The changing use of prescribed benzodiazepines and z-drugs and of over-the-counter codeine-containing products in England:

Transcription

1 The changing use of prescribed benzodiazepines and z-drugs and of over-the-counter codeine-containing products in England: a structured review of published English and international evidence and available data to inform consideration of the extent of dependence and harm. Dr Kylie Reed (a) * Dr Alyson Bond (a) Mr John Witton (a) Dr Rosie Cornish (b) Professor Matt Hickman (b) Professor John Strang (a) a - The National Addiction Centre, Kings College London b - School of Social and Community Medicine University of Bristol, University of Bristol * corresponding author. kylie.reed@kcl.ac.uk 1

2 Contents Section Title Page Definitions 6 Executive Summary Introduction and Background Benzodiazepines Z-drugs Over-the-counter codeine-containing products Prevalence of Misuse of and Dependence on - Benzodiazepines and z-drugs - Over-the-counter codeine-containing products Benzodiazepine and z-drugs: dispensing data Prescribing by GPs: special analysis using the GPRD A patient subgroup: GP benzodiazepine and z-drug prescribing to patients prescribed opiate substitution therapy (OST) Benzodiazepines: a review of the published literature Z-drugs: a review of the published literature Summary -Prevalence of misuse and dependence on benzodiazepines -Prevalence of misuse and dependence on z-drugs Over-the-counter codeine-containing products: National sales data Over-the-counter codeine-containing products: A review of the published literature Prevalence of misuse and dependence on over-the-counter codeinecontaining products: Summary Short- and long-term effects Benzodiazepines - Summary Z-drugs - Summary Over-the-counter codeine-containing products - Summary Treatment and management interventions Managing benzodiazepine withdrawal Guidelines on benzodiazepine and z-drug withdrawal Treatment and management interventions in benzodiazepine and z-drug misuse and dependence: Summary Treating and reducing misuse of over-the-counter codeine-containing products

3 4.5 Treating and reducing misuse of over-the-counter codeine-containing products: Summary Conclusions thus far Benzodiazepine and z-drug misuse and dependence Over the counter codeine-containing products misuse and dependence Knowledge Gaps and Future Research Recommendations 89 7 Acknowledgments 91 8 References 92 List of tables and figures Table/figure Title Page Figure 2.11 Figure 2.12 Figure 2.13 The Most Commonly Dispensed Benzodiazepines at England-level The Most Commonly dispensed Hypnotic medications in the London Strategic Health Authority The Most Commonly dispensed Hypnotic medications in the Yorkshire Strategic Health Authority Figure 2.14 Prescriptions Dispensed in the Community in England from 1991 to Figure 2.15 Figure 2.16 Figure 2.17 Figure 2.18 All Anxiolytic and Hypnotics Prescriptions Dispensed in the Community in England from 1991 to 2009 Anxiolytic Prescriptions Dispensed in the Community in England from 1991 to 2009 Benzodiazepine Prescriptions Dispensed in the Community in England from 1991 to 2009 Hypnotic Benzodiazepine and Z-drug Prescriptions Dispensed in the Community in England from 1991 to Figure 2.19 Prescriptions Dispensed in the Community in England from 1980 to Table 2.11 All Anxiolytic and Hypnotics Prescriptions Dispensed in the Community in England from 1991 to

4 Table 2.12 Table 2.13 Table 2.14 Anxiolytic Prescriptions Dispensed in the Community in England from 1991 to 2009 Benzodiazepine Prescriptions Dispensed in the Community in England from 1991 to 2009 Hypnotic Benzodiazepine and Z-drug Prescriptions Dispensed in the Community in England from 1991 to Table 2.15 Prescriptions Dispensed in the Community in England from 1980 to 2009 Table 2.21 Prescriptions for benzodiazepines for patients on methadone / buprenorphine Table 2.22 Prescriptions for z-drugs for patients on methadone / buprenorphine Table 2.23 Figure 2.21 Figure 2.22 Figure 2.23 Figure 2.24 Figure 2.25 Table 2.24 Number of z-drug prescriptions co-prescribed with methadone/ buprenorphine Percentage of patients on opiate substitution therapy prescribed benzodiazepines by their GP, Percentage of patients on opiate substitution therapy prescribed z-drugs by their GP, Proportion of patients on opiate substitution therapy (methadone or buprenorphine) who were co-prescribed temazepam Proportion of patients on opiate substitution therapy (methadone or buprenorphine) who were co-prescribed diazepam Proportion of patients on opiate substitution therapy (methadone or buprenorphine) who were co-prescribed nitrazepam Proportion of prescriptions for benzodiazepines and z-drugs that were part of a series of repeat prescriptions Table 2.25 Duration of benzodiazepine prescribing episodes 38 Figure 2.26 Duration of benzodiazepine prescribing episodes 38 Table 2.26 Duration of z-drug prescribing episodes 38 Figure 2.27 Duration of z-drug prescribing episodes 39 Tables 2.27 Length of benzodiazepine prescribing episodes by calendar year 40 Tables 2.28 Length of z-drug prescribing episodes by calendar year 40 Table 2.31 Benzodiazepine Misuse and Dependence: Literature Search 41 4

5 Table 2.32 Strategy Patterns of Benzodiazepine Use by subjects at three UK Addiction Treatment centers (Jaffe et al, 2004) 45 Table 2.41 Z-drug Misuse and Dependence: Literature Search Strategy 50 Figure 2.41 Percentage of falsified or forged prescriptions concerning zolpidem reported to the French network of Centres for Education and Information on Pharmacodependence from 1995 to 2002 (Victorri-Vigneau et al, 2007) 54 Table 2.61 Table 2.71 Table 4.21 Table 6 Sales of codeine products by number of tablets or capsules per carton Over-the-counter codeine-containing products: Literature Search Strategy Approximate dosages of common benzodiazepines and z-drugs equivalent to 5 mg of diazepam Misuse of and Dependence on Benzodiazepines, z-drugs and overthe-counter codeine-containing products in the UK - Knowledge Gaps Prescription Services Division of the NHS Business Services Authority. Data contained in these figures is Copyright (c) 2011, The Health & Social Care Information Centre, Social Care Statistics. All rights reserved. 5

6 Definitions Abstinence Refraining from drug use. Abuse Defined in the American Psychiatric Association s Diagnostic and Statistical Manual IV as a maladaptive pattern of use indicated by.continued use despite knowledge of having a persistent or recurrent social, occupational, psychological or physical problem that is caused or exacerbated by the use [or by] recurrent use in situations in which it is physical1y hazardous. Abuse liability The propensity of a particular psychoactive substance to be susceptible to abuse, defined in terms of the relative probability that use of the substance will result in social, psychological, or physical problems for an individual or for society. Benzodiazepines A group of structurally related drugs used mainly as sedatives/hypnotics, muscle relaxants, and anti-epileptics. Brief Intervention A therapy of short duration (typically 5-30 minutes) where the main principles include expressing empathy with the patient, not opposing resistance and offering feedback to increase the motivation of the patient. It is designed in particular for general practitioners and other primary health care workers. Dependence Defined by the World Health Organisation as a strong desire or sense of compulsion to take a substance, a difficulty in controlling its use, the presence of a physiological withdrawal state, tolerance of the use of the drug, neglect of alternative pleasures and interests and persistent use of the drug, despite harm to oneself and others. Iatrogenic Refers to adverse effects or complications caused by or resulting from medical treatment or advice. General Practice Research Database (GPRD), A computerised database of anonymised longitudinal records from primary care across the UK. Meta analysis The use of statistical techniques to integrate the results of a number of independent studies 6

7 Misuse The use of a substance not consistent with legal or medical guidelines Over-the-counter (OTC) medicines Medicines which can be purchased without a prescription. Legally there are two categories of over the counter medicines in the UK P, meaning that they must be sold by or under the supervision of a pharmacist; and GSL (general sales list), meaning that they can be sold from any pharmacy or non pharmacy outlet, off the shelf. Some OTC medicines, including some containing codeine are also available on prescription. The Propriety Association of Great Britain (PAGB) The UK trade association for manufacturers of branded over-the-counter medicines and food supplements, provides sale figures for these medicines. Prescription Cost Analysis (PCA) Analysis of all prescriptions dispensed in the community by community pharmacists and appliance contractors, dispensing doctors, and prescriptions submitted by prescribing doctors for items personally administered in England. Withdrawal syndrome A group of symptoms which occur on cessation or reduction of use of a psychoactive substance that has been taken repeatedly, usually for a prolonged period and/or in high doses. The syndrome may be accompanied by signs of physiological disturbance. A withdrawal syndrome is one of the indicators of a dependence syndrome. Z-drugs A group of three non-benzodiazepine hypnotics: zaleplon, zolpidem and zopiclone. 7

8 Executive Summary Prevalence of benzodiazepine misuse and dependence Dispensing data show an overall substantial decrease in dispensing of benzodiazepines at England-level across the 19 years from 1991 to This is mostly accounted for by the decrease in dispensing of hypnotic benzodiazepines. There was an overall increase in dispensing of anxiolytic benzodiazepines from 1991 to 2009, interrupted from by a decrease in anxiolytic benzodiazepine dispensing over that time. However, the overall anxiolytic benzodiazepine increase was less marked than the total decrease in all benzodiazepine dispensing across this period. There was also an overall trend of decreasing benzodiazepine dispensing from This is noted separately due to differences in data collection over this decade, limiting the comparability with the later figures. However, if the data are viewed together, total benzodiazepine dispensing can be seen to have decreased by 51.3% from 1980 to UK literature on the prevalence of benzodiazepine misuse and dependence in the UK is currently limited. It includes studies measuring benzodiazepine use by attendees at drug treatment centres, measuring benzodiazepine prescribing pre and post hospital inpatient admission, and measuring GP benzodiazepine prescribing for individual practices or sections of the UK, but not eliminating those prescribed benzodiazepines for epilepsy and not measuring length of prescriptions or repeat prescribing. Some studies noted DSM diagnosis, but others did not directly explore patient experience or link prescribing with any diagnostic criteria for misuse or dependence. GPRD data can be used to analyse national prescribing by GPs. In this review, to illustrate the potential, we analysed the benzodiazepine data within an available sample of a large national cohort also prescribed opiate substitution therapy. Around half of all benzodiazepine prescriptions coincided with an episode of opiate substitution treatment (methadone or buprenorphine). The vast majority of prescriptions for benzodiazepines in this GPRD data set were prescribed as part of a series, rather than as a stand-alone prescription. The median length of a benzodiazepine prescribing episode (series of prescriptions) was 29 days, so only marginally exceeding the maximum timeframe recommended by the NICE guidelines (National Institute for Health and Clinical Excellence, 2004; 2011). However, 35.3% were prescribed for more than 8 weeks. Higher proportions (over 50%) were prescribed treatment episodes lasting more than 8 weeks in the subset of patients who were prescribed benzodiazepines at the same time as receiving a methadone or buprenorphine maintenance prescription. In this cohort, we also found the proportion of co-prescribing in this population varied little over the seventeen years studied ( ), despite an overall decrease in benzodiazepine dispensing in the general population at this time, (while noting the limitations in comparing these two data sets). Prevalence of z-drug misuse and dependence Dispensing data show an increase in the dispensing of z-drugs at England-level across the 19 years from 1991 to The increase in z-drug dispensing does not precisely mirror nor 8

9 proportionally reflect the decrease in hypnotic benzodiazepine dispensing, since the latter occurs at a steeper rate. Thus there is a decrease in total hypnotic dispensing across this time frame. Figures of z-drug dispensing are very low prior to 1991, in keeping with the marketing authorisation dates in the UK. UK literature on the prevalence of z-drug misuse and dependence in the UK is currently very limited, including a small case series, a study measuring z-drug use by attendees at drug treatment centres, and a study measuring GP hypnotic prescribing (of which z-drugs were 30%), but providing no specific information on z-drug prescribing, such as length of prescriptions or repeat prescribing. GPRD data can be used to analyse national prescribing by GPs. In this review, to illustrate the potential, we analysed the z-drug data within an available sample of a large national cohort also prescribed opiate substitution therapy. Around half of all z-drug prescriptions coincided with an episode of opiate substitution treatment (methadone or buprenorphine). However, some of these prescriptions represent multiple prescriptions for the same individual more than once. If we look at individual patients, we see much lower rates (18.9%) of co-prescribing of opiate substitution therapy with z-drugs. The vast majority of prescriptions for z-drugs in this GPRD data set were prescribed as part of a series, rather than as a stand-alone prescription. Over 65% of prescribing episodes lasted no more than 4 weeks, in keeping with the guidelines and SPCs, but prescribing in one third of cases was outside the guidelines. In the subset of patients who were co-prescribed methadone or buprenorphine, an even higher percentage (43.5%) were prescribed z-drugs for periods exceeding 4 weeks, contrary to the SPC of each z-drug. However, across the 17-year period for the whole cohort, prescribing at the 1-4 week range proportionally increased while prescribing across the 4-8 week period decreased, suggesting a move towards prescribing for no more than 4 weeks, in keeping with the SPCs of each z- drug. Longer-term prescribing, however, of more than 8 weeks, has shown no consistent decrease or increase across the 17 year period, fluctuating around the 20% mark. Prevalence of misuse of and dependence on over-the-counter codeine-containing products An extensive literature search revealed only a small proportion of studies relating to codeine-containing OTC misuse in the UK, with supporting, but not directly comparable, evidence from the US on OTC medicines and prescription opioid-containing analgesic misuse from the US. One UK study suggested awareness among the UK population of the potential for misuse of and harm from OTC medicines. The UK published literature also highlighted pharmacists consistent reports of concern about misuse of OTC medications, including OTC codeinecontaining medicines. PAGB data showed total sales of OTC codeine-containing medicines in the UK of between 19.5 and 22.5 million packets (of varying sizes) from , with around 11 codeinecontaining OTC tablets sold per year per head of the population in

10 There is no increase in total sales of codeine-containing OTC products from 2007 to However, from this limited data set (three years) it is not possible to establish a clear picture of sales trends. There is a need for further sales data to explore whether sales may have plateaued in recent years. A small number of individual case studies are reported on in the literature of unintentional dependence developing with use of codeine-containing OTC medications, initially used asdirected. However, a more objective measure of the prevalence of the unintentional and intentional misuse of and dependence on codeine-containing or more generally opioid-containing OTC medicines in the UK is not yet available. Review of effects of benzodiazepines Benzodiazepines used to treat both anxiety and sleeping disorders worsen motor skills, attention and memory. The impairment is related to dose, age and compound, for example higher doses and older age revealing more general impairment, and lorazepam causing more memory impairment. The risks of accidents and injuries both at home and while on the road are also increased. The risk of overdose when benzodiazepines are taken alone is very low and can be reversed by flumazenil. The risk of fatal overdose is increased in those using high doses of benzodiazepines in combination with heroin. Gradual termination of benzodiazepines results in improvements in performance. Complete recovery to levels of non-users does occur a few years after stopping. Review of effects of Z-drugs In general all three z-drugs result in fewer hangover effects than benzodiazepine sleeping tablets. Hangover effects are related to length of drug action and the shortest acting sleeping tablet, zaleplon, has minimal adverse effects. Clinical experience with zaleplon is limited compared to older compounds, since zaleplon has been available on the market for a shorter period of time. Review of effects of over-the-counter codeine-containing products Little risk results from the appropriate use of codeine-containing OTC preparations to treat occasional pain when taken as directed and in the recommended doses. 10

11 Long-term use or excessive doses can lead to dependence, increased headache and potentially severe reactions. Treatment and management benzodiazepine and z-drug withdrawal Evidence-based recommendations for management of the withdrawal of benzodiazepines can only be preliminary because of a lack of good research evidence. Discontinuation strategies for benzodiazepine and z-drug use should include tapering. Discontinuation strategies should be flexible but regimens beyond 6 months should be avoided, unless clearly clinically indicated. For patients who have tried but failed to withdraw previously, a 6-month schedule may be necessary. There is no good evidence to support the use of adjunctive medications for symptomatic treatment. Treating and reducing misuse of over-the-counter codeine-containing products Currently, there is very little evidence to guide treatment for over the counter codeinecontaining medication misuse or dependence. Detoxification, psychotherapy and motivational interviewing have been utilised in the few studies identified, but there is not yet a sufficiently rigorous research base to draw definitive policy-guiding conclusions. The 2009 Royal Pharmaceutical Society of Great Britain guidelines outlined good practice around the sale of non-prescription medicines including over-the-counter codeine-containing products to the general public. 11

12 1. Introduction and Background This present review describes: 1. The prevalence of misuse and dependence on benzodiazepines, z-drugs, and codeinecontaining over-the-counter medicines 2. The short- and long-term effects of their use and misuse, and 3. Interventions to manage and treat cases of misuse and dependence. It addresses these areas through a comprehensive review of the published literature and data description and analyses, and identifies important caveats in our current knowledge and evidence base. 1.1 Benzodiazepines Benzodiazepines are a group of drugs that enhance transmission of the inhibitory neurotransmitter gamma-aminobutyric acid, to exert their pharmacological properties as hypnotics, anxiolytics, anticonvulsants, and muscle relaxants (Wieland, 1992; Ticku, 1983; Petitjean, 2007). The British National Formulary (BNF) groups benzodiazepines into hypnotics, used in some cases for the short-term treatment of insomnia, and anxiolytics which can be effective in alleviating anxiety states (Joint Formulary Committee, 2010). The BNF lists nitrazepam, flunitrazepam, flurazepam, loprazolam, lormetazepam and temazepam as hypnotics, (flunitrazepam and flurazepam cannot be prescribed within the NHS); while a further three benzodiazepines, diazepam, oxazepam and lorazepam, are licensed for both insomnia and anxiety (National Institute for Health and Clinical Excellence, 2004). Also listed under benzodiazepines in the anxiolytic section are alprazolam and chlordiazepoxide (also listed as an adjunct in acute alcohol withdrawal). As noted in the BNF s list of indications and in the summaries of product characteristics, diazepam may be prescribed in a number of other scenarios, including as an adjunct in acute alcohol withdrawal, and in status epilepticus (Electronic Medicines Compendium. Summary of Product Characteristics, Diazepam). Anxiety and sleep disorders are common occurrences. According to the 2007 Adult Psychiatric Morbidity Survey of England, 4.4% of the population met diagnostic criteria for generalised anxiety disorder (GAD) in the week prior to interview, around 3.4% of men, and 5.4% of women (NHS Information Centre for health and social care, 2009). Sleep disorders are yet more common: Chronic insomnia occurs in about 10% of the general population, and about 20% of the over 65s (Ancoli-Israel, 2005; Lader, 2009). Following more than four decades of market availability of benzodiazepines as hypnotics and anxiolytics, and concerns since the 1980s about their dependence potential, patterns of benzodiazepine prescription in industrialised countries have indicated continued frequent use in medical practice. For example, benzodiazepine sales data in the late 1990s in Canada indicated 36 defined daily dose (DDD)/1000 inhabitants (Borgoño, 1999), while more recent Swiss figures estimate 43.3 DDD per 1000 inhabitants (Petitjean et al., 2007). Estimates of the extent to which these data may represent dependent or problematic use vary greatly with chosen methodology and agreed definitions, and are explored further in section 2.3 of this review, Those who develop misuse of, or become dependent on benzodiazepines on z-drugs may be subdivided into those who seek medical help during a period of anxiety or temporary 12

13 insomnia, but continue their prescription beyond the recommended timeframe or at doses outside the recommended range, or are maintained on this by their prescriber. The recipient of the hypnotic may or may not understand that its continued use, or increased dose could lead to dependence. This group is differentiated from a second population who actively seek the hypnotic for its intentional abuse as a sedative psychoactive drug. Members of this second group may be more likely to have a comorbid diagnosis of another substance-misuse disorder, and to derive their z-drug from varied sources a prescriber, illicit sales, or internet sites (Levine, 2007). Weizman et al (2003) quote a high lifetime prevalence of benzodiazepine dependence in the opiate-dependent population (in or out of treatment) ranging from 61 94% (Gelkopf et al., 1999; Iguchi et al., 1993; San et al., 1993; Darke et al., 1992). These two categories will not cover all cases. There also exist a group of those with substance misuse problems who may seek a short term prescription for sleep problems and may be given a z-drug rather than a benzodiazepine, but who are at greater risk of developing an additional iatrogenic abuse problem (Sikdar, 1998). In considering the effects, either group can be further subdivided. For example, those prescribed benzodiazepines by physicians may usefully be divided into younger and older adults, (for example, under and over 65 years), noting that both insomnia and benzodiazepine prescribing for insomnia increase with age (Lader, 2009; Petitjean, 2007), while there are also special concerns about adverse effects of benzodiazepines in this same population (Lader, 2009; Kamel, 2006; Bain, 2006). As in other areas of medicine, an understanding is important of both the intended potential benefits and the risks or possible side effects that benzodiazepines may incur if prescribed in any individual case. The short and long term effects of benzodiazepine use are described and referenced in section 3.1 of this review. As outlined in the introduction, this review addresses the changing use of prescribed benzodiazepines in England, reviewing published English and international evidence and available data to inform consideration of the extent of dependence and harm, and identifying gaps in the current evidence base. 1.2 Z-drugs The z-drugs (zaleplon, zolpidem, and zopiclone), developed more recently, were intended to overcome some of the reported disadvantages of benzodiazepines, such as next-day sedation, dependence, and withdrawal (Gibson, 2004), although the 2004 NICE Technology Appraisal did not find any firm evidence of differences in the effects of z-drugs and the shorter-acting benzodiazepines. The z-drugs comprise a group of three non-benzodiazepine hypnotics: zaleplon, zolpidem and zopiclone (the z-drugs). Like benzodiazepines they are agonists of the GABA receptor complex and enhance GABA mediated neuronal inhibition (National Institute for Health and Clinical Excellence, 2004). They differ from one another in terms of their elimination halflives and some of the details of their indications. Zaleplon has an elimination half-life of just one hour. It is licensed for the treatment of patients who suffer with initial insomnia (difficulty falling asleep), and is indicated only when the disorder is severe, disabling or subjecting the patient to extreme distress (National Institute for Health and Clinical Excellence, 2004). 13

14 The NICE guidance on the use of z-drugs for the short term management of insomnia (National Institute for Health and Clinical Excellence, 2004) notes that the concerns over dependence led the Committee on Safety of Medicines to recommend that the use of benzodiazepines for the treatment of insomnia should...not be continued beyond 4 weeks. In keeping with this, the summary of product characteristics (SPC) for each of the z-drugs advise that the duration of a single treatment episode should not exceed as 2-4 weeks, including tapering off where appropriate. The Summary of Product Characteristics (SPC) for zaleplon states that it should be prescribed for a maximum of 2 weeks (Electronic Medicines Compendium. Summary of Product Characteristics, Zaleplon). Zolpidem, with an elimination half-life of 2.5 hours, is licensed for the short-term treatment of insomnia where it is debilitating or is causing severe distress for the patient. The SPC for zolpidem states that the duration of treatment should usually vary from a few days to 2 weeks with a maximum of 4 weeks, including tapering off where appropriate (Electronic Medicines Compendium. Summary of Product Characteristics, Zolpidem). Finally, zopiclone has a slightly longer elimination half-life of hours. It is licensed for the short-term treatment of insomnia (including difficulties in falling asleep, nocturnal awakening and early awakening, transient, situational or chronic insomnia, and insomnia secondary to psychiatric disturbances) in situations where the insomnia is debilitating or is causing severe distress for the patient. The SPC states that long-term continuous use is not recommended, that a course of treatment should employ the lowest effective dose, and a single period of treatment should not exceed 4 weeks including any tapering off. The SPC also states that the duration of treatment should be 2 5 days for transient insomnia and 2 3 weeks for short-term insomnia, although these terms are not clearly defined (Electronic Medicines Compendium. Summary of Product Characteristics, Zopliclone). The SPCs for all three z-drugs carry warnings about their potential to cause tolerance, dependence and withdrawal symptoms (National Institute for Health and Clinical Excellence, 2004). To quote Malcolm Lader, Tolerance, rebound, dependence and abuse are all negative aspects of the use of hypnotics, and have excited much concern. (Lader, 2005); although...the abuse and dependence potential of zopiclone and zolpidem was also found to be...lower than for benzodiazepines. (Lader 2005; Johansson et al., 2003). As shown in figures 2.14, 2.18 and 2.19 of this review, there was a plateauing of z-drug dispensing from 2004 to 2005, but a continued increase in z-drug prescribing subsequently, (and a decrease in hypnotic benzodiazepine prescribing). A survey of GP attitudes at that time indicated a possible emerging belief of z-drugs as safer and more effective hypnotics than benzodiazepines (Siriwardena, 2006). A more recent, small (n=74) study by the same author reported that GPs favoured z-drugs over benzodiazepines, and favoured non pharmacological treatments of insomnia and anxiety even more highly - although were not necessarily implementing these in practice: despite respondents being negative to hypnotic prescribing overall they also felt pressured to prescribe by patients and tended to blame other GPs, secondary care providers and nursing homes for maintaining current prescribing practices. (Siriwardena, 2010). Other commentators have reported lower abuse liability for z-drugs over benzodiazepines (Nutt, 2005; Soldatos et al., 1999). As outlined in the introduction, this review addresses the changing use of prescribed z-drugs in England, reviewing published English and international evidence and available data to inform consideration of the extent of dependence and harm, and identifying gaps in the current evidence base. 14

15 1.3 Over-the-counter codeine-containing products Over the counter (OTC) medicines are those which can be purchased without a prescription. Legally there are two categories of over the counter medicines in the UK P, meaning that they must be sold by or under the supervision of a pharmacist; and GSL (general sales list), meaning that they can be sold from any pharmacy or non pharmacy outlet, off the shelf. Examples of medicines categorised as GSL include packs containing no more than 16 tablets of paracetamol (MHRA public assessment report, 2009). If codeine is included in the analgesic, in amounts up to 12.8mg per tablet for a two tablet dose, or if dihydrocodeine is included in amounts up to 7.46mg per tablet for a two tablet dose the medicine is classified as a P medicine (MHRA public assessment report, 2009); while at doses above this, codeine or dihydrocodeine-containing analgesics would be classified as prescription-only medicines (POM). Some OTC medicines can also be purchased. For the purpose of this review, where codeine-containing OTC medicines are referred to, this can be taken to also include those containing dihydrocodeine, unless stated otherwise. In some sections of the review, the phrase opioid-containing OTC medicines are referred to, where surveys and other studies have not made a distinction between codeine-containing OTC medicines and other opioid-containing OTC medications. Codeine is an opiate, derived from the opium poppy; and dihydrocodeine a semi-synthetic opioid. Both act at opioid receptors to exert their analgesic properties, as well as respiratory depression and euphoria, which are explored in the later section on short and long-term effects. Dihydrocodeine has an analgesic efficacy similar to that of codeine (British National Formulary 60) and is found in only one OTC medicine in the UK. Use of codeine and dihydrocodeine carries risks, including dependence, which again are explored further in section 3.5 of this review, on short and long-term effects of codeine-containing over the counter medicine use. Some of the studies on which we later report (Good & Ford, 2007; Hughes, 1999), describe two populations of those who become dependent on codeine-containing OTC medicines. The first group includes those with pain who begin by using the medication for the appropriate medical indication - either prescribed by a doctor or purchased from a pharmacy - but find that it does not adequately ease their discomfort when the medication is used in line with the instructions provided with the product, and so either intentionally or unintentionally exceed the recommended daily dose or use the medication for longer periods that indicated, (Roumie, 2004; National Council on Patient Information and Education 2002 and Heard 2006). Unintentional misuse may be due to poor awareness of the instructions (e.g. because of failing to read the instructions on the packet or because of insufficient advice from the pharmacist or healthcare provider). The second group includes those who are taking large amounts of codeine-containing medicines because they are opiatedependent. A proportion of this population could already be in contact with drug-treatment services and some of these could be in receipt of an opiate-substitute, prescription. However, others in this population will use solely (or mainly) codeine-containing OTC medicines and may never have presented to drug services (either because they do not wish to engage with services, or perhaps because they do not feel the available services will meet their needs). We may hypothesise also that a proportion of this group only attempt to purchase codeine-containing OTC medicines when they are withdrawing and unable to access their prescribed methadone or illicit opiates. Whilst it is helpful to consider the two main categories in considering appropriate responses, it is important to acknowledge that, at present, we do not have a clear idea of how many are in each group, and it is unlikely that all those with concerns about their use codeine- 15

16 containing OTC products fall into just these two categories. In sections of this review, we will address the changing use of over the counter codeine containing products in England, reviewing published English and international evidence and available data to inform consideration of the extent of dependence and harm, and identifying gaps in the current evidence base. 16

17 2 Prevalence of Misuse and Dependence on Benzodiazepines and z-drugs 2.1 Benzodiazepine and z-drugs: dispensing data Prescription information is taken from the Prescription Cost Analysis (PCA) system, supplied by the NHS Prescription Services of the NHS Business Services Authority, and is based on a full analysis of all prescriptions dispensed in the community i.e. by community pharmacists and appliance contractors, dispensing doctors, and prescriptions submitted by prescribing doctors for items personally administered in England. Also included are prescriptions written in Wales, Scotland, Northern Ireland and the Isle of Man but dispensed in England. The data do not cover drugs dispensed in hospitals, including mental health trusts, or private prescriptions. Prescribers are GPs, hospital doctors, dentists and non medical prescribers such as nurses and pharmacists, (and thus the vast majority of prescribers). Prescriptions are written on a prescription form. Each single item written on the form is counted as a prescription item. As cautioned elsewhere in this section, this means that one item may represent very different doses or periods of time to another item, (for example, a prescription for 10mg diazepam tablets taken more than once a day for several days, or a single 2mg diazepam dose). PCA data were provided for the purpose of this review covering the following years: 1. Full-year individually named benzodiazepine and z-drug community dispensing data for at strategic health authority (SHA) level Summary figures (NHS Information Centre Prescribing Support Unit reference no 3073) of all anxiolytics and hypnotics prescribed in the community in England over this nineteen year period. The data provided also shows the number of anxiolytic and hypnotic prescription items which are benzodiazepines and z-drugs. In both the data and the set Clonazepam and Clobazam were not included, since they are licensed for epilepsy and not for insomnia or anxiety. Although both may still be misused, since it is not possible to ascertain the indications for medications from the PCA data, it is assumed that in many cases these two benzodiazepines will have been appropriately prescribed long term in the management of epilepsy, so including them in the figures here would be misleading As noted in figure 2.19 in which the data are shown, data prior to 1991 are not directly comparable to the data after this time as prior to 1991 the PCA was restricted to prescriptions dispensed by community pharmacists and appliance contractors only and based on a sample of 1 in 200 prescriptions. The PCA system was extended in January 1991 to cover all prescriptions dispensed in the community. No information on why a drug is prescribed is available from this data set, nor information provided on individual doses, lengths of prescriptions, or repeat prescriptions. From the dispensing data it is also not possible to ascertain whether the dispensed medications were 17

18 used as directed, or misused, used at all, or used by the correct person. There may be cases where dispensed medication has not been used at all by the patient. There may also be case where prescribed medications have not been dispensed, so the PCA figures do not inform us directly about prescribing activity, nor use. It is also impossible to ascertain from these data whether the patients meet any diagnostic criteria for dependence. There may be case where prescriptions written have not been dispensed or used by the patient. However, the 30 year data set provides visual illustration of the dispensing trends across this period, shown in figures Figure 2.11 illustrates the dispensing of the most commonly dispensed benzodiazepines at England-level over this three-year period, while figures 2.12 and 2.13 illustrate comparative dispensing rates in two randomly selected SHAs, to illustrate dispensing at a more local level, for the most commonly prescribed of both groups of hypnotic medications - the z-drugs and the hypnotic benzodiazepines. In keeping with the PCA system and BNF classification for hypnotics, (section of the BNF), diazepam and lorazepam have not been repeated in the hypnotics section, and are recorded in the anxiolytics data. Comments on trends where there are only three data points should be viewed with caution, but here they can also be viewed alongside the larger data sets shown in figures We see in figure 2.11 that diazepam dispensing at the smaller doses appears to have increased, This may be explained by diazepam s role in substitute prescribing, described in section 4.2 of this review, although without information on indications for prescribing any such explanations can only be speculative. Notably, dispensing of diazepam at the higher dose (10mg) has not shown any increase. In figure 2.11, there is a pattern of increased dispensing of zopiclone across the three-year period from , with a decrease in temazepam dispensing, especially at the more commonly prescribed 10mg dose. While it should be noted that the data provide figures on dispensing, rather than direct prescribing figures, the trend provides an indication of a pattern of prescribing. If viewed independently of the preceding years, this appears not to be consistent with the 2004 NICE guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia. The NICE guidance compared the clinical and cost effectiveness of the Z-drugs with benzodiazepines approved for the treatment of insomnia and concluded with the recommendation that the drug with the lowest purchase cost be prescribed (National Institute for Health and Clinical Excellence, 2004). As described in detail in section 3.3 of this review, this NICE guidance has been heavily criticised by a group of experts in a series of journal contributions which may explain the dispensing trends seen here. However, the longer term trends shown in figures 2.14 and 2.19, showing benzodiazepine and z-drug dispensing across the last 3 decades, do suggest impact by the 2004 guidelines, as described below. 18

19 Figure 2.11 The most commonly dispensed benzodiazepines at England-level (Prescription Services Division of the NHS Business Services Authority) Figure 2.12: The most commonly dispensed hypnotic medications in the London Strategic Health Authority (Prescription Services Division of the NHS Business Services Authority) 19

20 Figure 2.13 the most commonly dispensed hypnotic medications in the Yorkshire Strategic Health Authority (Prescription Services Division of the NHS Business Services Authority) 20

21 Figure 2.14: Prescriptions Dispensed in the Community in England from 1991 to 2009 (Prescription Services Division of the NHS Business Services Authority) The data shown in figure 2.14 above are broken down into four separate sections: Total anxiolytics and total hypnotics dispensed from 1991 to 2009, (figure 2.15 and table 2.11); Total anxiolytics and benzodiazepine anxiolytics (figure 2.16 and table 2.12); All benzodiazepines dispensed from 1991 to 2009 (figure 2.17 and table 2.13); and all hypnotics, including hypnotic benzodiazepines and z-drugs dispensed from 1991 to 2009 (figure 2.18 and table 2.14). 21

22 Figure 2.15: All Anxiolytic and Hypnotics Prescriptions Dispensed in the Community in England from 1991 to 2009 (Prescription Services Division of the NHS Business Services Authority) Year All Anxiolytics BNF All Hypnotics BNF (items (000s)) (items (000s)) , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Table 2.11: All Anxiolytic and Hypnotics Prescriptions Dispensed in the Community in England from 1991 to 2009 (Prescription Services Division of the NHS Business Services Authority) 22

23 Figure 2.16: Anxiolytic Prescriptions Dispensed in the Community in England from 1991 to 2009 (Prescription Services Division of the NHS Business Services Authority) Year All Anxiolytics BNF Anxiolytic Benzodiazepines (items (000s)) (items (000s)) , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Table 2.12: Anxiolytic Prescriptions Dispensed in the Community in England from 1991 to 2009 (Prescription Services Division of the NHS Business Services Authority) 23

24 Figure 2.17: Benzodiazepine Prescriptions Dispensed in the Community in England from 1991 to 2009 (Prescription Services Division of the NHS Business Services Authority) Year All Benzodiazepines items (000s) Hypnotic Benzodiazepines (items (000s)) , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Anxiolytic Benzodiazepines (items (000s)) Table 2.13: Benzodiazepine Prescriptions Dispensed in the Community in England from 1991 to 2009 (Prescription Services Division of the NHS Business Services Authority) 24

25 Figure 2.18: Hypnotic Benzodiazepine and Z-drug Prescriptions Dispensed in the Community in England from 1991 to 2009 (Prescription Services Division of the NHS Business Services Authority) Year All Hypnotics BNF (items (000s)) Z-drugs (items (000s)) Hypnotic Benzodiazepines (items (000s)) , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , Table 2.14: Hypnotic Benzodiazepine and Z-drug Prescriptions Dispensed in the Community in England from 1991 to 2009 (Prescription Services Division of the NHS Business Services Authority) 25

26 In figures we see: 1. An overall substantial decrease in dispensing of benzodiazepines at England-level across the 19 years from 1991 to As the figure shows, this is mostly accounted for by the decrease in dispensing of hypnotic benzodiazepines. 2. A less marked increase in dispensing of anxiolytic benzodiazepines and all anxiolytics from 1991 to The dispensing of anxiolytic benzodiazepines showed a small decrease in 2004, possibly accounted for by the publication of the NICE clinical guidelines on anxiety (NICE CG22 replaced in 2011 by CG113) in that year. These figures then re-increased from , despite the publication of the amended NICE clinical guidelines on anxiety in 2007 (NICE CG22 now CG 113), although in 2009 still not reaching the dispensing levels in 2003, prior to the 2004 decline. However, it is important to recall that the dispensing data show only a simplified representation of actual prescribing trends: we cannot deduce doses, frequencies, patterns of repeat prescribing, indications for prescribing, or anything of the patient experience from the dispensing data. Thus, the increase in dosing could, for example, represent prescriptions for lower doses or fewer total days being dispensed following more frequent doctor/patient visits and closer monitoring of the patient symptoms and experience by the doctor. Thus, this relatively small increase cannot be assumed to equate to increase prescribing from , or any other prescribing trends, as it only shows us a dispensing trend. 3. Across this 19 year period we see an increase in the dispensing of z-drugs. While remembering that dispensing and prescribing are not directly comparable, the dispensing trends shown here suggest that that a proportion of former hypnotic benzodiazepine prescribing may have switched over this time period to z-drug prescribing, with the latter overtaking the prescribing of hypnotic benzodiazepines in 2006, and continuing to increase thereafter. there is a clear flattening out of z-drug dispensing from 2004 to 2006, coinciding with the NICE technology appraisal on insomnia in 2004 (Technology appraisal TA77). 4. The increase in z-drug dispensing does not precisely mirror the decrease in hypnotic benzodiazepine dispensing, since the latter occurs at a steeper rate. Thus there is a decrease in total hypnotic dispensing across this time frame. Total hypnotics prescribed, having fallen from 1991, ceased to fall in 1996 (10, 555, 200 items dispensed), showing a small increase over the next seven years (10, 638, 800 items dispensed in 2003). Then in 2004, they decreased to 10, 520, 000 items dispensed less than the dispensing figures eight years prior), and continued to decrease over a two year period, before increasing again. 26

27 5. This drop from is mirrored by a decrease in dispensing of all anxiolytics and benzodiazepine anxiolytics, suggesting a measurable two-year impact by both the NICE 2004 anxiety clinical guidelines and the NICE 2004 insomnia technology appraisal. This does not appear to have been repeated by the reissuing of the anxiety guidance in 2006, although noting the limitations in equating dispensing data to prescribing trends have been mentioned already. Across this 19 year period, the dispensing of hypnotic benzodiazepines has shown a steep decline. Although not matched by anxiolytic benzodiazepines and z-drugs, the data suggest that the national guidance made a notable impact, with a decline or plateauing of dispensing across all hypnotics and anxiolytics from 2004 to However as cautioned throughout this section on the dispensing data, definitive conclusions about both prescribing trends, and use of the dispensed medication cannot be assumed from these data. One item may, for example, represent a prescription for 10mg diazepam tablets taken more than once a day for several days, or it may represent a one-off single 2mg diazepam dose. Two prescriptions of the latter would count as two items, yet would represent lower total doses, lower frequencies, and potentially more doctor-patient contact than the former, which would count as only one item. So, the data shown here, while showing dispensing trends across nearly two decades, offer only a simplified view, and if not interpreted with the aforementioned cautions in mind could give a misleading picture of the complex pathway from prescribing to use of these medications. Shown in figure 2.19 is further data provided by the NHS Information centre. The NHS Information centre noted that they have doubts about the quality of the data provided, and that they have not and do not use this dataset. As highlighted on the graph the data from prior to 1991 and from 1991 onwards are not directly comparable. In addition to the points noted on the graph, although items are defined in the same way across the three decades, the PCA data for are based on fees, whereas for 1991 onwards they are based on items. However, despite the differences in sampling these dispensing data further our picture of benzodiazepine and z-drug dispensing trends at England-level over the past thirty years. (The 2010 dispensing data, not available at the time of writing, are published by the NHS information centre in April 2011.) 27