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Cancer Pain Relief, Second Edition, With a guide to opioid availability, World Health Organization, 1996. [Ordering information] A portion of this publication, the guide to opioid availability, appears here with the permission of the World Health Organization. All rights reserved.
Background
New knowledge, new hope
Impediments to cancer pain relief
The WHO strategy
Difficulties in obtaining opioids
The participants in the drug distribution chain
Description and purpose
Exceptions
The drug distribution system
National estimates of medical need for opioids
Communication between health personnel and regulators
Obtaining a supply of opioids
The reporting system
Is the international system working?
Drug abuse versus patient need
Suggested guidelines for regulation of health professionals
This part explains the system by which morphine and other opioids are made available to patients who need them. It is intended for use by both drug regulators and health care workers and to promote communication between the two groups. Opioid availability is discussed in the context of the problem of cancer pain and international efforts to address it. A number of the terms used in what follows are defined in Annex 1.
The text has been reviewed by the International Narcotics Control Board (INCB), the body responsible for administering the Single Convention on Narcotic Drugs (6), the treaty that governs opioid availability in the world. National drug regulatory authorities in ten countries have also commented on the text.
Research in management of cancer pain has produced new knowledge about pain and how opioids act in the body in relation to pain. Traditionally, the opioid analgesics have been used to manage acute pain. Long-term use of opioids has been discouraged because of the risk of tolerance or physical or psychological dependence. Studies have shown that, while physical dependence and tolerance do occur in patients who take opioids over a long period, psychological dependence is extremely rare. Consequently, the risk of such dependence should not be a factor in deciding whether to use opioids to treat the cancer patient with pain.
Studies have also shown that morphine and some other opioids do not have a "ceiling effect". Morphine can be safely administered in increasing amounts until the pain is relieved without producing an "overdose", as long as the side-effects are tolerated. There is no standard dose of morphine; the correct dose is the one that relieves the pain. This dose may vary from patient to patient; a few patients with severe pain may require several thousand milligrams of oral morphine daily to relieve pain.
In general, studies on the use of opioids to treat pain in cancer patients indicate that public and professional expectations about relief from cancer pain should be much higher than they are at present.
There are many reasons why cancer pain is not adequately treated at present (7), including:
To respond to these issues, WHO advocates a strategy with the following key components (Fig. 2):
These foundation measures are important if existing knowledge is to be implemented rationally. They cost very little but can have a significant effect (14).
Fig. 3 shows the global consumption of morphine according to population density. [note: Please refer to the original publication for Figure 3] It can be seen that morphine consumption varies greatly from country to country. Consumption figures do not completely indicate the extent to which opioids are used for treatment of moderate to severe cancer pain; however, they provide probably the best single indicator available.
WHO monitors morphine consumption in individual countries as an index of improvements in pain management. Global morphine consumption was relatively stable until 1984, when WHO began to emphasize the need to use morphine in the treatment of cancer pain. From 1984 to 1992, global consumption of morphine more than tripled.
Many countries have fundamental difficulties in obtaining and distributing drugs for any type of illness. In these countries, the unavailability of drugs is often due to a combination of factors, such as inadequate funding of health services, lack of health care delivery infrastructure and inadequate facilities for the storage and distribution of medicines.
These problems are being addressed by WHO through its Action Programme on Essential Drugs. This programme recommends that a national policy on essential drugs should exist in every country, together with an action plan to guarantee the availability at a reasonable cost of a limited number of drugs of significant therapeutic value. The goal is to satisfy the health care needs of the majority of the population. More than 100 countries have so far adopted lists of essential drugs.
The model list of essential drugs (2) includes three opioid analgesics. Codeine and morphine are on the main list; pethidine is on the complementary list. In many countries, however, morphine and other opioids are not available, or available only under very strict conditions, because of national laws aimed at preventing drug abuse. Some of these laws were established long before oral opioids became widely recognized as indispensable for the treatment of cancer pain. In such cases, it is essential for health care workers and drug regulators to cooperate in order to make opioid analgesics available while preventing their abuse. The next chapter reviews the Single Convention on Narcotic Drugs, explains the steps that must be taken to make morphine and other opioids available for the treatment of pain, and offers suggestions for doing this efficiently.
At the outset, it should be emphasized that each participant in the chain of distribution should fulfil all the legal requirements. The chain of distribution includes:
The 1961 Single Convention on Narcotic Drugs, as amended by the 1972 Protocol (6, 8), is the principal international treaty regulating availability of opioids. It classifies the opioids, and requires the registration of all handlers and the estimation of medical needs for opioids. It establishes rules concerning production, manufacture and distribution, and requires statistical reports. The Single Convention governs how opioids are shipped between countries, using a system of import and export approval. The treaty also defines to some extent the requirements for safe distribution within a country.
Governments that are party to the Single Convention have agreed to bring their laws and regulations into line with its requirements. A list of the parties is updated and published annually by the INCB (9). Countries that are not party to the Single Convention often follow its basic procedures.
The preamble of the Single Convention on Narcotic Drugs (6) recognizes that "the medical use of narcotic drugs continues to be indispensable for the relief of pain" [and] "addiction to narcotic drugs constitutes a serious evil".
Thus, the broad purpose of the treaty is to prevent the abuse of narcotics or opioids, while guaranteeing their availability for medical use.
The Single Convention classifies the opioids into four schedules, depending on each drug's dependence potential, abuse liability and therapeutic usefulness. These schedules do not necessarily correspond with those in national laws. The stronger opioid analgesics, such as fentanyl, morphine, hydromorphone and oxycodone are in Schedule I. Codeine and its derivatives, which are less strictly controlled, are in Schedule II. Schedule III contains specified preparations of codeine and dextropropoxyphene that are exempted from certain requirements. Schedule IV contains opioids that are considered to be particularly susceptible to abuse.
Preparations containing not more than 100 mg of codeine with one or more other ingredients per dosage unit, and those with a concentration of not more than 2.5% codeine in undivided preparations, such as syrups, are exempted from certain control measures under the Single Convention.
These drugs are controlled by the Convention on Psychotropic Substances, 1971.
A country obtains its supply of opioids for medical purposes by importing them from another country, manufacturing them itself, or both. These opioids are then distributed by manufacturers or wholesalers to hospitals and pharmacies, and subsequently dispensed to patients by health care personnel.
The Single Convention requires that all individuals and enterprises in the distribution system should be licensed or otherwise appropriately authorized, and that transfers of opioids take place only between properly registered parties. Patients may use opioids only according to a physician's prescription. Certain records must be kept, and reports on consumption must be filed with the national regulatory authority. These, along with security arrangements and inspections, permit the detection of "leakage" or "diversion" from the legitimate system of drug distribution.
It is vital that a country should have enough opioids to meet the demand for treatment of patients in pain. The INCB has recognized that opioids are underused in the treatment of pain, especially cancer pain, and has called on governments to re-evaluate their needs.
Every year, national drug regulatory authorities prepare an estimate of the amount of Schedule I opioids that will be needed in the country during the following year. The estimate must be submitted to the INCB six months in advance of the period to which it applies. Under the Single Convention, the quantity of opioids manufactured in or imported into a country must not exceed the government's official estimate of the amount needed.
The treaty requires the INCB to confirm the national estimate before the national government may permit the import or manufacture of opioids. In this way, excessive manufacture or import can be monitored and the risk of diversion to non-medical use is minimized.
The treaty also requires the INCB to endeavour to ensure that opioids are available for medical purposes, and to confirm national estimates as quickly as possible. If an annual estimate proves to be inadequate, the national drug regulatory authority is permitted by treaty to submit an amendment to the INCB; the INCB will confirm amendments as soon as possible.
The responsibility for determining the amount of opioids necessary to meet the medical need in a country rests entirely with the national government, in particular with the drug regulatory authority. Countries may use different methods to calculate the estimate, but the INCB must be informed of the method used and of any changes. Typically, an estimate will reflect to some degree the amount of each opioid consumed in previous years.
Communication between health workers and drug regulators is essential in order to ensure that each understands the other's aims. It is important for pain management experts and medical associations to understand the opioid distribution system in their country, learn about the national estimate of opioid needs, and be aware of the concerns of regulators. Opioid abuse is a reality, and health care workers must cooperate in the campaign to prevent diversion.
It is also important for regulators to learn about the importance of pain relief both for individual patients and for public health in general. Information about cancer pain, where and how cancer patients are treated, and the training of health care personnel will help regulators whose job it is to ensure the integrity of the distribution system. The knowledge that opioid use needs to increase will help regulators to make appropriate changes in the annual estimate.
Health care personnel should make sure that regulators know the salient facts related to pain relief, for example:
Health care workers should tell regulators exactly which opioids are needed, including the dosages and dosage forms required, in order to ensure that the estimate is adequate to meet the needs of patients.
After the estimate has been confirmed by the INCB, a country may either import or manufacture opioids. In both cases, the participants in the distribution chain should endeavour to ensure that the supply is reliable. Interruptions in the distribution of opioids is distressing for both patients and families and must be avoided.
Some or all of the opioids needed may be manufactured by enterprises in the country itself, which will be regulated (or operated) by the government. Regulation of manufacture of opioid products includes licensing, requirements for record-keeping and reporting, and quality control. Resources are required for record-keeping, to provide secure facilities and maintain security procedures from the acquisition of raw materials until the distribution of the finished products, in order to prevent diversion.
The products available in a country may be limited to the opioids and dosage forms that have been approved for marketing by the national health authority.
A manufacturer may distribute the finished products directly to licensed pharmacies or hospitals, or they may be distributed by a wholesaler. Wholesalers must also be licensed by the national drug regulatory authority, and must obey rules concerning security and record-keeping.
Often, some or all of the opioid products a country needs are imported. The import and export requirements of the Single Convention are outlined here, so that the participants in the opioid distribution system can see what needs to be done to complete the process quickly. Specific requirements may vary from country to country.
The Single Convention lays down a step-by-step process to ensure that the movement of opioids between countries occurs only after authorization by the drug regulatory authorities, and that the amounts imported stay within the approved estimate of the importing country. The import and export certificates are the proof that the products are changing hands legally. Both certificates must be approved and must accompany each shipment. There is no standard certificate, although a model import certificate (Annex 2) has been developed by the United Nations Commission on Narcotic Drugs.
The following information must appear on the import certificate:
The import/export process is outlined below and in Fig. 4. It should be noted that many countries also have a certification procedure to prevent marketing of pharmaceutical products that are falsely labelled, counterfeit or substandard (11).
It is important that there is complete, accurate and prompt communication between the participants to minimize the time between the various steps in the process.
National drug regulatory authorities must report all imports and exports of opioids to the INCB every quarter. They are also required to make an annual inventory and report the total amount of opioids manufactured, consumed and in stock. The annual inventory does not include drugs stored in pharmacies, which for official purposes are considered to have been consumed.
The INCB, in turn, uses these data to prepare reports and monitor global production and consumption of opioids. INCB statistical reports (9) can be useful to health care workers who need to know the quantity of opioids consumed in their country in previous years. These statistics also provide a global picture of morphine consumption. For statistical purposes, a "defined daily dose" (DDD) has been calculated to allow a rough comparison of consumption of drugs of different potencies in different countries. The DDD for morphine is 30 mg. It must be emphasized that the DDD has no significance in terms of medical use or for drawing up estimates of opioid needs, but is intended only as a tool for analysing differences in consumption around the world.
The annual reports of the INCB provide useful information about its work, as well as patterns of medical use and diversion of opioids. The INCB also produces periodic special reports that focus attention on critical issues, such as the 1989 special report Demand for and supply of opiates for medical and scientific needs (12) which called on governments to re-evaluate medical needs for opioids.
In recent years, the INCB has reported to the United Nations Economic and Social Council that the international control system continues to operate satisfactorily (13).
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.
The INCB has also reported on its efforts to improve opioid availability for the treatment of pain. In the special report mentioned above (12), the INCB reviewed the availability of opioids for medical and scientific purposes in consultation with WHO. The INCB concluded that the medical need for opioids is not being fully met, particularly in respect of cancer pain. The INCB made recommendations to governments, WHO, professional associations and medical instructors, on the need to:
The Single Convention recognizes that individual governments must decide the level of regulation of the individuals directly involved in dispensing opioids - pharmacists, physicians and nurses. However, it expresses several principles that should be observed:
The Single Convention recognizes that governments have the right to impose further restrictions if they consider it necessary, to prevent diversion and misuse of opioids. However, this right must be continually balanced against the responsibility to ensure opioid availability for medical purposes.
In deciding the appropriate level of regulation, governments should bear in mind the dual aims of the Single Convention. The INCB has observed that in some countries fear of drug abuse has resulted in laws and regulations, or interpretations thereof, that make it unnecessarily difficult to obtain opioids for medical use.
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 of access to opiate medications (12).
The WHO Expert Committee on Cancer Pain Relief and Active Supportive Care (7) has commented on special multiple-copy prescription programmes that are required by governments in some countries and in several states of the United States of America. Typically, these programmes reduce prescribing of covered drugs by 50% or more. Although the Expert Committee acknowledged that they may reduce careless prescribing and "multiple doctoring", it also noted:
. . . the extent to which these programmes restrict or inhibit the prescribing of opioids to patients who need them should also 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 licences 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.
It is understood that regulatory requirements for physicians, nurses and pharmacists to dispense opioids to patients will differ from country to country. However, the following are general criteria that can be used to develop a practical system.
Appropriate records must be kept. If physicians are required to keep records other than those associated with good medical practice, the extra work incurred should be practicable and should not impede medical activities. Hospitals and pharmacists must be legally responsible for safe storage and the recording of opioids received and dispensed.
Reasonable record-keeping and accountability provisions should not discourage health care workers from prescribing or stocking adequate supplies of opioids.
Doyle D, Hanks GWC, MacDonald N. eds. Oxford textbook of palliative medicine. Oxford, Oxford University Press, 1993.
Foley KM, Bonica JJ, Ventafridda, V, eds. Second International Congress on Cancer Pain. New York, Raven Press, 1990 (Advances in Pain Research and Therapy Vol. 16).
Twycross RG. Pain relief in advanced cancer. Edinburgh, Churchill Livingstone, 1994.
US Department of Health and Human Services. Management of cancer pain.
Rockville, MD, 1994 (Clinical Practice Guideline, No. 9).
Narcotic
In this publication, the term "narcotic" is used only in relation to the Single Convention on Narcotic Drugs, 1961, in which the term is used in a legal rather than a pharmacological sense. The Single Convention includes substances that are not narcotics from a pharmacological point of view, for example marijuana and cocaine.
Opioid
In this publication, opioid refers to codeine, morphine, and other natural and synthetic drugs whose effects are mediated by specific receptors in the central and peripheral nervous systems.
Tolerance
Increased resistance to the usual effects of a drug as a result of long-term continual use.
Physical dependence
"Physical dependence" is used to describe the neuroadaptation of the body to the presence of an opioid, and is characterized by the onset of acute symptoms and signs of withdrawal if the opioid is stopped or an opioid antagonist is administered.
Psychological dependence
"Psychological dependence" is used to describe a behavioural pattern characterized by a craving for the mood-altering effects of a drug and an overwhelming preoccupation with obtaining and using the drug.
MODEL FORM OF IMPORT CERTIFICATE
Certificate of Official Approval of Import No.............................. (date)
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INTERNATIONAL OPIUM CONVENTION OF 1925
SINGLE CONVENTION ON NARCOTIC DRUGS, 1961
| 1. To be completed in all cases | 1. I hereby certify that [name of Authority], being the Authority charged with the administration of the law relating to the drugs to which the 1925 and 1961 Conventions apply, has approved the importation by |
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(a) ........................................................................................................ ........................................................................................................ ........................................................................................................ |
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of (b) ........................................................................................................ ........................................................................................................ ........................................................................................................ ........................................................................................................ ........................................................................................................ |
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from (c) ........................................................................................................ ........................................................................................................ ........................................................................................................ subject to the following conditions: |
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(d) ........................................................................................................ ........................................................................................................ ........................................................................................................ |
| 2. To be completed only if the consignment is required for other than medical or scientific purposes. | 2. See note below. |
| 3. Duration of validity | 3............................................................................................................... Signed on behalf of [name of Authority] Signature ......................................................................................................... Official rank..................................................................................................... Date.............................................................................................................. |
| Note: It should be indicated for which of the following purposes the
consignment to be imported is required: (a) for the preparation of a flavouring
agent in the case of coca leaves; |
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