International Access to Therapeutic Opioids
James F. Cleary
Martha A. Maurer
S. Asra Husain
Over three decades ago, the World Health Organization (WHO) concluded that most pain due to cancer could be relieved if health professionals followed a simple medical treatment method called the three-step analgesic ladder, which recommends using various types of analgesics (including opioid analgesics), in combination with adjuvant drugs when needed, depending on the severity of the patient’s pain.1 This approach also has been recognized by the WHO as appropriate with HIV/AIDS patients experiencing pain throughout the disease.2
United Nations (UN) health and regulatory agencies have repeatedly appealed to governments and health professionals to cooperate in order to implement the WHO analgesic method and remove barriers that block patient access to opioid pain medications.3,4,5,6,7,8,9,10,11,12 Although drug regulations and opioid availability have improved in some countries, the vast majority of cancer and HIV/AIDS patients in low- and middle-income countries (LMICs), and many in high-income countries (HICs), still lack access to these essential medications.13,14 The inadequate access to opioids is further illustrated by the disparity in reported medical consumption of opioid medicines between HICs comprising a small proportion of the global population and the large and growing population of LMICs.15 With the shifting burden of cancer to LMICs,16 the public health problem of inadequate availability of pain medications and unrelieved pain is projected to become far worse.
The purpose of this chapter is to outline the body of knowledge and experience that is relevant to understanding and improving national opioid availability and patient access to controlled pain medicines. It is critically important for health care professionals and government drug regulators, as well as advocates involved in the area of palliative care and pain relief, to understand the policies that govern the use of opioid medicines and how they can impact medication availability and patient access to opioid medicines. This chapter begins with background about the importance of pain relief in cancer and HIV/AIDS control. Focusing on opioids indicated for the relief of moderate to severe pain (e.g., hydromorphone, fentanyl, morphine, oxycodone), this chapter discusses the designation of these opioid medicines as both essential and controlled by international authorities. The disparities in opioid consumption globally and regionally are detailed, followed by an overview of common barriers preventing the adequate availability and accessibility of opioid medicines. Lastly, the UN’s recommendations to address the barriers to opioid availability are described followed by a summary of recent initiatives to improve the availability and access to opioid medications.
Pain Relief Is Part of Cancer and HIV/AIDS Control
The global incidence and prevalence of cancer and HIV/AIDS is a public health problem of great concern. The WHO estimates that in 2012, approximately 14.1 million individuals were newly diagnosed with cancer and more than 8 million died from this noncommunicable disease.17 Experts predict that the cancer burden will increase by 70% in the next two decades, with major impacts on LMICs, where it is estimated that the majority of new cases and deaths from cancer, including children, will occur.17 The global occurrence of HIV/AIDS is also a public health problem of great concern. The Joint United Nations Programme on HIV/AIDS (UNAIDS) indicated that in 2015, 36.7 million people were living with HIV, and 1.1 million people died from HIV/AIDS.18
People with HIV/AIDS19,20 and/or cancer21,22,23,24,25 experience pain and a variety of other symptoms during the course of their disease that have a negative impact on their quality of life. Patients who are approaching the end of life are likely to experience even more severe symptoms,7,8,26,27 which include pain, anxiety, constipation, cough, depression, dyspnea, and nausea.1,7,8 Although it is necessary to address all symptoms, this chapter focuses on the need for adequate pain relief and access to opioid pain medications. In LMICs, most cancers are diagnosed in late stages of the disease,16,28,29 when people often experience severe pain.7,8,26,27
PAIN AND PALLIATIVE CARE
Palliative care, including the critically important component of pain management, is a model of care aimed at relieving symptoms of disease and its treatment and improving the patient and family’s quality of life throughout the course of the disease. The WHO has long recognized that relieving pain and other symptoms in cancer1 and HIV/AIDS2,30 is a necessary part of palliative care, including for children.31,32 In 2014, the Worldwide Hospice and Palliative Care Alliance and the WHO collaborated to produce the Global Atlas of Palliative Care at the End of Life, which examines the state of palliative care and hospice programs globally, quantifying the need for and availability of palliative care worldwide.26 They found that over 20 million people require palliative care at the end of life every year, with the highest proportion of adults in need of palliative care (78%) living in LMICs.26 Despite this great need, palliative care is underdeveloped in most of the world, and access to quality palliative care is very rare in LMICs.26
Palliative care and pain relief medicines should be available and accessible to all individuals who have pain and other symptoms.8,26 There is a strong international imperative that palliative care, including pain management, should be included in national cancer and HIV/AIDS control efforts. The WHO has repeatedly reaffirmed the necessity of including palliative care as a critical component of cancer or HIV/AIDS control efforts in a country.33,34 At the country level, national policies should provide a policy framework for developing and expanding health care services to reach patients who need disease treatment as well as relief of pain and other symptoms. Notably, in 2014, the World Health Assembly (WHA), for the first time in its history, adopted a palliative care resolution that urges member states to integrate palliative care into their health care systems, to improve training for health care workers, and to ensure that relevant medicines, including strong pain medicines, are available to patients.11
Opioids Are Essential Medicines and Controlled Substances
Guidance from the WHO dating back to 1986 acknowledges the need for a varied approach to managing pain, including nonpharmacologic therapies, and that not all types of pain will respond equally, if at all, to opioids.1 Indeed, there are many useful pharmacologic and nonpharmacologic therapies for treating cancer pain.7,27 And yet, opioid medicines, and in particular orally administered morphine, are regarded by international health experts as the first choice for relieving moderate to severe pain due to cancer.35,36,37 Since 1977, the WHO Expert Committee on the Selection and Use of Essential Medicines has designated morphine as an essential medicine for the treatment of cancer pain.38 According to WHO, essential medicines are those medicines that “… satisfy the priority health care needs of the population … are selected with due regard to public health relevance, evidence on efficacy and safety, and comparative cost-effectiveness.”39 By giving them this designation, the WHO is asserting that these medicines “… are intended to be available within the context of functioning health systems at all times in adequate amounts, in the appropriate dosage forms, with assured quality and adequate information, and at a price the individual and the community can afford.”39
In 2012, at the request of the WHO, the International Association for Hospice and Palliative Care (IAHPC) led an expert group to develop a summary of the evidence available for essential medicines for palliative care. As a result of these recommendations, the WHO’s 18th Model List of Essential Medicines published in April 2013 contained a new section specific to palliative care, which included both immediate- and sustained-release morphine for the treatment of pain and listed hydromorphone and oxycodone as alternatives to morphine.40 The WHO’s 20th Model List of Essential Medicines published in March 2017 expanded the opioid medicines indicated to treat cancer pain to include transdermal fentanyl and methadone.41
In addition to being medicines that are essential for relieving pain, opioids have a potential for being misused or abused, which can result in harms. Therefore, they are designated as controlled substances by an international treaty, the Single Convention on Narcotic Drugs, 1961, as amended by the 1972 Protocol Amending the Single Convention on Narcotic Drugs, 1961 (Single Convention) (Fig. 16.1).42 The term narcotic drugs refers to a subset of controlled substances and is a legal term that will be used where the context requires. Nearly every government in the world has formally acceded to the Single Convention, thereby agreeing to adopt laws, regulations, and administrative procedures to carry out the dual aims of the Single Convention, which are to prevent the abuse and diversion of opioid medicines while making them available for medical purposes.
The Single Convention establishes an international framework of prohibitions and requirements for governments concerning the legitimate production, manufacture, and distribution of narcotic drugs that is intended to prevent illicit trafficking, nonmedical use of narcotic drugs, and diversion (the illegal movement of controlled medications from the licit distribution system into the illicit market). The principal international requirement is that the legitimate trade in narcotic drugs is regulated, including the cultivation of opium and manufacture of medicinal opioids such as codeine and morphine. To prevent diversion, an import-export system is established to limit trade to the amounts necessary for medical use; trade is regulated by the International Narcotics Control Board (INCB), an independent and quasi-judicial monitoring body to implement UN international drug control conventions.43
The Single Convention establishes several national obligations, among them that governments must regulate all entities that handle controlled substances. The goal is to create a closed distribution system, including security and record keeping. Only clinical professionals authorized under national law, using “medical prescriptions,” may prescribe and dispense controlled substances to individuals and only for medical purposes. Distribution outside of the regulated system is prohibited in order to prevent diversion of controlled drugs from medical to nonmedical uses. Efforts to prevent diversion should be balanced so as not to interfere in medical practice and patient care.4,10
 FIGURE 16.1 The United Nations Single Convention on Narcotic Drugs, 1961, as amended by the 1972 Protocol Amending the Single Convention on Narcotic Drugs, 1961. |
Examples of efforts to lessen the risks of abuse and diversion include clinical training of health care professionals and students regarding appropriate pain management as a means to reduce inappropriate use.6,44,45,46 Some countries have provided informational sessions for health officials and drug regulators when policies were updated to facilitate their knowledge of the new legal requirements.45,46 Some areas of India47 and countries such as Sierra Leone48 and Uganda49 have successfully increased the availability of morphine without experiencing diversion and abuse of these medicines; such activities require sound security, record keeping, and prescriptive practices.
GOVERNMENTS MUST ENSURE ADEQUATE OPIOID AVAILABILITY
In addition to controlling drugs to prevent their diversion and nonmedical use, the Single Convention stipulates a second obligation to ensure adequate availability of narcotic drugs for medical and scientific purposes. The Single Convention clearly recognizes the importance of narcotic drugs as analgesic medications and asserts that medical access to opioids for relief of
pain is to be assured by governments because they are obligated to conform their laws to the Single Convention, “… the medical use of narcotic drugs continues to be indispensable for the relief of pain and suffering and that adequate provision must be made to ensure the availability of narcotic drugs for such purposes.”42
pain is to be assured by governments because they are obligated to conform their laws to the Single Convention, “… the medical use of narcotic drugs continues to be indispensable for the relief of pain and suffering and that adequate provision must be made to ensure the availability of narcotic drugs for such purposes.”42
The availability obligation is no less important than the obligation to prevent diversion, but it is poorly understood and implemented by health professionals and governments. There is no indication that the medical value of controlled substances is lessened as a result of scheduling under the Single Convention. Scholars of international narcotic drug policy have concluded that the Single Convention, as amended, recognizes that the basic purpose of international drug control is to reduce the availability of drugs for nonmedical purposes but “that this should not affect or limit their therapeutic use.”50
The Single Convention establishes a critically important policy framework, the principle of balance, which asserts that governments’ obligation to control controlled medicines is not only to prevent drug abuse but also to ensure their availability for medical purposes.10 Controls aimed at preventing drug abuse and diversion must not prevent the adequate availability of opioid medicines for patients’ pain relief. Drug abuse controls that hinder opioid availability and patient access to effective pain treatment would be considered unbalanced and should be identified and corrected (Table 16.1).
To accomplish these dual objectives, the Single Convention requires that governments adopt laws, regulations, and administrative procedures to implement two specific mechanisms that are intended to ensure adequate availability of opioid medicines in countries while preventing nonmedical use. First, governments must annually establish an estimate of the amounts of opioids that will be required for all medical and scientific needs for the coming year.51 Licit trade in narcotic drugs can be lawfully conducted only within this amount. If imports exceed a country’s estimated requirements, exporters are obligated to refrain from further trade with the country, unless the INCB approves a supplementary estimate from the importing country that increases the estimated amount of the narcotic. Governments are encouraged to develop valid estimation methods, to establish estimates that take increasing demand into consideration, to cooperate with health professionals to obtain information about unmet needs, and to increase the estimate whenever necessary to always satisfy medical needs.51 Second, governments must report the amounts of each narcotic drug consumed (i.e., distributed to the retail level) to allow identification of consumption that either exceeds or falls short of the estimate.52
TABLE 16.1 The Central Principle of “Balance” | ||
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Each Party to the Single Convention is expected to establish a drug control program not only to prevent illicit trafficking and diversion but also to ensure the adequate availability of narcotic drugs for medical and scientific purposes4 and to designate an agency called the Competent National Authority (CNA) to implement the functions required by the Single Convention.43 This office is usually located in the pharmaceutical department of the Ministry of Health, the national drug control, or public security agency, or the functions may be divided between agencies. The CNA is the principal national administrative authority for carrying out the estimation and statistical reporting procedures that are necessary for ensuring that opioid medicines are adequately available for medical and scientific purposes. Guidelines for estimating the amounts of opioids required for medical and scientific use and for reporting consumption statistics are useful for those who want to understand the administrative procedures to be followed by CNAs.51,52,53 The INCB provides guidelines for CNAs to comply with the Single Convention, including the administration of effective mechanisms to ensure opioid availability.54
Disparities in Opioid Consumption
The Single Convention requirement that national governments report annual consumption statistics provides a unique source of data to describe global and national opioid consumption trends and to study disparities. Consumption means the amounts of opioid medicines distributed for medical purposes to the “retail” level in a country (i.e., to those institutions and programs that are licensed to dispense to patients, such as hospitals, nursing homes, pharmacies, hospices, and palliative care programs). The INCB uses consumption statistics to (1) monitor compliance of governments with the provisions of the Single Convention, (2) identify trade discrepancies between importing and exporting countries, (3) detect imbalances between quantities of medications available and disposed within a country, (4) identify trends in the worldwide availability of opioids and other drugs for medical needs, and (5) monitor and maintain a global balance of supply and demand of opioids for medical and scientific needs.52
Opioid consumption statistics have several useful applications for those who study and improve opioid availability to (1) identify whether a country has available opioids that can relieve moderate to severe pain, (2) learn whether the amounts indicate any substantial current consumption or progress over time,27 and (3) evaluate the outcome of efforts to improve opioid availability.
Consumption statistics provided in INCB reports have several limitations that should be considered when using them as an indicator of opioid availability:
In any given year, the data may be incomplete or invalid as a result of some governments reporting late, not reporting for a particular year or period, or submitting inaccurate data. These deficiencies may be corrected in subsequent years. Each year, the INCB publishes updated statistics for the previous 4 years of data which reflect corrections to previous reports and data submitted after the deadline.
The INCB’s published reports do not include the exact amounts of consumption for quantities less than 1 kg. Instead, the symbol “<<” is used to signify that a country reported between 0 and 0.499 kg, and consumption amounts between 0.5 and 0.999 kg are rounded up to 1 kg.55 Knowing the exact amounts of small quantities of controlled medicines consumed is particularly important for countries with small populations or those which have recently initiated efforts to increase their consumption of controlled medicines for pain or other health care needs.
Consumption statistics are reported as one aggregate amount of controlled substance consumed. Therefore, they do not provide information about
The proportion of the amount used for different clinical indications. For example, methadone is used to treat pain and dependence syndrome, and fentanyl is used for analgesia or anesthesia.
The location where the controlled substances are being used, such as hospitals and hospices, or
Which products or dosage forms of an opioid are available within a country (i.e., whether an opioid is in oral, parenteral, or transdermal form).
Consumption statistics are not a valid clinical indicator of the quality of pain control in a country.
Each year for nearly two decades, the Pain & Policy Studies Group/WHO Collaborating Center for Policy and Communications in Cancer Care (PPSG/WHOCC) has received from the INCB consumption data for six principal opioids used to treat moderate to severe pain (fentanyl, hydromorphone, methadone, morphine, oxycodone, and pethidine). The PPSG/WHOCC has developed an in-house global database of opioid consumption statistics and provides these data on its Web site (Table 16.2).
MORPHINE EQUIVALENCE METRIC
For decades, the WHO has considered a country’s annual consumption of morphine to be an indicator of the extent that opioids are used to treat severe cancer pain and an index to evaluate improvements in the capacity for treating pain.7,27 However, additional opioid analgesic medications and formulations such as fentanyl, hydromorphone, and oxycodone have been introduced in global and national markets over the past 30 years, which should also be taken into consideration when studying opioid consumption in a country, region, and globally.
In an effort to compare morphine consumption with the consumption of other opioids, the PPSG/WHOCC developed a morphine equivalence (ME) metric for five principal opioids used to treat moderate to severe pain: fentanyl, hydromorphone, morphine, oxycodone, and pethidine.56,57,58 A total ME statistic combines consumption of those opioid medicines into one metric. The conversion values were based on standard units of measurement for presenting drug utilization statistics from the WHO Collaborating Centre for Drug Statistics Methodology in Oslo, Norway.59 All ME statistics are adjusted for population, expressed in milligram per capita, allowing for cross-country or regional comparisons. These data are obtained directly from the INCB, thereby eliminating the small quantity limitation; however, the other limitations of opioid consumption statistics apply to the data expressed in the ME metric.
TABLE 16.2 Pain & Policy Studies Group/World Health Organization Collaborating Center for Policy and Communications in Cancer Care Opioid Consumption Data Resources | ||||||
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In a 2013 study, PPSG/WHOCC statistically examined the extent that morphine consumption reflected the aggregate consumption of all other opioids consumed on the global, regional and national levels, finding that over time, morphine has become less and less of a valid indicator of overall opioid consumption.60 Most recently, in 2014, PPSG/WHOCC conducted a descriptive analysis of opioid consumption trends,58 which is presented in the following section including the most recently available data from the INCB.
GLOBAL OPIOID CONSUMPTION TRENDS
The 35-year global opioid consumption trend ending in 2015 in Figure 16.2 shows that prior to 1986, morphine consumption was very low and stable throughout the world and was paralleled by total ME opioid consumption. After WHO announced its cancer pain relief three-step analgesic ladder1 in 1986 and encouraged use of oral morphine, morphine consumption began to increase with total ME consumption increasing more rapidly and diverging from morphine use. With the emergence of additional opioid products and dosage forms in the mid-1990s, total ME opioid consumption increased even more so that morphine use became less and less of a valid indicator of global opioid consumption. In 1986, global morphine consumption was 33% of total ME opioid consumption, compared to 12% in 2015. And yet, morphine has continued, until recently, to be designated by WHO as the primary essential medicine for the treatment of severe cancer pain. IAHPC included both immediate-release and sustained-release oral morphine in their recommended list of essential medicines for palliative care. Furthermore, several notable clinical guidelines continue to recommend morphine as one option for first-line treatment of severe cancer pain.36,61,62
Since the late 1990s, fentanyl and oxycodone accounted for the greatest portion of opioid consumption, at least for the global aggregate data. The global total ME opioid consumption trend mirrors the trend lines for oxycodone and fentanyl, which have been increasingly consumed throughout the world. The increasing clinical use of opioids other than morphine is reflected in WHO’s recent expansion of their Model List of Essential Medicines to include oxycodone and hydromorphone as alternative opioid medicines for treating cancer pain40 and methadone and transdermal fentanyl for the treatment of cancer pain.41 Fentanyl is commonly used intravenously in the perioperative period which may account for some of its increase.
Another noteworthy trend is the long-term decline in consumption of pethidine (meperidine), likely due to increasing recognition of the potential risks associated with accumulation of the toxic metabolite norpethidine. Pethidine has been used in many countries mainly by injection for postoperative pain because of a perception that its very short duration of action reduces the risk of dependence. Pethidine is no longer recommended by the WHO for the treatment of pain,63,64 although it continues to be used. Programs that move away from pethidine should ensure that other suitable opioids are accessible; if pethidine is available, there should be no regulatory barrier to this
transition, as pethidine and other opioids such as morphine are controlled in the same schedule and are typically subject to the same international and national controls.
transition, as pethidine and other opioids such as morphine are controlled in the same schedule and are typically subject to the same international and national controls.
 FIGURE 16.2 Global opioid consumption morphine equivalence (ME) (milligram per capita). |
DISPARITIES IN CONSUMPTION BY INCOME LEVEL
At the national and regional level, there are great disparities in the amount of morphine consumed between HICs and LMICs. The INCB has consistently reported that a small number of HICs consume most of the morphine in the world, whereas the remaining countries, which are composed of over 80% of the world’s population, consume a small fraction.6 A recent statistical analysis of opioid consumption over an 11-year period by the INCB found substantial increases over time and confirmed that HICs in North America, Oceania, and Europe accounted for the large increase in consumption, whereas LMICs experienced very little change in consumption levels.15
Regional Opioid Consumption Trends
ME opioid consumption trends for each of the six WHO geographic regions (Table 16.3) illustrate great variability in consumption in different parts of the world (Fig. 16.3), notably that opioid consumption tends to be significantly lower in regions predominantly composed of LMICs and higher in regions with many HICs. Throughout the 35-year period, the WHO region of the Americas (AMRO) had the highest consumption of all regions and was substantially higher than the global ME consumption. In 2015, AMRO ME consumption was more than 4 times higher than the global mean consumption (43.5 mg per capita). The WHO region for Europe (EURO) had the next highest consumption, which also consistently exceeded the global ME consumption over the years, followed by the Western Pacific region (WPRO), whose ME opioid consumption was lower than EURO but considerably higher than the other three WHO regions (EMRO, AFRO, and SEARO), likely due to the influence of the HICs in the region. The remaining three WHO regions (EMRO, AFRO, and SEARO) had substantially lower ME opioid consumption than the global mean throughout the period, and in 2015, their ME consumption represented 5%, 3%, and 1% of the global mean ME consumption, respectively.
Examining ME opioid consumption trends within each WHO region provides information about which opioids were available for the treatment of pain throughout the 35-year period.
WORLD HEALTH ORGANIZATION REGION FOR AFRICA (AFRO)
From the early 1980s to the late 2000s, the total ME consumption trend in the AFRO was largely composed of morphine and pethidine consumption with some minimal contributions of fentanyl and oxycodone (Fig. 16.4). Beginning in 2008, fentanyl ME consumption began to increase surpassing pethidine consumption. Following a spike in 2010, fentanyl ME consumption decreased but still remained higher than ME pethidine consumption.
WORLD HEALTH ORGANIZATION REGION FOR THE AMERICAS (AMRO)
Prior to the mid-1990s, the total ME opioid consumption in the AMRO was composed of a somewhat equivalent contribution of all the individual opioid consumption trends (Fig. 16.5). Beginning in the late 1990s, there was a notable and consistent increase in oxycodone and fentanyl consumption, while at the same time, morphine consumption increased steadily, and hydromorphone consumption rose notably beginning in the early 2000s. It is likely that opioid consumption in HICs in North America (e.g., Canada and the United States) primarily drives the regional consumption trend. Furthermore, as discussed earlier, the total ME consumption trend for the AMRO is the most similar to the global total ME opioid consumption trend. However, when considering the opioid medicines that individually contribute to the overall trend line, for AMRO, oxycodone consumption is the highest followed by fentanyl, and for the global trend, it is the opposite as fentanyl consumption is higher than oxycodone.
TABLE 16.3 World Health Organization Regions and Their Member Countries | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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