Availability of Opioids for Cancer Pain: Recent Trends, Assessment of System Barriers, New World Health Organization Guidelines, and the Risk of Diversion

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Reprinted by permission of Elsevier Science Inc.: Availability of Opioids for Cancer Pain: Recent Trends, Assessment of System Barriers, New World Health Organization Guidelines, and the Risk of Diversion, by David Joranson. Journal of Pain & Symptom Management, Volume 8(6): 353-360. Copyright 1993 by the U.S. Cancer Pain Relief Committee.

Availability of Opioids for Cancer Pain: Recent Trends, Assessment of System Barriers. New World Health Organization Guidelines, and the Risk of Diversion

David E. Joranson, MSSW
Pain Research Group, University of Wisconsin Medical School, and World Health Organization Collaborating Center for Symptom Evaluation in Cancer Care, Madison, Wisconsin

Introduction

The World Health Organization (WHO) recommends a basic three-part strategy for developing a cancer pain relief program in a country: (a) the national (or state) government health and regulatory authorities should establish and support a policy that makes cancer pain relief a high priority in the health care system;¹ (b) the public, policymakers, and regulators should be informed that cancer pain can be relieved; health care professionals should be trained to manage cancer pain using the three-step ladder; and (c) analgesics, including opioids such as morphine, should be made available.² A demonstration project can be a useful tool for developing understanding and support for this strategy.³

Trends in Morphine Consumption

Oral opioid analgesics such as codeine, fentanyl, hydromorphone, morphine, and oxycodone are now considered to be the cornerstone of cancer pain management. Opioids such as these must be made available for medical use if a cancer pain relief strategy is to succeed. The WHO considers a country's morphine consumption to be an important indicator of progress to improve cancer pain relief.⁴

There is little or no use of morphine in nearly half of the countries in the world.⁵ Almost all morphine is consumed in developed countries. Trends in morphine consumption for medical purposes vary greatly, with recent increases in many countries and decreases in some others. The consumption of morphine for medical purposes throughout the world was low and stable for many years before 1984, when the WHO cancer pain relief program began. From 1984 to 1991, the global consumption of morphine increased by 272%.

In 1991, 57% of all morphine was consumed by the ten countries that have ranked highest in per capita consumption for a number of years. These are developed countries and include Australia, Canada, Denmark, Iceland, Ireland, New Zealand, Norway, Sweden, the United Kingdom, and the United States. In fact, the 20 countries with the highest per capita consumption of morphine are developed countries. Together, the top 20 countries account for 86% of the morphine consumed in the world. The remaining 14% of morphine was consumed in approximately 100 other countries that have the majority of the world's population.

Table 1 lists all countries that had an increase in morphine consumption from 1984 to 1991. Some developed countries that had low per capita consumption are now experiencing rapid increases, including Italy, Germany, Spain, Israel, France, Norway, Austria, Japan, and Finland.

Morphine consumption also increased in less developed countries, including China, Uruguay, Venezuela, Argentina, Zimbabwe, Romania, and Malta. Morphine has recently become available for the first time in Mexico, Vietnam, and India as part of these countries' efforts to make cancer pain relief a priority.^6-9 Efforts are underway to improve opioid availability in China and Indonesia. However, 60 countries reported little or no morphine consumption in 1991.

Table 2 lists the countries that had a decrease in the use of morphine from 1984 to 1991, including Hungary, Malaysia, Mexico, Cuba, Bulgaria, India, Nicaragua, Kenya, Albania, Zambia, and Bangladesh.

Barriers to Opioid Availability

International health and drug regulatory authorities have recognized that opioid analgesics are not sufficiently available for the treatment of cancer pain in many places throughout the world.^4,13 The International Narcotics Control Board (INCB), which regulates global production and distribution of opioids, has asked all countries to take steps to assure that opioids are available for pain management, particularly for cancer pain.¹³

A number of economic and historic factors contribute to the current lack of oral opioid availability. Many countries do not have the resources and health care infrastructure to produce and distribute medicines.⁴ Traditionally, the treatment of pain has not been as high a priority as the treatment of disease. Injectable morphine has long been recognized as a potent analgesic, but the broader realization that oral morphine is also very effective is more recent. Although the international narcotics control treaty has recognized for many years that opioids are indispensable in the management of pain, some countries have drug laws that prohibit or restrict the availability and medical use of opioids.¹³ In addition, misunderstanding and fear of addiction impede the rational use of opioids in cancer pain relief throughout the world.¹⁴

Assessing the Barriers to Availability

A suggested first step to improve the availability of opioids in a country is for a small group of knowledgeable and committed professionals to take responsibility for developing an action plan. A logical place to begin is to identify the barriers that exist in the national drug distribution system. The specific reasons for the poor availability of opioids may vary from country to country and from place to place. These barriers as well as their underlying causes should be carefully identified so that the limited time and energy of health care professionals can be focused efficiently on the actions that are necessary to correct the situation. A diagnostic instrument has been prepared to assist health professionals in a country to identify the barriers at different points in the drug distribution system, and to assess the relative importance of each (Table 3). Several individuals from the same country could complete the survey in Table 3 and then compare their ratings on each item. This information can be used to develop a working consensus on the most serious barriers. The usefulness of this instrument remains to be determined and comments would be welcomed by the author.

Countries	% increase	Actual increase (in kg)
Table 1 Countries with an Increase in Morphine Consumption, 1984-1991
Italy	3831	65=>2555
West Germany	1178	27=>345
Spain	969	16=>171
Israel	900	2=>20
France	807	27=>245
South Korea	725^a	3=>33
Norway	600	11=>77
China	575	4=>27
Iran	550	2=>13
Netherlands	476	29=>98
Austria	467	5=>51
Belgium	433	9=>48
Sweden	427	41=>216
Denmark	412	52=>266
Japan	411	44=>225
Greece	400	1=>5
Uruguay	400	1=>5
USA	369	719=>3373
Ireland	335	17=>74
Finland	300	3=>12
Philippines	300	0=>3
Yugoslavia	300^a	1=>4
Canada	300	163=>652
North Korea	300	0=>3
Egypt	300	0=>3
Switzerland	211	18=>56
Chile	200	1=>3
Iraq	200^a	0=>2
Saudi Arabia	200^a	1=>3
Vanezuela	200	0=>2
Romania	180	5=>14
Argentina	175	3=>22
Zimbabwe	175	4=>11
Portugal	150^a	14=>35
New Zealand	143	29=>71
South Africa	136	53=>125
Poland	124	25=>56
UK	123	605=>1351
Czechoslovakia	100	13=>26
Iceland	100	1=>2
Luxembourg	100	0=>1
Malta	100	0=>1
Syria	100	0=>1
United Arab Emirates	100	0=>1
Turkey	71	7=>12
Australia	62	174=>282
Colombia	50	6=>9
USSR	39	289=>402
Thailand	33	3=>4
East Germany	29^a	14=>18
^a1984-1990

Developing an Action Plan

After identifying barriers to opioid availability, an action plan must be developed to remove them. In general, this involves deciding (a) which government agencies or industries should be contacted, (b) with whom contact should be made, (c) who are the best people to make these contacts, and (d) what kind of preparation is necessary. These preparations can be aided by a new resource from the WHO Expert Committee on Cancer Pain Relief and Active Supportive Care, which has prepared a Guide to Opioid Availability. The purpose of the Guide is to assist health care workers and national regulators in their efforts to improve the availability of essential drugs, including the opioid analgesics that are preferred for cancer pain management.^15-17

The Guide has been reviewed by the INCB and a number of national drug regulators. It provides information about the requirements for opioid production and distribution that must be observed in making morphine and other opioids available for patients. These requirements are necessary to prevent drug diversion to illicit uses. It also discusses the cancer pain problem and the use of opioid analgesics, emphasizing that cancer pain can and should be relieved. The Guide outlines several key considerations, as follows:

Communication and Cooperation. The Guide promotes communication and cooperation between regulators, health care professionals, and pharmaceutical manufacturers. If the medical need for opioids is not being met, it may be because the authorities do not have up-to-date information about the cancer pain problem and the importance of using oral opioids. Health care workers may not be familiar with the requirements of international law to control the distribution of opioids. The Guide provides an overview of these subjects and encourages regulators and health care personnel to talk with each other and cooperate to assure that opioid analgesics become available for cancer pain relief, as is intended under international treaties. A listing of the national drug control authority in each country is available. ¹⁸

Understanding the Drug Control System. It is not well known among health professionals that the purpose of the Single Convention on Narcotic Drugs and the INCB is to assure the medical availability of opioids, as well as to prevent their diversion and abuse.¹⁹ Even though most countries have agreed to conform their laws to this treaty, the efforts of a national government to control abuse of opioids may have overshadowed the importance of assuring their availability for pain relief. It is important for health professionals to realize that most countries are parties to the Single Convention and that governments have, as a matter of international law, an obligation to make opioid analgesics available to meet medical needs.

Countries	% decrease	Actual decrease (in kg)
Table 2 Countries with a Decrease in Morphine Consumption, 1984-1991
Albania	100	1=>0
Bangladesh	100	7=>0
Kenya	100	1=>0
Nicaragua	100	1=>0
Zambia	100	2=>0
India	80	411=>83
Bulgaria	50	6=>3
Cuba	50	2=>1
Mexico	50	2=>1
Malaysia	33	3=>2
Hungary	15	13=>11

Under the Single Convention, it is the national (not international) government that determines the amount of opioid analgesics that can be imported or manufactured by the country. Annually, the national drug regulatory authority is to prepare and submit to the INCB an estimate of the quantity that the country will need for medical and scientific purposes during the next year. Although the INCB must confirm all national estimates, it is the responsibility of the national government to determine the medical need for opioids in its own country. Professionals who have information about the extent of the cancer pain problem and how cancer pain can be relieved using the WHO analgesic ladder can help regulators to understand the need to increase the national estimate for opioids. The government and pharmaceutical manufacturers must then arrange for the import or manufacture of a sufficient and reliable supply of opioid analgesics.

If a country's annual estimate proves to be inadequate during the year, the national authority may submit an amended estimate to the INCB. The INCB fully recognizes the need to increase the use of opioid analgesics and is able to confirm revised estimates quickly. When working properly, the international and national drug control system will allow the import or manufacture of a sufficient quantity of opioids to meet the demand created by prescriptions written for patients. Government regulations should not impede the smooth flow of opioid analgesics from suppliers to hospitals and clinics and, ultimately, to patients.

Regulation of Health Care Workers. Although the licensing requirements for physicians, pharmacists, and nurses will differ from country to country, the Guide to Opioid Availability recommends the following basic criteria:

Legal ability. Physicians and other health care workers as appropriate should be empowered by law to prescribe, dispense, and administer opioid analgesics to patients.
Accountability. Individuals who handle opioids must be accountable for providing them only for medical purposes. Opioids should be distributed only between duly authorized individuals. Opioids should be stored in secure places and appropriate inventory records must be kept. Accountability requirements should not be so burdensome nor penalties be so onerous as to discourage physicians from appropriate prescribing or pharmacists from stocking adequate supplies.
Prescriptions. A prescription for opioids must be in writing and contain at least the following information: name and address of the patient; date of issue; drug name, dosage strength and form, and quantity; directions for use; and physician's name, address, and original signature.

The Guide also discusses issues involving patient access to opioid analgesics, medical decision making, and the risk of addiction:

Patient access. Recognizing that countries differ in geography, resources, and health care delivery systems, it is nonetheless a goal to have opioids available in locations that will be accessible to as many cancer patients as possible.
Medical decisions. Decisions about the type of drug, the strength, number of dosage units, and duration of therapy are best made by medical professionals based on the individual needs of patients. These decisions should not be made by government regulation.
Risk of addiction. Physical dependence and tolerance are natural physiologic consequences of the presence of an opioid in the body, and commonly develop in patients when opioids are used to treat chronic pain. Health professionals and regulators should not confuse these phenomena with addiction, which is the compulsive, nonmedical, and harmful use of drugs for effects other than pain relief. Health professionals should also be aware of pseudoaddiction, a pattern of drug-seeking behavior of pain patients who receive inadequate pain management and that can be mistaken for addiction.²⁰ The appropriate response to pseudoaddiction is to improve pain management.

Table 3 Inventory of System Barriers to Opioid Availability 0, not a problem; 1, minor problem; 2, moderate problem; 3, serious problem; and (X), don't know
____ 1)	The country's resources for health care are fundamentally inadequate to support a program to make opioids available for cancer relief pain.
____ 2)	The medical use of opioid analgesics such as morphine is prohibited.
____ 3)	Although opioids are not prohibited, the government has not made arrangements for the import or domestic manufacture of the desired opioid analgesics.
____ 4)	The government's official estimate of medical need for opioids is insufficient to allow production of adequate supplies.
____ 5)	There are long delays in making the government decisions necessary to make opioids available.
____ 6)	Key decision makers lack awareness of cancer pain and rational use of opioids.
____ 7)	Key decision makers are overly concerned about drug abuse, addiction, or diversion.
____ 8)	Government controls over opioid manufacturing and distribution are not sufficiently developed or reliable to prevent diversion of opioid analgesics to illicit uses.
____ 9)	Pain management and palliative care is a low priority in the health care system.
____ 10)	The national government lacks a cancer pain relief policy or national medical guidelines on the rational use of opioid analgesics in pain management.
____ 11)	There is a lack of communication about the need for opioids for cancer pain between key groups including health care professionals, health policy makers, drug regulators, and drug manufacturers.
____ 12)	There is a lack of effective leadership from health professionals to make cancer pain relief a higher national priority.
____ 13)	Opioids are available but not the right ones that are needed, e.g., morphine and other opioids.
____ 14)	The amount of opioids, e.g., the number of milligrams or number of doses, that can be prescribed by physicians is restricted by law or regulation.
____ 15)	The amount of opioids that can be dispensed or stocked by pharmacies or hospitals is restricted by law or regulation.
____ 16)	Shortages or interruptions in opioid manufacture or distribution periodically restrict patient access to opioid analgesics.
____ 17)	Opioids are available but not in the needed dosage forms (e.g., oral).
____ 18)	Opioids are available but not for cancer pain.
____ 19)	Opioids are available but not for children with cancer pain.
____ 20)	Opioids are available but not for patients who could or do live at home.
____ 21)	Opioids are available but only in a few places (e.g., only a few hospitals).
____ 22)	There is an insufficient number of health care professionals who know how to manage cancer pain.
____ 23)	Too few physicians and pharmacists are approved by the government to prescribe and dispense opioid analgesics. Opioid analgesic products are too expensive.
____ 24)	Physicians are reluctant to prescribe opioid analgesics.
____ 25)	Nurses are reluctant to administer opioid analgesics.
____ 26)	Pharmacists are reluctant to stock or dispense opioid analgesics.
____ 27)	Patients are reluctant to take opioid analgesics.
____ 28)	Family members are reluctant about the patient taking opioid analgesics.
____ 29)	There is a lack of education and training opportunities in cancer pain management for health care professionals.
____ 30)	There is a lack of education about cancer pain management for patients.
____ 31)	There is a lack of education about cancer pain management for the public.
____ 32)	The cost of opioid analgesic products makes it difficult for patients or health care facilities to purchase them.
____ 33)	Other; specify:_________________________________________

Balancing Concern About Drug Abuse with Patient Needs

The Single Convention on Narcotic Drugs recognizes that individual governments have the right to be more restrictive if it is deemed necessary to prevent the diversion of opioid analgesics to illicit use. However, governments must continually balance the need for restrictions on prescribing opioids with the responsibility of providing pain relief to patients. The INCB has observed that, in some countries, fear of drug abuse has resulted in laws and regulations that unduly impede opioid availability:

Prevention of availability of opiates for medical use does not necessarily guarantee prevention of the abuse of illicitly procured opiates. Overly restrictive approaches may, in the end, merely result in depriving a majority of the population access to opiate medications.¹³

The WHO Expert Committee on Cancer Pain Relief and Active Supportive Care has commented on special multiple-copy prescription programs that are used by some governments:

The extent to which these programmes restrict or inhibit the prescribing of opioids to patients who need them should be questioned . . . Health care workers may be reluctant to prescribe, stock or dispense opioids if they feel that there is a possibility of their professional licenses being suspended or revoked by the governing authority in cases where large quantities of opioids are provided to an individual, even though the medical need for such drugs can be proved.⁴

Excessive legal constraints on the medical use of opioid analgesics for the treatment of pain is a topic of increasing discussion in the international pain management community, and efforts have begun to identify regulatory barriers.^21-26 The modification of drug regulations that inhibit pain management should be undertaken in cooperation with the drug regulatory authorities. This has begun to occur in some places.^27-31 The goal is to achieve a positive regulatory climate for the rational use of opioid analgesics to manage cancer pain.

The Risk of Diversion

Drug abuse is a reality throughout the world, and preventing diversion of drugs to illicit uses is a major responsibility of regulators and health care professionals. Consequently, health professionals should be prepared to demonstrate their willingness to comply with and promote reasonable safeguards against diversion.

The Wisconsin Model

What is the risk of diversion and abuse when the use of opioids for cancer pain increases significantly? Wisconsin is being used as a laboratory to evaluate this question in a developed country that has both a cancer pain problem and a drug abuse problem. The Wisconsin Cancer Pain Initiative, which was formed in 1986, became a WHO demonstration project because of its vigorous interdisciplinary and grass roots education program to make cancer pain relief a priority in the state's health care system. The Wisconsin Initiative has succeeded in focusing considerable attention on the rational use of opioid analgesics throughout the state.

The University of Wisconsin Pain Research Group, a WHO collaborating center, is monitoring the increasing use of morphine and is evaluating whether there is any increase in diversion in Wisconsin. From 1986 to 1990, the consumption of morphine in Wisconsin increased by 160% (from 421 to 1093 kg) and exceeded the US national average by 21%. Diversion trends are evaluated using statistics from the State Crime Laboratory. These statistics reflect the number of laboratory analyses conducted on drugs that are seized by police throughout the state. For prescription morphine, these were less than ten for any year during the period. The data for other prescription opioid analgesics such as codeine, hydromorphone, and oxycodone remain similarly low.

The State Crime Laboratory data have been a valid indicator of the trends in prescription drug diversion for more than 15 years in Wisconsin.³² For example, there were several hundred State Crime Laboratory analyses of prescription amphetamine and pentazocine products when diversion of these drugs was at its peak. Furthermore, admissions to drug-abuse treatment programs of individuals who were dependent on these drugs increased in the years when diversion was high. Subsequently, these data decreased to virtually zero as the sources of diversion were eliminated by a cooperative effort of government agencies and professional organizations.^32-34

The International Model

The International Narcotics Control Board has been monitoring the diversion of opioids to illicit use throughout the world for a number of years and has concluded that the system of diversion controls established by the treaties is working well:

Diversion of narcotic drugs from the licit trade into illicit channels remains relatively rare and the quantities involved are small in comparison with the large volume of transactions. That holds true for drugs in the international trade as well as in domestic wholesale circuits. ¹⁸

The experience of the international drug control authority and the Wisconsin model demonstrates that if there are reasonable controls over drug distribution, the use of opioid analgesics can increase significantly without a concurrent increase in opioid diversion and abuse.

Professionals involved in the treatment of cancer pain are urged to become familiar with the drug distribution system and to identify barriers to opioid availability. If no barriers are found, all energies can be dedicated to education, training, and patient care. If barriers are identified, health professionals should organize and work closely with regulators, policymakers, and pharmaceutical manufacturers to correct the situation so that opioid analgesics are available for cancer pain relief. Progress should be communicated to WHO's Cancer and Palliative Care Unit in Geneva.

Acknowledgments

Comments and suggestions from Robert T. Angarola, Esq., Charles S. Cleeland, PhD, Koli Kouame, Dra. Liliana De Lima, and Sandra Ward, PhD, and the assistance of Aaron Gilson, MS, and Heather Horn, MA, are gratefully acknowledged.

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