Regulating opioid prescribing to provide access to effective treatment while minimizing diversion: an overdue topic for research

The opioids are very effective in controlling acute and chronic pain of malignant and non-malignant origin [1]. The longer-acting oral opioids buprenorphine and methadone are also used to treat opioid dependence [2]. When given under medical supervision in a therapeutic setting, these longer-acting agonists have been demonstrated to reduce illicit opioid use, criminal activity, risks of overdose and blood-borne viral (BBV) infection and to provide opportunities for rehabilitation [2]. In developed countries, opioids for analgesia or dependence can be obtained only by medical prescription. This is intended to ensure their appropriate medical use, reduce the risks of iatrogenic dependence and fatal overdose and minimize their diversion to the ‘black market’ (in this instance, the sale of medications obtained from unregulated sources, such as other users or from drug dealers). The regulatory challenge with the prescription systems in these countries has been striking a balance between providing good access to opioids for analgesia while minimizing their diversion and abuse. This editorial identifies some priorities for research on the effectiveness and cost-effectiveness of different strategies for minimizing opioid diversion. We intend ‘diversion’ to cover the use of opioids for non-therapeutic purposes; we do not include patients' use of additional doses to supplement an inadequate analgesic or maintenance dose. We have made our task manageable by imposing the following restrictions on our scope. First, we have restricted our attention to the situation in developed countries such as Australia, the United Kingdom and the United States, where there has been some research on diversion. As we will see, there are major lacunae in research even in these countries; there is very little research on diversion in developing countries. Secondly, we recognize that prescribed opioids may find their way to the black market in a variety of ways [3] that may differ between countries. These may include, in addition to the diversion of prescribed opioids, purchases over the internet, pharmacy theft and prescription fraud. In this editorial, we focus primarily on opioid prescribing because this source of diverted opioids is the one most amenable to regulatory intervention. Historical experience indicates that prescribing can be a major source of diverted opioids for drug-dependent patients [4,5]. In Britain during the late 1950s and early 1960s good communication between illicit opioid users allowed a few prescribers, such as Lady Frankau, who prescribed 600 000 heroin tablets in 1962, to unwittingly supply hundreds of London heroin-dependent users [4]. Dr Frankau's injudicious prescribing seems to have been motivated by misguided therapeutic zeal. She was convinced that her prescribing benefited her patients because it reduced their need to use the black market, an aim she achieved by changing the addict's role ‘from customer to supplier’ ([4], p. 19). She acceded to her patients' requests because she was convinced that she could tell when they were lying to her. The testimonials of many grateful patients contributed to ‘an unshakeable confidence in the correctness of her methods and a haughty intolerance of other approaches’ ([4], p. 20). Similar prescribing habits informed by similar attitudes were revealed recently in the decision by the General Medical Council (GMC) to remove Dr Colin Brewer from the UK medical register [6]. Dr Brewer prescribed large quantities of opiates and other drugs to patients for maintenance treatment and do-it-yourself home detoxification. Like Lady Frankau, Dr Brewer was convinced that his clinical experience provided a better basis for prescribing than treatment guidelines. In his concluding statement to the GMC inquiry he continued to defend his prescribing practices and criticized as ‘bureaucratic’ the need to document his assessment of patients, his reasons for prescribing and his efforts to monitor patient compliance [7]. Overdose deaths are often the most obvious public health harm caused by diverted opioids. In Britain, methadone overdose deaths among polydrug users who were not in treatment comprised 50% of all opioid overdose deaths in Britain between 1985 and 1995 [8]. This compared with 20% of overdose deaths in Australia, where many more patients per capita were prescribed methadone, but where supervised dosing was much more widespread [8]. In 1996 the UK Department of Health recommended that methadone should be consumed under supervision to reduce diversion, something that had been standard practice in the United States since the 1970s. Some practitioners regarded this as an unwelcome intrusion upon their clinical autonomy, but recent surveys of practice suggest that despite this initial reluctance, in the decade since then prescribers have followed these (and subsequent) treatment guidelines. The result is that more opioid-dependent patients are now treated in Britain, with lower rates of overdose deaths and with more adequate maintenance doses of methadone and buprenorphine [9]. Recent US experience indicates that injudicious opioid prescribing by family physicians can also cause major public health problems. In the late 1990s and early 2000s there was a large increase in prescribing of sustained-release (SR) formulations of short-acting pharmaceutical opioids (such as oxycodone and morphine) for chronic pain by US primary care physicians. This more liberal prescribing produced an epidemic of iatrogenic opioid dependence among chronic pain patients, and increased the rate of opioid overdose deaths among others who used these drugs for recreational purposes [10–13]. The North American epidemic seems to have been driven by the diversion of SR opioids that were prescribed liberally by primary care physicians for broadly defined analgesic indications. The most popular of these products, OxyContin®, a sustained-release form of oxycodone, was approved by the Food and Drug Administration (FDA) as an ‘initial treatment for moderate to severe non-cancer pain’[11] on the mistaken ground that the SR formulation minimized the risks of diversion and dependence [11]. OxyContin® was marketed initially to oncologists, palliative care physicians and pain specialists for the FDA-approved indication. Primary care and family practitioners were encouraged subsequently to prescribe the drug liberally by pain management specialists, who participated in professional education programmes funded by the manufacturer [11]. The drug was also marketed directly to patients via videos and the internet using product information that downplayed the risks of opioid dependence (‘less than one in a thousand’ on the basis of data of doubtful validity). The product information also unintentionally alerted polydrug users to the drug's abuse potential by advising patients not to crush or dissolve the tablets because this released a large dose of the drug [11]. The effects of the more liberal prescribing of OxyContin® were observed first in areas where illicit opioid use was rare, such as the rural Appalachians [11]. Subsequently there was a large increase in opioid overdose deaths attributed to pharmaceutical opioids in many large cities across the United States [12,13]. The increase in the non-medical use of these opioids became common enough among adolescents and young adults to be detected in the Monitoring the Future and national household drug surveys [10,11]. Less dramatic increases have been reported in the use of diverted pharmaceutical opioids in Australia and Canada [14,15]. In the largest cities in Australia (Sydney and Melbourne), which have had a substantial illicit opioid (primarily heroin) problem for three decades, increased prescribing of SR opioids coincided with a marked decline in the availability of heroin [14]. The use of pharmaceutical opioids by Australian injecting drug users (IDU) has increased over the past decade in all states and territories, with use most prevalent in those jurisdictions that historically had the least dependable heroin supply [14]. The simplest and bluntest way to prevent abuse of prescription opioids is to reduce radically all prescribing by primary care and specialist physicians. This strategy reduces diversion but at the obvious and unpalatable cost of restricting opioid availability for legitimate medical use. The challenge is to find a mix of regulatory strategies that dampen the historical oscillation between overly liberal prescribing (with the attendant risks of iatrogenic dependence, diversion and fatal overdose), and overly restrictive prescribing that denies both adequate analgesia for patients with chronic pain and sufficient access to effective agonist maintenance treatment for patients who are opioid-dependent. A range of strategies is potentially available to reduce opioid diversion [1]. These vary as to whether the target for intervention is the prescriber or the patient and include: education of patients and doctors about the risks of diversion and misuse; better monitoring of duplicate prescriptions to detect lax prescribing and minimize doctor-shopping by patients; the use of urine screening to detect polydrug use among patients prescribed opioids; and enrolling opioid-dependent patients in oral agonist maintenance treatment. Potential technical solutions include developing less readily abused formulations of opioids (e.g. products that contain opioid antagonists that are activated only if the drug is injected) and SR formulations of longer-acting opioids that may be less likely to be abused [1]. There are insufficient data to assess the comparative effectiveness and cost-effectiveness of these strategies in minimising diversion. There are, however, some plausible hypotheses that can be tested in research. First, strategies that aim to identify patients at high risk of diversion or abuse are probably much more costly and likely to have a lower public health impact than strategies that identify liberal prescribers. This is simply because there are many fewer prescribers than patients—and prescriptions leave a paper trail that is easier to follow than patients. Secondly, recent British experience suggests that it may be more efficient to change prescribing practices by using guidelines than to rely on a slow and cumbersome professional judicial process (which took 2.5 years to reach a decision in the Brewer case). A disciplinary process is necessary to stop poor prescribing by individual doctors, but it probably cannot be relied upon to improve general professional standards. Thirdly, professional regulation may be more effective if it results in more immediate sanctions such as loss of entitlement to prescribe. In the United States, for example, the Drug Enforcement Agency has the power to remove physicians' rights to prescribe Schedule 2 drugs. This legal sanction may provide a more effective deterrent to liberal prescribing than the uncertain prospect of a finding of professional misconduct by a tribunal. The relative efficacy and efficiency of the different methods of policing prescribing employed in the United States and United Kingdom would be a suitable subject for comparative research. A critical requirement in improving regulatory systems is better data on the contribution that different forms of diversion make to non-medical opioid use in any country. There are plenty of anecdotes but surprisingly few systematic data, even in the United States [3], and these data are limited [1]. We need comparative studies between countries of: (i) the extent and principal means of pharmaceutical opioid diversion; and (ii) the public health consequences of diversion, such as individuals seeking treatment for dependence on pharmaceutical opioids, the prevalence of opioid pharmaceuticals in fatal overdoses, data on the availability and street prices for pharmaceutical opioids and the prevalence of their use among injecting drug users. This research can be conducted most easily in developed countries with good data on prescribing, vital statistics and substantial illicit opioid-using populations, such as Australia, Canada, the United Kingdom, the United States and, possibly, the Scandinavian countries. In the interim, we need clearer guidelines for primary care physicians on prescribing opioids for analgesia and opioid dependence, better methods of monitoring diversion in the population (e.g. by monitoring trends in the use of diverted pharmaceuticals among IDU [16]) and more timely methods of monitoring and, when necessary, reducing inappropriate opioid prescribing by physicians. The recent US experience with Oxycontin® suggests that we should be wary of encouraging all primary care practitioners to prescribe opioids. Primary care physicians should be able to prescribe opioids but only if they have been trained to prescribe appropriately, and they have ready access to specialist advice when they have any doubts about whether a prescription is appropriate. Thanks to the anonymous referees, whose comments very much improved our editorial, Sarah Yeates for her assistance in preparing the paper for publication and Briony Larance for her useful comments on a final draft of this editorial. The authors undertook research on opioid overdose deaths in the United Kingdom for the Advisory Council on the Misuse of Drugs inquiry into drug-related deaths in 1999. Louisa Degenhardt has received an untied educational grant from Reckitt Benckiser to investigate the diversion of buprenorphine–naloxone by injecting drug users in Australia.

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