Publications

Epidemiology of use and associations with HIV

Meth/amphetamine use appears to be increasing in many parts of the world, but many countries have scant or no data on the prevalence, routes and forms of meth/amphetamine use. On the basis of the evidence reviewed in this report, problematic meth/amphetamine use appears more prevalent in East and South East Asia, North America, South Africa, New Zealand, Australia and a number of European countries; use of meth/amphetamine appears to be currently less common in Central and South Asia, Latin America and the Caribbean, the Pacific, North Africa, some countries in Sub-Saharan Africa and the Middle East.

The prevalence of HIV and HCV among meth/amphetamine injecting drug users (IDUs) is poorly documented in almost every country, with data on meth/amphetamine injecting risk generally scant. Meth/amphetamine injectors and users are often younger than opioid users, so different strategies for targeting this group may be required. Some studies have suggested an increased likelihood of injecting risk and HIV seroconversion among meth/amphetamine injectors compared to injectors of other substances, others have not. More comprehensive data and research on this issue are needed.

Perhaps not surprisingly, given their younger age and the context of meth/amphetamine use for some users, high risk sexual behaviours have been documented as more common among this group. This provides an additional avenue through which HIV and other sexually transmitted infections (STIs) may be transmitted, and may be important where HIV transmission is occurring primarily through sexual contact and particularly among men who have sex with men (MSM). Research findings on the association between sexual risk and meth/amphetamine use are mixed, suggesting this is a complex issue that requires further investigation.

Other harms associated with meth/amphetamine use

A range of adverse consequences have been associated with meth/amphetamine use in addition to associations with HIV and STI infection. Among the acute physical effects are sweating, heart palpitations, headaches, tremors, and increases in body temperature^{1 2}. Adverse psychological side effects include restlessness, anxiety, dizziness, irritation, confusion and aggression. Cardiovascular toxicity and cerebrovascular toxicity can also occur.

Those who use the drug heavily over a period of time face the attendant risks of developing dependent use. There are also risks of meth/amphetamine induced psychosis, associations with violence and aggressive behaviour.

Problematic use tends to be concentrated within high risk groups in many countries; population prevalence estimates of past year use, derived from household survey methodologies, are therefore of limited usefulness for providing information about the extent to which meth/amphetamine use is causing harm in a given country.

Better monitoring of use, risks and harm among known at-risk populations is required. Most of what little we currently know about the associations between meth/amphetamine use and harm is dominated by research from higher income countries; how applicable this knowledge is to low and middle income countries is uncertain. Future work must address this gap, and we list some of the possible research areas later.

The importance of form and route of administration

Available data strongly suggest that both route of administration and form of meth/amphetamine are important factors affecting the nature and extent of associated harms. Given the limited data available, however, it is difficult to tease apart the relative contribution of these two factors and further work is needed. Other factors (such as dose) may also be important.

Although the focus of this report is on the injection of meth/amphetamine, ‘smoking’ is an important route of administration in countries where crystal methamphetamine is known to be available and is likely to be a problem (for example in Thailand, Australia and the United States). There is evidence that “smoking” crystal methamphetamine also carries particular risks and that there is an association between ‘smoking’ or ‘injecting’ crystal methamphetamine and elevated risk of dependence.

Although it is unclear to what extent crystal methamphetamine users who are ‘smoking’ the drug will make the transition to injecting, this transition may be more likely in countries where there is already an established population of injecting drug users (IDUs), and where access to smoking equipment is banned. It would be prudent to focus attention on countries where smoking methamphetamine is common, where dependent use has emerged, and where injecting of other drugs is becoming more prevalent (for example in South East Asia).

Possible responses

Supply reduction

Precursor control

In many, if not most, countries the first response to increased availability of meth/amphetamine by governments seems to be consideration of changes in the scheduling of precursors for its manufacture. The impact of domestic scheduling changes upon meth/amphetamine related harms has been evaluated in the United States with some evidence of a reduction following increased restrictions. Restrictions upon availability in one country often lead to a shift by manufacturers to obtaining precursor chemicals from alternative sources. For example, the effects of this change in the US have not been sustained, given that production increased in Mexico as a consequence of the US restrictions on precursors. Attempts to control supply may limit supply but are unlikely to significantly reduce availability or use as long as demand for the drug continues to be strong. Harm and demand reduction must play an important role in any attempts to address use and harm.

Laws related to drug possession or supply

There are little available data regarding the impact of changing laws surrounding penalties for possession of small quantities of meth/amphetamine. It is unlikely that increases in the severity of penalties for possession of meth/amphetamine will substantially reduce consumption (based upon prior studies examining cannabis use). There is a risk that such measures may further disadvantage users who are detected by police and who are likely to already be experiencing problems related to their drug use.

Demand reduction

Treatment of meth/amphetamine dependence

The successful treatment of drug dependence and reduced drug use are associated with a concomitant reduction in HIV risk and sexual risk behaviours. In addition treatment of drug dependence may improve access and adherence to HIV treatment for those requiring it.

A wide range of interventions have been examined for the treatment of meth/amphetamine dependence. At present there is no strong evidence of the effectiveness of agonist pharmacotherapies for meth/amphetamine dependence, and interest among meth/amphetamine users in current medications may be limited. The drugs used to date may be effective among a select group of people, and may be best used as an adjunct to psychosocial interventions rather than being a primary component of treatment. The potential use and benefits of agonist-pharmacotherapies warrant further investigation.

Some evidence exists that behavioural interventions are effective in the treatment of meth/amphetamine dependence. The approaches that appear to have the greatest promise include cognitive behavioural therapy and contingency management. Treatment manuals and guidelines for general practitioners have been developed and such resources should be promoted to service providers as they represent the synthesis of current evidence in this area.

Community education

In many countries so-called “fear campaigns” have been developed in response to meth/amphetamine and other drug use. The evidence for the effectiveness of such approaches is poor. Factually based and balanced messages are preferable, will be less stigmatising, and will avoid the tendency for messages to be accurately identified as biased or exaggerated by those with knowledge of the drug concerned.

Harm reduction

Injecting related harm reduction

Needle and syringe programmes (NSPs) have been shown to reduce HIV transmission and injecting risk behaviour. Current NSP models in countries where they have been established for some time appear to be less effective at engaging certain populations of IDUs, including meth/amphetamine IDUs. These users are unlikely to attend regularly such services, and are more likely to obtain multiple needles at a given visit, reducing the opportunities for engagement.

Investigation of alternative methods of service delivery including a greater emphasis upon peer models of engagement, and delivery of non drug-related harm reduction strategies might allow for both sex and injecting risks to be addressed. In countries where Internet access is high, delivery of brief interventions and harm reduction information electronically may provide some benefits to those unwilling to present to traditional drug treatment services.

Harm reduction strategies should be aimed at preventing the uptake of injecting as well as encouraging current IDUs who are unwilling or unable to stop to use non-injecting routes of administration. Recent evidence suggests that both frequency of injection and injecting risk are reduced if there is greater access to smoking equipment. Outlawing smoking equipment may have a negative impact upon this group by increasing the occurrence of injecting and consequently the risk of blood borne viral infection (BBVI). Provision of smoking equipment through NSPs should be considered as an additional harm reduction measure.

The risks of “smoking” crystal methamphetamine should be communicated to users in a balanced manner. The involvement of peers (i.e. other users) in the design and delivery of these messages is recommended.

Sexual risk reduction

High risk sexual behaviours are more common among meth/amphetamine users and constitute a further potential route of HIV transmission. It is not clear yet whether this link is predominantly causal or just an association. Interventions have been developed (largely in the United States) to reduce sexual risk behaviours with individual, community outreach, peer level, family and structural approaches. The authors of a recent review concluded that there are many areas in which research is still needed, particularly in resource-poor settings. Notwithstanding such gaps, there is a clear public health imperative to introduce programmes to reduce sexual risk behaviour including provision of condoms and accurate information as well as voluntary HIV counselling and testing.

Interventions to address HIV among meth/amphetamine IDUs

Interventions to address HIV among meth/amphetamine IDUs should be consistent with the Joint United Nations Programme on HIV/AIDS (UNAIDS) Comprehensive Package for prevention and care of IDUs. Integrated service provision should be a focus of both policy and treatment for those working with meth/amphetamine IDUs and those working in the HIV sector.

HIV treatment

Highly active antiretroviral therapy (HAART) should be available to meth/amphetamine users living with HIV. In low and middle income countries, access to such treatment is especially difficult and access to effective treatment for HIV is not universally accessible for persons with HIV, which includes those who are meth/amphetamine dependent. It is very likely that people who are HIV positive and are also meth/amphetamine dependent are less likely to receive HAART than those who are not meth/amphetamine dependent.

HIV positive persons who are also meth/amphetamine dependent should be encouraged to address their drug use, and offered help to reduce their drug consumption or become abstinent. Those actively using drugs should be offered treatment for HIV and clinicians should provide support to assist patients with adhering to medication.

Current World Health Organization (WHO) guidelines state that current meth/amphetamine users should receive HAART but should not be prescribed ritonavir or lopinavir/ritonavir. Further research investigating potential interactions between meth/amphetamine and antiretroviral (ARV) medication is needed.

Future research

There must be a concerted investment in research across all domains considered in this report. This research should be conducted in varying countries and particularly focused upon low and middle income countries where little is known, but use appears to be high. Research areas include but are not limited to (not in order of importance):

Collection of routine data on the route, form, frequency and quantities of meth/amphetamine use among users across countries.
Studies of HCV and HIV risk among meth/amphetamine injectors.
Better estimates of the population prevalence of dependence.
Studies of the natural history of meth/amphetamine use and dependence.
Careful research across countries and populations on the association of meth/amphetamine use with sexual risk behaviours.
Studies of the motivations and functions of meth/amphetamine use across countries.
Studies of the risks of meth/amphetamine induced psychosis and possible gene-environment interactions.
Prospective studies examining the magnitude and nature of risks of HIV and HCV infection faced by meth/amphetamine users/injectors across countries where the context of use and background prevalence of HCV and HIV differ.
Studies of the impact of HAART on injecting risk behaviours among IDUs.
Studies of possible meth/amphetamine-ARV interactions.
Research into interventions to address meth/amphetamine dependence, including concerted efforts to develop effective and attractive pharmacotherapies.
Research on methods of addressing sexual risk behaviours among heterosexual meth/amphetamine users in low and middle income countries.
Examination of better models of service delivery for meth/amphetamine users – both harm and demand reduction services.
In countries where Internet access is high, research into the use of the Internet to deliver brief interventions and harm reduction information.

Conclusions

Problematic meth/amphetamine use appears more prevalent in East and South East Asia, North America, Mexico, some European countries, South Africa, New Zealand and Australia. Good epidemiological data on the extent of the problem are disappointingly scarce. Ongoing monitoring of drug use among at-risk groups must occur, with a focus on form, route of administration, frequency and amounts used.

Both injecting and smoking pose a particular risk for meth/amphetamine dependence, and those who begin smoking the drug may switch to injecting after some time. The evidence on injecting risk behaviours was inconsistent. This review was unable to document the prevalence of HIV and HCV among meth/amphetamine users in most countries; some studies found a lower prevalence than for other groups of IDUs, but the evidence is far from conclusive. Much more work must be done in this area.

There must be a strategic and concerted drive towards completion of research on meth/amphetamine use, injection, dependence and the association with HIV. It is a much more widely used drug than heroin, yet the body of evidence on the issue is comparatively limited. There must be research conducted in low and middle income countries where use is more recently increasing, the context of use is likely to differ compared to high income countries, and where HIV transmission may be a particularly high risk for users.

Based on the existing data, sexual risk behaviours appear more common among this group, which poses risks for HIV and other STI transmission. Overly simplistic conceptions of the association between sexual risk and meth/amphetamine use are unhelpful as there are multiple factors that may account for the relationship. These issues require further attention.

Better strategies for engaging meth/amphetamine users with drug treatment and harm reduction services are needed. HIV treatment should be provided to HIV positive users, with appropriate handling of risks for drug interactions. More research is needed on effective treatments, but particularly into more attractive service models of consumer engagement.

A considerable investment should be made in research across countries to examine the context, risk and harm associated with meth/amphetamine use and injection, and effective interventions to reduce the attendant problems.

A note on terminology

This report uses a number of different terms to describe the problems associated with pharmaceutical use outside the bounds of a medical professional’s prescriptions. ‘Diversion’ describes the unsanctioned supply of regulated pharmaceuticals from legal sources to the illicit drug market, or to a user for whom the drugs were not intended. It does not refer to use of medications by a patient outside the doctor’s recommended treatment regime.

‘Misuse’ refers to the use of pharmaceuticals for purposes not in line with either medical or legal guidelines. Misuse, ‘non-medical use’ and ‘extra-medical use’ are often used interchangeably in practice. The term extra-medical use makes clear that use is without a prescription, but does not exclude the possibility that the user may have medically driven reasons for using the drug.

‘Harmful use’ refers to a pattern of drug use that is causing negative impacts upon health and may have negative social consequences. The term ‘abuse’ is not used in this report because of the ambiguity and negative connotations of this term.

Scope of this report

The focus in this report is on pharmaceutical opioids. Opioid dependence is a problem of considerable concern, and dependence through use of prescription opioids has increased in low and middle income countries as well as high income countries.

Injection of other pharmaceutical drugs is also worthy of investigation and future work might examine in detail the epidemiology of injection and harm related to these drugs. Injection of pharmaceutical drugs such as performance and image enhancing drugs (PIEDs) is likely to be concentrated among specific subpopulations in high income countries and to our knowledge, has not been noted as an issue in low and middle income countries. Although injection of benzodiazepines is associated with significant harm, it is thought to be typically concentrated among persons who are primarily opioid dependent.

The risks of extra-medical opioid use and diversion are acknowledged by multiple international organisations, including those which monitor pharmaceutical opioid availability, and those which address injecting drug use, HIV and the treatment of pain. All of these agencies also emphasise the importance of providing medical treatment for those who need it and are unanimous in assertions that pharmaceutical opioids must be made available for this purpose.

The 1961 Single Convention stipulates that although the provision of designated drugs (including morphine-like opioids) is restricted to prevent recreational use, their availability and supply should meet medical and scientific need. The International Narcotics Control Board (INCB) is required to report on the adequacy of availability of drugs covered under the 1961 Convention. This report summarises published data from the INCB Annual reports on the kinds of opioids available, and the extent of their availability adjusted for population size. There are massive inequities in the availability of pharmaceutical opioids for medical and scientific purposes across countries and regions, inequities that do not preclude misuse and injection occurring in many regions of the world.

There is a complex interplay of factors that appear to be linked to the extent of pharmaceutical opioid misuse and injection, and associations with HIV. This report attempts to highlight several that seem core: the extent of opioid availability – heroin and opium as well as pharmaceutical opioids; regulation of pharmaceutical opioids and their availability; the existence of established populations of injecting drug users, and of dependent opioid users; and the prevalence of HIV in different locations and within certain populations. Once illicit opioid use of any sort is established, and injecting occurs among some users, the extent to which HIV harm reduction interventions are in place – particularly needle and syringe programmes (NSPs) and opioid substitution treatment (OST) – may modify both the extent of injection of pharmaceutical opioids and of incident HIV cases.

This report provides an overview of the availability of pharmaceutical opioids and the evidence on the extent of misuse, diversion, injection and associated HIV. It is intended to stimulate further research into the many complexities surrounding this issue. There are huge gaps in our understanding of the extent of misuse, injection and attributable HIV transmission. Literature on the mechanisms and comparative risks of diversion, misuse and injection is also very limited.

The use of pharmaceutical opioids outside of prescribed bounds

There are numerous motivations for the extra-medical use, diversion and/or injection of pharmaceuticals. Not all extra-medical use is via injection. Some use pharmaceuticals for extra-medical purposes and take them orally and irregularly; these groups do not attract the attention of authorities and little is known about this use. Few population studies have been conducted looking at motivations for the extra-medical use of pharmaceuticals; most have examined motivations among injecting drug users (IDUs). Different responses will be required depending upon the reason for initiation and maintenance of use: not all misuse is occurring for the same reasons.

Different opioids differ in the extent to which they are likely to be misused. In large part this is because of their varying potency which is a key determinant of dependence potential. In the case of misuse or diversion for injection, different opioids will also vary in the likelihood of misuse depending upon how easily they can be injected (e.g. whether in injectable, tablet or patch form), and degree to which adverse effects occur following injection.

Availability plays an obvious role. It is affected by the extent to which clinicians can and do prescribe different opioids, and how easy they are to obtain from a health professional. Misuse and diversion will also depend upon the availability of illicit drugs, particularly heroin and opium.

Regular use of opioids (even in therapeutic applications) can lead to dependence, and this is one of the reasons that clinicians are hesitant to prescribe opioids for pain over extended periods of time. Dependence is more likely with higher doses consumed for longer durations. There is considerable debate about the frequency of dependence developing under usual clinical conditions.

Mechanisms of diversion

As with all psychoactive medications, opioid substitution and pain medications carry a risk of diversion. Diversion can occur anywhere along the wholesale to consumer chain. Few studies have attempted to estimate the relative contributions of different diversion sources to the pool of diverted medication; many discussions refer to long lists of potential mechanisms without attempting to prioritise their importance; others make strong claims about which are the most important sources of diversion without providing the data upon which such claims are made.

Although limits to supply of opioids may include the costs of these drugs and other structural factors it is clear that fears of diversion drive many countries’ policies around pharmaceutical opioids: a default position of limiting or precluding supply of prescription opioids for medical conditions appears to be the norm. This can have the serious consequence of depriving patients in need of access to essential medications that would be highly effective in treating them.

Such an approach also appears unsuccessful in avoiding diversion and injection. Even in countries where legitimate access is currently limited, epidemics of pharmaceutical opioid injecting and HIV transmission have been documented; this has occurred in a number of South Asian countries. When opioid injection of any kind is established, and HIV is prevalent, there is an additional public health imperative to introduce OST which has been demonstrated as an effective strategy in the prevention of HIV transmission.

More sophisticated and coordinated policy approaches can and have been developed. Key organisations affiliated with the WHO have been working successfully with several countries to ensure a more balanced approach towards supply and control of these medications.

Clinical uses of pharmaceutical opioids

There are two broad clinical indications for the use of pharmaceutical opioids: 1) management of pain that is often dichotomised as either acute or chronic, and as cancer or non-cancer related; 2) OST in the management of opioid dependence.

As outlined above, it is likely that some diversion of pharmaceuticals occurs at the level of importation or production, particularly in countries where there is only limited capacity to monitor this. In many countries, however, it seems reasonable to assume that the bulk of opioids that are diverted, or used extra-medically, are acquired from health professionals and patients. There are good reasons to assume, however, that the risk of diversion and misuse is not the same for all patient groups.

Harms associated with pharmaceutical opioid injecting

When medications are used outside the guidelines for safe and effective use, adverse effects are more likely, particularly those due to over-dosing. Additional risks are associated with the concomitant use of other substances, particularly sedative drugs, and in the presence of pre-existing conditions for which opioid use may be contra-indicated. The injection of pharmaceutical opioids also carries risks such as the potential transmission of BBVIs if injecting equipment is shared as well as harms related to injection of a non-sterile medication that is intended for consumption by other routes. The risk of developing opioid dependence (see below) may also be greater if used outside of or without medical oversight.

The literature on the magnitude of risk for HIV transmission among IDUs injecting pharmaceutical opioids is limited but there is reason for concern. We were unable to locate specific studies examining the relative risk of HIV transmission among IDUs injecting pharmaceutical opioids, but it seems reasonable to assume that in countries where most injecting drug use is occurring with pharmaceutical opioids, and where HIV transmission also occurs, that unsafe injection of these drugs is driving the epidemic.

Globally, between 5-10% of HIV infections result from injecting drug use (IDU), but in some countries in Asia and Europe, over 70% of HIV infections are attributed to IDU; in many countries in these regions, pharmaceutical opioids are commonly injected drugs. Of particular concern here is South Asia. Unsafe injecting drug use – including dextropropoxyphene and buprenorphine injection – is a significant issue in some countries in this region, and is also a significant cause of the spread of HIV. From such high-risk groups the virus is now reportedly spreading to non-injecting populations through sexual transmission.

Pharmaceutical opioid availability, extra-medical use, injection, and HIV

This report summarises pharmaceutical opioids available for the treatment of pain and for OST, from peer reviewed and grey literature, and using the INCB’s consumption estimates. INCB data are the only data collected internationally on pharmaceutical opioid availability. There is a range of issues that make it difficult to comprehensively evaluate adequate coverage of required medical needs or estimate the scale of misuse/diversion across different countries.

Data from extensive searches are presented on misuse and injection, and HIV among injectors of these drugs. In many countries there seems to be a reluctance to provide opioids for the treatment of pain and to a greater extent for OST. To provide insufficient pharmaceutical opioid coverage (for pain and illicit opioid dependence) is against the recommendations of international health and regulatory bodies. Such an approach also clearly fails to preclude misuse, diversion and injection.

Eastern Europe and Central Asia

In almost every country in the region, large populations of injecting heroin users have become firmly established, and HIV has become prevalent among these IDUs. Opioid substitution treatment is available in some but not all countries; in many places OST programmes that are available are limited in size and entry to these programs is difficult. Access to opioids for the management of pain appears to be limited in a number of countries in the region which would limit the availability of these drugs for extra-medical use. In some countries, there was evidence of injection of pharmaceutical opioids among already established populations of heroin dependent IDUs; in some cases this extra-medical use was occurring despite less than adequate provision of opioids for medical purposes.

In Belarus the injection of methadone is becoming increasingly common, however OST is not available in this country. Methadone is rarely diverted in the Czech Republic, but buprenorphine is frequently diverted, and in some locations is more commonly injected than heroin. Both drugs are available for OST, but buprenorphine can be prescribed by any general practitioner regardless of training whereas methadone is only available in specialist settings. In Georgia methadone is available as OST but buprenorphine is not; the injection of buprenorphine, believed to be diverted from nearby countries where it is legally available, has recently been reported as increasingly common among IDUs who perceive it to be a preferable alternative to heroin.

South Asia

In some South Asian countries there have been marked problems related to pharmaceutical opioid misuse and increasingly, injection, particularly in India, Nepal and Bangladesh. Some have suggested that a shift from heroin smoking to pharmaceutical opioid injection may have been related to reduced availability or increased costs of heroin at certain times, the low cost and easy availability of pharmaceuticals, and legal controls introduced in India to address heroin supply. The pharmaceutical opioids being misused in this region are typically lower potency opioids such as codeine, nalbuphine and dextropropoxyphene, in contrast to the pharmaceutical opioids being used by IDUs in other regions around the globe that include oxycodone and morphine, and high dose buprenorphine.

These problems have occurred despite very low levels of licit opioid medication consumption for medical purposes in this region suggesting that misuse has not been avoided simply through having limited supplies of the drug for medical purposes. Consistent reports indicate that prescribing for all types of pain is inadequate in this region; OST is available in some countries but much better coverage is needed, particularly since unsafe injecting is driving the HIV epidemic in some countries. HIV and HCV co-infection are common among IDUs in the region.

A recent UNODC report concluded that the diversion of pharmaceutical opioids for misuse and trafficking is occurring on a large scale both within and outside the region, primarily because of the limited enforcement of pharmaceutical regulations. It is thought that India accounts for significant large-scale diversion both within the country and to other countries in the region, and to countries further afield through illegal online pharmacies based in India.

East and South East Asia

In East and South East Asia, pain relief has been noted as “poor” with low availability of opioid medications, but some efforts are being made to increase coverage. Few reports of pharmaceutical opioid diversion or injection were noted, with the exception of Singapore. This was in contrast to the prominence of heroin as a drug of dependence in this region: all countries are close to the heroin producing region of the “Golden Triangle”. OST availability has traditionally been extremely limited, but concerted efforts have been made to establish and roll out OST in several countries, particularly China, Malaysia, Thailand and Indonesia.

Singapore had widespread and relatively poorly regulated availability of buprenorphine as an OST for heroin dependence, leading to a significant problem with injection of the drug, sometimes by persons who had been initiated to injecting with this drug. Rather severe restrictions were introduced in 2005 to address this problem, with removal of patients from this form of OST through detoxification. The impact of this has not yet been reported in the literature.

Caribbean

Coverage of opioids for medical purposes is clearly inadequate in many countries in this region. Governments are preparing legislation to improve the nature of controls over pharmaceutical substances: this includes the Bahamas and Dominica. Few data could be located on the extent of pharmaceutical opioid misuse, injection or diversion. Given the low levels of consumption it seems likely that the extent of pharmaceutical opioid misuse and diversion is not great, but there is a need for much better coverage of opioid medications for the treatment of pain and for OST.

This is particularly the case in Puerto Rico, where injecting drug use is a major cause of HIV transmission and heroin injection is the most commonly injected drug. The general population prevalence of HCV in San Juan is 6.3%, with estimates of 39% for heroin injectors. HIV incidence rates are much higher among IDUs in Puerto Rico than in New York, whereas methadone and HIV treatment coverage is much worse, although methadone has been piloted in prison settings.

Latin America

The availability of pharmaceutical drugs in general is poor in many countries of Latin America. In response to the high cost of drugs, some countries in the region have developed methods for encouraging generic brands of these medications and ensure swift registration.

Access to opioids for pain and drug dependence is inadequate; few mentions of pharmaceutical drug misuse in this region could be found, with most focus in this region being upon cocaine production, trafficking and use. Access to opioid medication is very low. A meeting of cancer pain physicians, researchers and government representatives over a decade ago considered the use of opioid medication in Latin America and concluded that opioids were severely underutilised for the treatment of cancer pain in all countries in the region because of cost, bureaucratic requirements that dissuaded physicians from prescribing stronger opioids, a clinical orientation to short term mild opioids for acute pain only, and limited training leading to fear of prescribing by doctors and failure to stock medications by pharmacists. Efforts have been made in some countries to improve inadequate standards of care for dependent drug users.

Use and injection of opioids in general (including heroin) is thought to be low in this region. The exception is Mexico, which has an established population of heroin users (and injectors), and is one of the heroin producing countries of the world. Heroin is the most common drug used by Mexican IDUs and increased poppy cultivation, greater security at the US border, and reduced prices may be related to the establishment of significant heroin use in the country. Risky practices among IDUs are reportedly high and risk perception is low; there are some indications that HIV prevalence may be increasing among this group, with estimates of 4% prevalence in 2003. OST treatment has been available in Mexico since 2001. No reports of pharmaceutical opioid diversion were located from studies of treatment or out of treatment drug users.

Oceania and the Pacific

Pharmaceutical opioid misuse was not noted as an issue in most countries in this region. This is almost certainly because of very minimal availability of these drugs for medical use. Most countries in this region have minimal levels of opioid consumption reported to the INCB. Two exceptions are Australia and New Zealand. These countries have comparatively high opioid consumption, including comparatively good levels of coverage for pain treatment.

In Australia, OST for the treatment of illicit opioid dependence is long-established and there is a high level of coverage of the opioid dependent population. OST is highly regulated and there is highly regulated availability of other opioid medications. OST is considered a “low threshold” treatment, in accordance with a policy designed to minimise harms associated with illicit opioid use. Markets for diverted opioids in Australia have been described as “small scale” and “disorganised” and seems typically to occur sporadically among established heroin injectors, and is probably related to the availability of their preferred opioid (heroin).

In New Zealand, misuse and injection of prescription opioids has been a more longstanding issue among established injecting drug users, related in part to the poor availability of heroin for many years as a result of the disruption of a major heroin trafficking ring in the 1970s. In 1990, 81% of opioid users presenting to a drug treatment clinic for treatment of their opioid dependence reported the injection of buprenorphine within the past month, and 68%, morphine. Following the introduction of buprenorphine-naloxone in 1991, among clients presenting for treatment, 57% were injecting buprenorphine-naloxone, with patients reportedly having learnt to inject buprenorphine-naloxone at doses and frequencies that would allow them to avoid withdrawal.

Canada, United States and Western Europe

In terms of extra-medical use, injection and diversion, the United States appears to have the largest per capita problem in the world. Even the INCB voiced significant concern about the extent of problems in the country. It accounted for half (49%) of the world’s estimated morphine consumption in 2005, despite only comprising 4.7% of the world’s population. Controlled-release oxycodone is widely misused, and the country accounts for 99% of the world’s consumption of this opioid. It was estimated in 2001 that prescription opioid misuse cost US$8.5 billion; given that problems seem to be increasing, the figure is likely to be much larger today. Dependence, non-fatal and fatal overdoses related to pharmaceutical opioid misuse continue to increase across the country, particularly oxycodone misuse. Methadone is increasingly being used for pain management, and the number of dosage units of the tablets used for pain increased by 277% between 2000 and 2005, as compared to a 163% increase in diskettes used both for pain and opioid treatment, and a 99% increase in liquid used in opioid treatment. Between 1999 and 2004, the number of poisoning deaths mentioning methadone increased 390%, while the number of deaths mentioning other opiates such as oxycodone and hydrocodone increased 90%.

Multiple formulations of varied opioids are available, and many appear easily obtained from general physicians for diffuse, non-specified pain conditions. It seems to be this feature of the US policy context that is in part related to the extent of the problem with oxycodone, but other important aspects played a part. The pharmaceutical company that manufactures the most popular of these products, OxyContin® (Purdue Pharma), aggressively marketed the drug as a treatment for both cancer and chronic non-cancer pain to oncologists, palliative care physicians and pain specialists, claiming it had a low dependence liability. In May 2007, the company agreed to pay $600 million in fines and other payments to resolve the criminal charge of "misbranding" its product; further lawsuits are currently underway.

In Canada, there has been sustained research and community attention upon the misuse and injection of pharmaceutical opioids among regular illicit opioid users, with evidence of increasing use and injection of pharmaceutical opioids, probably related to inconsistent heroin supply in most areas of the country. Despite this, population level data on illicit opioid use (including heroin) are limited. Data suggest that OST coverage in the country is around 23%, representing a very substantial increase relative to the poor availability of OST until a decade ago. There is no national monitoring system in place to track the diversion and extra-medical use of prescription drugs although district-level systems are in place.

In Western Europe, there is certainly less population-level consumption of these drugs compared to Canada and the United States, and it is not related to OST coverage; in many countries (for example, France) OST coverage is decidedly superior. Some countries had notably low levels of pharmaceutical opioid consumption, such as Albania, Andorra, Serbia, and Montenegro, and no data could be located on the existence or extent of misuse or diversion in these countries. There is a need for better coverage of OST in some of these areas however, given evidence of heroin dependence and HIV prevalence among these populations.

Misuse and diversion is occurring in Western Europe. Although very good monitoring occurs through the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), routine reporting does not appear to stress differentiation between heroin and pharmaceutical opioids. As a result it is not clear in some countries to what extent problems related to these pharmaceuticals are a concern. Future monitoring might separate heroin from other opioids.

In Finland there have been high levels of diversion of buprenorphine from OST for some years. In 2005, buprenorphine was the most frequently injected drug among IDUs attending an NSP (73%) and was reportedly commonly used to avoid withdrawal. Some evidence has suggested that it might be a more common problem among younger drug users. Since the introduction of buprenorphine-naloxone, many IDUs said that they had injected the drug (68%) but 80% of these users reported a negative experience; the street price of this formulation was also reportedly half that of buprenorphine. Overdose deaths are likely to involve buprenorphine but overdose rates are low.

In France a similar problem has been reported related to buprenorphine, but much of the misuse appears to be among users enrolled in OST, which is widely available and dispensed through pharmacies. A 1997 study found some evidence of a younger cohort of IDUs who only injected buprenorphine (not heroin or cocaine); compared to an older group who also injected these other drugs, they injected drugs more frequently and were more likely to be enrolled in buprenorphine treatment. There is evidence of doctor shopping and prescription fraud among OST clients: one study found two profiles for forged prescriptions: males under 45 years, presenting with stolen prescription forms and requesting opioids; and women aged over 45 years presenting with altered prescriptions for benzodiazepines or opioids.

Middle East and Northern Africa

Medication for severe pain is inadequate in supply in many countries in the region. According to the INCB, pharmaceutical preparations containing controlled substances are easily obtained on unregulated markets in this region, with considerable unregulated sale of pharmaceuticals over the counter without prescriptions occurring. Misuse of these preparations is reported to be taking place but no data were available to quantify this. Drug control legislation prohibiting such practices is in place in most countries, but it is often not adequately implemented and enforced. Due to insufficient funds, there is apparently a shortage of trained pharmacists and pharmacy inspectors in many African countries, which is often exacerbated by a lack of funds to fill vacancies. The INCB recently voiced concern about controlled drugs being sold via illegally operating internet pharmacies in larger cities. Data on the extent of this possible problem are seriously lacking.

Sub-Saharan Africa

Provision of pharmaceutical opioids for the management of severe pain is severely limited in this region and repeated calls are being made for dramatic changes to availability and use. There are significant structural barriers to the provision of medication in some countries, and doubtless fears of limited capacity to control diversion add to difficulties in achieving change.

An added issue is the fact that many African countries now serve as routes for the trafficking of illegal drugs, including heroin, through to the richer markets of Europe. It is likely that countries such as India may account for significant and/or increasing supply of diverted pharmaceutical opioids to this region, which needs to be addressed. The development of noticeable drug problems has been noted in multiple transit countries in Sub-Saharan Africa, with many countries unequipped with national policy frameworks to address these issues. Policies are being introduced across the continent to address illegal drug use and related harm. The development of populations of dependent heroin users is an issue of significant concern given the very high population prevalence of HIV already existing in the country. OST should be introduced as a matter of priority in countries where heroin injection has become an issue.

Discussion

Pharmaceutical opioids have an important role in the treatment of a range of medical and psychological conditions, but globally, they are inadequately prescribed for the conditions for which we know they are highly effective. Patients (particularly those who are terminally ill) should be given relief from severe pain; and OST should be introduced to help dependent users and avoid the significant risks of HIV transmission and other harm.

Diversion and injection of pharmaceutical opioids is occurring in many countries, but it is important to consider this within the context and the manner of licit availability. Considering the level of concern about its occurrence, there is comparatively little data with which to understand the extent and nature of extra-medical use in each country, but it seems reasonable to expect some level of diversion will occur. Monitoring of trends in South Asia and South East Asia is important – these countries are likely to account for the majority of users injecting pharmaceutical opioids. The evidence on associated harms of pharmaceutical injection is dominated by research in high income countries where use and diversion of pharmaceutical opioids probably differs from low and middle income countries.

On the basis of the current evidence, extra-medical use, diversion and injection of pharmaceutical opioids appears to be a significant problem for the United States, South Asia, South East Asia, and some Eastern European countries. The nature of the populations injecting these pharmaceuticals seems very different across countries. In India, for example, populations of IDUs appear to be developing dependent, injecting use of these drugs; in Australia, injection may be more common among IDUs whose preference is heroin and for whom injection is less frequent; in the United States, a generalised epidemic of pharmaceutical opioid use appears to have been driven by overly liberal prescribing for non-specific pain states, leading to a new cohort of dependent opioid users who may switch to injecting.

Different opioids have different dependence potential, and the forms available may also affect the likelihood of misuse and diversion for injection. There needs to be much more routine monitoring work conducted to provide data on the extent of the problem (or otherwise). There appears to be a general tendency for those opioids that are more available to be those which are more likely to be misused. If a range of pharmaceuticals is available, those which are more potent appear to be more sought after and misused. In countries where strong opioids are not available (e.g. India) other less potent opioids are still used and injected. Where pharmaceutical opioids (even less potent ones) are introduced without sufficient regulation, it seems that there is a risk of misuse and diversion (e.g. the United States and Singapore). The challenge is ensuring that such problems are addressed without implementing policy that is overly restrictive and ensuring that patients are not deprived of appropriate treatment.

In terms of injecting risk, the evidence on this topic is limited. Some studies have suggested increased injecting risk among pharmaceutical opioid injectors compared to other IDUs, others have not. The context of opioid use – whether it is among IDUs in contexts where OST is currently available, or whether pharmaceuticals are largely used by otherwise naïve IDUs – may be related to this. The prevalence of HIV and HCV among this group of IDUs is poorly documented in almost every country, except where these drugs are the major drugs of injection. The evidence on the magnitude of HIV risk associated with pharmaceutical opioid injecting – relative to other opioids such as heroin – is limited, although it may be lower if injection occurs less frequently.

Responses to misuse, diversion and injection should not further discourage what we know are inadequate levels of medical use of opioids for the treatment of pain. Unfortunately, there has been little research examining the relative benefits of different policy interventions, a gap that would benefit from systematic research examining different contexts and policy responses across countries, and there seems to be few cases where national policies spanning palliative care, HIV and AIDS, OST and other pain management have been produced. There is much that is not known about how, why, where and how much diversion is occurring.

For users who have developed dependent use, treatment should be provided: it has positive impacts upon illicit drug use, physical and mental health, and public amenity. OST is an effective HIV prevention strategy that should be considered for implementation as a treatment for IDUs with opioid dependence in communities at risk of HIV epidemics.

Regulatory responses
“Optimally-designed” drug diversion control programmes have three goals: a) limit access to only those with a legitimate need for the drug; b) track and identify cases where control over this access is compromised; and c) minimise the effect of these controls upon legitimate medical practice. These general principles must be used to produce a mix of strategies to apply to the context of a given country. The question is: how does a country balance the needs and risks?

International bodies can and do play an important role in determining pharmaceutical opioid availability. The INCB in particular can place pressure upon countries to increase or further regulate pharmaceutical opioid availability. They have urged many countries to make opioids more available for the effective management of pain, and this is an important change that must be made.

The INCB can also play an important part in ensuring the availability of opioids for OST where illicit opioid dependence has developed as an issue. Given the documented benefits of widespread OST implementation – reduced HIV transmission, reduced opioid overdose, improved wellbeing for patients and improved public amenity – there is a clear public health imperative for international agencies to assist countries to make OST available where it is required.

In many countries it may be appropriate to register a greater number of opioid medications for use. As the tables in this report showed, many countries not only have highly inadequate opioid supply, they also do not stock the medicines listed by WHO as essential in the treatment of acute and chronic pain. Fewer still stock the model medicines for treatment of illicit opioid dependence.

Pharmaceutical companies can play an important role in opioid pharmaceutical use and misuse. The US example of oxycodone highlights the very significant risk that unbalanced depictions of dependence risk, and overly generalised marketing to health professionals, may pose for populations that are predisposed to taking up medications for a variety of health conditions. One way in which availability needs to be regulated therefore includes monitoring of drug company promotion of pharmaceutical opioids to the medical profession and the broader community to ensure that appropriate use occurs.

Drug preparations and formulations

The pharmacological formulation of different pharmaceuticals may impact on their potential for misuse and/or injection. Approaches can include the addition of naloxone to deter injection, less injectable formulations, or formulations which prevent drug tampering. This avenue of research should be continued as a matter of priority for obvious public health reasons.

Not all people who inject drugs will cease injecting, even if pharmaceucitcal opioids are less amenable to injection. Some IDUs will inject formulations or preparations that are designed not to be injected. For IDUs who have not responded to standard oral OST and repeatedly struggle to remain in treatment, provision of injectable formulations such as morphine or heroin may represent an alternative treatment option and warrants further research.

Harm reduction

As described earlier in this report, OST reduces the level of HIV risks and HIV transmission and allows for stabilisation of persons who have already contracted HIV. OST can therefore be seen as an HIV harm reduction measure in addition to an intervention to reduce demand for diverted pharmaceutical opioids.

Needle and syringe programmes (NSPs) have been shown to reduce HIV transmission and injecting risk behaviour. Injecting equipment must be made available as a matter of priority in regions where access is currently limited, yet pharmaceutical opioid injection is occurring and HIV risk behaviours are common, such as South Asia.

Another issue is whether equipment that facilitates the injection of pharmaceutical preparations (e.g. pill filters, large barrels/needles and vein infusion kits) should be made available. Some have recommended reducing the availability of equipment for injection of formulations not designed for injection, such as methadone syrup. However, not all IDUs will cease injecting. In one study in Australia, among those IDUs who continued to inject methadone syrup after large-barrelled syringes and winged infusion sets (or ‘butterflies’) stopped being distributed by NSPs, there was greater re-use of injecting equipment; it was recommended that additional policy initiatives were required to further address this issue.

There is a tension between providing equipment that facilitates injection of these non–injectable drugs, and reducing overall injection at the expense of those who choose to continue doing so. It has been suggested that more comprehensive responses (including dilution of methadone syrup, for example) were required, since removing access to equipment for injecting methadone syrup clearly has not led to a complete cessation of injecting for some IDUs.

Particularly in countries where pharmaceutical opioid injection is occurring, attempts should be made to provide factual information to IDUs about the risks of injecting these medications, and ways in which harm can be reduced.

HIV treatment

Interventions to address HIV among those who inject pharmaceutical opioids should be consistent with the UNAIDS essential package for prevention and care of injecting drug users. The package includes:

Information, education and communication (IEC);
Full range of opioid substitution treatment options;
Implementation of harm reduction measures;
Voluntary confidential HIV counselling and testing;
Prevention of sexual transmission of HIV;
Access to primary heath care;
Access to antiretroviral therapy;
Promotion, protection and respect for human rights - and particularly anti-stigma and discrimination measures.

Those actively using drugs should be offered treatment for HIV, but clinicians should provide good support to assist clients with adhering to medication. Part of good clinical practice involves assessment for potential non-adherence and this should be conducted carefully. Adherence counselling should be a component of treatment.

Future research

There is an imperative for good research on this topic. Concerns about inappropriate responses to evidence of diversion and injection should not preclude research into this issue. Lack of data on the topic will only serve to maintain the status quo, which appears to be a tendency to limit availability of pharmaceutical opioids for medical and scientific purposes. Some areas of research include but are not limited to:
Systematic collection of detailed data on pharmaceutical opioid availability for medical purposes;
Regular collection of data on the extent and nature of extra-medical use of pharmaceutical opioids, including injection;
Studies examining the relationship between pharmaceutical opioid injection among injecting drug users and the availability of other illicit drugs;
Studies examining the reasons for pharmaceutical opioid extra-medical use and injection among users from different country contexts and different subpopulations of users within countries;
Studies examining the factors that maximise attractiveness of OST while minimising diversion risk;
Research documenting the prevalence of HIV and HCV among those who inject pharmaceutical opioids;
Research into formulations of pharmaceutical opioids that reduce the risk of injection;
Research into formulations of pharmaceutical opioids that pose less risk of harmful use;
Evaluation of national policies for regulation of pharmaceutical opioids in low and middle income countries;
Research to examine the feasibility and cost effectiveness of injectable forms of OST for those clients who have not succeeded in standard forms of OST;
Further research into the ways in which opioids can be used for chronic pain: which patients benefit from this form of therapy, and in which circumstances;
Research examining the influence of policy in both facilitating and restricting health promotion and harm reduction among those who inject pharmaceutical opioids;
Review of current national and international legislation through which pharmaceutical companies can be held accountable for policies and procedures that facilitate large- scale diversion of their products.

Conclusions

There are understandable reasons why clinicians and policymakers are concerned about overly liberal access to opioid medications that might place users at risk of developing dependence upon these drugs. It is abundantly clear, however, that the number of people who are not receiving effective medication for their pain (perhaps 10 million out of 20 million new cases of cancer each year, for example) is far larger than the population of persons with illicit opioid dependence. This means that a huge number of people are being denied effective treatment that has been described as “absolutely essential” by the World Health Organization.

Some diversion should be expected to occur when opioids are made available for medical purposes. That is not sufficient grounds for a priori refusal of treatment to all patients who would receive relief from pain. There is a great imperative for many countries to design effective systems for access to opioids for those who need them, ensuring that prescriptions are provided by those providing good clinical care, and without placing patients at undue risk of developing dependent use of these drugs.

Further research must be conducted into the many complexities surrounding this issue. There are huge gaps not only in our understanding of the extent of misuse, injection, and attributable HIV. We need to know more about why misuse occurs, particularly in countries where it has begun among previously opioid naïve users. The literature on the mechanisms of diversion and comparative risks of diversion, misuse and injection is also very limited. Until further data are produced, fear of diversion will probably continue to dominate policy decisions, efforts to control diversion will be misdirected and lead to overly restrictive control of supply, prescriptions for legitimate medical conditions will continue to be inadequate, and yet diversion will continue.