs: a set amount of prescribed drug within a certain time period (e.g. >2 DDDs day -1 over a 30-day period) [26]; large prescriptions (e.g. more than twice the recommended amount in any prescription) [27]; and frequent prescribing (e.g. only a few days between prescriptions) [23]. Other researchers have indicated that as many as 3 7 DDDs day -1 have been abused by patients and this supports the limits we have set [28]. One report found that patients using as little as DDD day -1 over a longer period of time had difficulties in stopping their use [29], so we defined this as pseudo-therapeutic long-term use [22]. Such use is characterized by the use of therapeutic or lower-thantherapeutic doses over a longer time period than recommended [30]. We found an average maximum therapeutic intensity among the pseudo-therapeutic long-term users of 0.4 DDD day -1. This low maximum therapeutic intensity confirms that this is not abuse or dependence in the traditional sense. Our criteria for high level of use of carisoprodol may be viewed as too stringent, and this must be taken into account when considering our findings. However, our main conclusions on the extent of carisoprodol abuse were not altered much even with a higher limit. We also set an arbitrary limit of 100 DDDs year -1 for defining high level of use of benzodiazepines and opioids. This limit helped us to single out different patterns of drug abuse. We know from case reports [31] and case series [16, 17] that carisoprodol is often taken in large doses together with other prescription drugs of abuse, but less often with illegal drugs. Many patients took large amounts of carisoprodol together with large amounts of opioids. This illustrates that many probably have at least some pain problem as the rationale for their carisoprodol use. A household study from the USA has shown that a large proportion of carisoprodol was prescribed for lower back pain, mostly to younger patients [32]. The limits set for high level of use of benzodiazepines and opioids also helped to demonstrate that pure carisoprodol abuse is a rather rare phenomenon. Carisoprodol is the only centrally acting muscle relaxant left on the Norwegian market. The Norwegian sales of 2.4 DDDs per 1000 inhabitants per day [33] is seven to eight times higher than found in Spain (personal communication, M. A. Maciá, Spanish Agency for Medicines and Medical Developement), Sweden [34] or Denmark [35]. All these countries also have other centrally acting muscle relaxants for sale. In other countries such as France, Finland and the Netherlands Br J Clin Pharmacol 64:2 215

7 J. G. Bramness et al. Table 3 Pharmacoepidemiological data on drug use, drug abuse parameters and concomitant use of benzodiazepines and opioids for the different users of carisoprodol, codein combinations, diazepam, esomeprazole, metformin and salbutamol N Drug user characteristics Drug abuse parameters Other prescriptions Age (years), mean (SD) Female gender, Drug (DDDs year -1 ), Share from GPs*, (%) Lorenz 1%,%of all drug dispensed Max. therapeutic intensity (highest prescription: DDDs day -1 ), Number of pharmacies, Number of prescribers, More than 3 prescribers From 1% highest prescribers Benzodiazepines (DDDs year -1 ), Opioides (DDDs year -1 ), mean (SD) Carisoprodol (14.0) Codeine combinations exclusive psycholeptics (18.8) Diazepam (18.4) Esomeprazole (17.2) Metformin (14.3) Salbutamol (25.8) (64.4) (57%) (65%) (54%) (48%) (54%) 45 (110) 51 (118) 114 (191) 166 (170) 236 (160) 122 (224) (3.3) (3.9) (6.2) (9.9) (11.8) (12.2) (0.5) 7 (0.45) (0.5) 1.5 (0.5) (0.5) 1842 (2.2) (3.7) (2.7) (1.4) 839 (1.4) 1456 () (13.0) (8.5) (14.3) 8650 (7.7) 4749 (8.0) 8835 (6.6) 74 (295) 51 (213) 154 (310) 37 (175) 24 (123) 29 (167) 59 (194) 56 (138) 52 (174) 26 (120) 15 (74) 19 (110) Data are given as mean (standard deviation) or as number (percentage of total number in group) (Norwegian Prescription Database 2004). *General practitioners (GPs) were specialists of family medicine. Doctors could be practising as GPs for some years without being specialists in family medicine. The number of defined daily doses (DDDs) of the drug for each patient receiving at least two prescriptions for the drug was divided by the number of days until the next prescription. If a patient received two prescriptions for the drug on the same day, the number of DDDs on these two prescriptions were added and divided by the number of days until the next prescription. The highest DDD per day for each patient was recorded. The doctors were characterized according to how much of the total amount of benzodiazepines or opioids they prescribed. The highest prescribing doctors were the 1% of the doctors that had prescribed most of these drugs. For all drugs [including N05BA01 (diazepam) and N02AA59 (codeine combinations)] all opioids and benzodiazepines are included :2 Br J Clin Pharmacol

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