International Drug Scheduling; Convention on Psychotropic Substances; Single Convention on Narcotic Drugs; World Health Organization Scheduling Recommendations for Ephedrine, Dihydroetorphine, Remifentanil, and Certain Isomers

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 98N-0148]

International Drug Scheduling; Convention on Psychotropic

Substances; Single Convention on Narcotic Drugs; World Health

Organization Scheduling Recommendations for Ephedrine,

Dihydroetorphine, Remifentanil, and Certain Isomers

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is providing interested

persons with the opportunity to submit written comments and to request

an informal public meeting concerning recommendations by the World

Health Organization (WHO) to impose international manufacturing and

distributing restrictions, under international treaties, on certain

drug substances. The comments received in response to this notice and/

or public meeting will be considered in preparing the U.S. position on

these proposals for a meeting of the United Nations Commission on

Narcotic Drugs (CND) in Vienna, Austria, in March 1999. This notice is

issued under the Controlled Substances Act.

DATES: Written comments by February 10, 1999; written requests for a

public meeting and the reasons for such a request by January 26, 1999.

ADDRESSES: Submit written comments to the Dockets Management Branch

(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,

Rockville, MD 20852. Submit written requests for a public meeting and

the reasons for such a request to Nicholas P. Reuter (address below).

FOR FURTHER INFORMATION CONTACT: Nicholas P. Reuter, Office of Health

Affairs (HFY-20), Food and Drug Administration, 5600 Fishers Lane,

Rockville, MD 20857, 301-443-1382, or e-mail: ``[email protected]''.

SUPPLEMENTARY INFORMATION:

I. Background

The United States is a party to the 1971 Convention on Psychotropic

Substances (the Convention). Section 201(d)(2)(B) of the Controlled

Substances Act (the CSA) (21 U.S.C. 811(d)(2)(B)) provides that when

the United States is notified under Article 2 of the Convention that

the CND proposes to decide whether to add a drug or other substance to

one of the schedules of the Convention, transfer a drug or substance

from one schedule to another, or delete it from the schedules, the

Secretary of State must transmit notice of such information to the

Secretary of Health and Human Services (HHS). The Secretary of HHS must

then publish a summary of such information in the Federal Register and

provide opportunity for interested persons to submit comments. The

Secretary of HHS shall then evaluate the proposal and furnish a

recommendation to the Secretary of State which shall be binding on the

representative of the United States in discussions and negotiations

relating to the proposal.

As detailed below, the Secretary of State has received two

notifications from the Secretary-General of the United Nations (the

Secretary-General) regarding substances to be considered for control

under the Psychotropic Convention. These notifications reflect the

recommendations from the 31st WHO Expert Committee for Drug Dependence

(ECDD), which met in June 1998. In the Federal Register of March 18,

1998 (63 FR 13258), FDA announced the WHO ECDD review and invited

interested persons to submit information for WHO's consideration.

The full text of the notifications from the Secretary-General is

provided in section II of this document. Section 201(d)(2)(B) of the

CSA requires the Secretary of HHS, after receiving a notification

proposing scheduling, to publish a notice in the Federal Register to

provide the opportunity for interested persons to submit information

and comments on the proposed scheduling action.

The United States is also a party to the 1961 Single Convention on

Narcotic Drugs. The Secretary of State has received a notification form

the Secretary-General regarding substances to be considered for control

under this convention. The CSA does not require HHS to publish a

summary of such information in the Federal Register. Nevertheless, in

an effort to provide interested and affected persons an opportunity to

submit comments regarding the WHO recommendations for narcotic drugs,

the notification regarding these substances is also included in this

Federal Register notice. The comments will be shared with other

relevant agencies to assist the Secretary of State in formulating the

U.S. position on the control of these substances. The HHS

recommendations are not binding on the representative of the United

States in discussions and negotiations relating to the proposal

regarding control of substances under the Single Convention.

II. United Nations Notifications

The formal United Nations notifications which identify the drug

substances and explain the basis for the recommendations are reproduced

below.

A. Notification on l-ephedrine, and d,l ephedrine

Reference: NAR/CL.18/1998 CU 98/215

TLAB/CSSS/303/98

UNDCP 42nd CND

WHO/ECDD 31 (1971C)

The Secretary-General of the United Nations presents his compliments

to the Secretary of State of the United States of America and has

the honour to inform the Government that the World Health

Organization (WHO), pursuant to article 2, paragraphs 1 and 4, of

the Convention on Psychotropic Substances of 1971, has notified the

Secretary-General by note dated 30 September 1998 that it is of the

opinion that (1RS2S)-2-methylamino-1-phenylpropan-1-ol (also known

as l-ephedrine) and the racemate (1RS2SR)-2-methylamino-1-

phenylpropan-1-ol (also known as d,l-ephedrine) should be included

in Schedule IV of that Convention.

In accordance with the provisions of article 2, paragraphs 1 and

4, of the Convention, the Secretary-General hereby transmits the

text of the notification as annex I to the present note.

The World Health Organization, in connection with the

notification has also submitted advance excerpts from the report of

the thirty-first meeting of the WHO Expert Committee on Drug

Dependence (23-26 June 1998), which reviewed the substance with a

view, inter alia, to possible international control. The excerpts

from that report concerning the substance recommended for scheduling

are hereby transmitted as annex II.

In accordance with the provisions of article 2, paragraph 2 of

the Convention, the notification from the World Health Organization

will be brought to the attention of the Commission on Narcotic Drugs

at its next session in March 1999. Any action or decision taken by

the Commission with respect to this notification, pursuant to

article 2, paragraph 5, of the Convention, will be notified to

States Parties in due course. Article 2, paragraph 5, reads as

follows:

``The Commission, taking into account the communication from the

World Health Organization, whose assessments shall be determinative

as to medical and scientific matters, and bearing in mind the

economic, social, legal, administrative and other factors it may

consider relevant, may add the substance to Schedule I, II, III or

IV. The Commission may seek further information form the World

Health Organization or from other appropriate sources.''

In order to assist the Commission in reaching a decision, it

would be appreciated if an economic, social, legal, administrative

or other factors the Government may consider relevant to the

possible scheduling of l-ephedrine and the racemate could be

[[Page 1630]]

communicated at the latest by 4 January 1999 to the Executive

Director of the Office for Drug Control and Crime Prevention, c/o

Commission and Secretariat Services Section, P.O. Box 500, A-1400

Vienna, Austria, fax: +43-1-26060-5885.

11 November 1998

NAR/CL.18/1998

Annex I

Annex I

Note dated 30 September 1998 addressed to the United Nations By the

World Health Organization

The World Health Organization presents its compliments to the

United Nations and has the honour to transmit, in accordance with

Article 2, paragraphs 1 and 4 of the Convention on Psychotropic

Substances, 1971, assessments and recommendation of the World Health

Organization concerning the proposed inclusion of ephedrine (l-

ephedrine and its racemate) in Schedule IV of the said Convention,

as set forth in Annex hereto.

The World Health Organization avails itself of this opportunity

to present to the United Nations the assurance of its highest

consideration.

11 November 1998

NAR/CL.18/1998

Annex II

Annex II

Ephedrine

1. Substance identification

Ephedrine (2-methylamino-1-phenylpropan-1-ol) exists in fours

stereoisomeric forms and two corresponding racemic mixtures. They

are designated traditionally l-ephedrine, d-ephedrine and l-

pseudoephedrine and d-pseudoephedrine. l-Ephedrine, also designated

as (-)-ephedrine, is chemically (1R,2S)-2-methylamino-1-

phenylpropan-1-ol. Racemic ephedrine also designated as d,l-

ephedrine or ()-ephedrine, is chemically (1RS,2SR)-2-

methylamino-1-phenylpropan-1-ol.

2. Similarity to known substances and effects on the central nervous

system

Ephedrine is chemically and pharmacologically similar to

amphetamines. It is also similar to cathine which is (+)-

norpseudoephedrine. Ephedrine is both an - and -

adrenergic agonist and enhances the release of norepinephrine from

sympathetic neurons. In general, ephedrine is viewed as being a less

potent central nervous system stimulating agent but a more effective

bronchodilator. Ephedrine increases motor activity and mental

alertness, and diminishes the sense of fatigue. Ephedrine decreases

appetite and promotes weight loss.

3. Dependence Potential

In humans with histories of substance abuse, l-ephedrine, d-

amphetamine (INN: dexamfetamine), d-methamphetamine (INN:

metamfetamine), phenmetrazine, and methylphenidate injected

subcutaneously produced similar increases in respiratory rate and

blood pressure and similar types of subjective changes, including

euphoria. The agents differed in relative potency. In general,

amphetamine-like stimulants differed only in relative potencies when

given orally. l-Ephedrine was five times less potent than

amphetamine in producing amphetamine-like subjective and

physiological effects in substance abusers, but was more potent than

amfepramone (diethylpropion).

In monkeys trained to self-administer cocaine, l-ephedrine

maintained responding rates greater than saline in substitution

tests. In rats trained to discriminate cocaine from placebo, l-

ephedrine generalized to cocaine - though at a slightly lower rate

than d-amphetamine. Ephedrine generalized to cocaine and d-

amphetamine in other drug discrimination studies in rats. In

amphetamine-trained monkeys, an oral dose of 10 mg racemic ephedrine

was discriminated as amphetamine. In monkeys trained to self-

administer cocaine, l- and racemic ephedrine had definite

reinforcing effects. d-Ephedrine was both less efficacious and

potent than the l-isomer in its ability to generalize to

amphetamine.

4. Actual abuse and/or evidence of likelihood of abuse

Of the 50 countries which have returned the questionnaire to

WHO, ephedrine was available for medical use in 46 countries. Of the

46 countries, the following 12 countries have indicated present or

past ephedrine abuse or illicit traffic in ephedrine presumably

associated with its abuse: Belgium, Burkina Faso, China, Costa Rica,

Germany, Finland, France, Ireland, Sudan, Slovakia, Thailand and

USA. Although quantitative information is difficult to obtain, the

extent of ephedrine abuse was significant enough for some

governments to implement various regulatory controls. The current

problem of abuse seems to be particularly serious in certain African

countries. When abuse exists, it seems to involve ephedrine single

entity products. In addition, in the USA, combination products

containing ephedrine in herbal preparations have been abused.

The problem of ephedrine diversion was reported in the material

provided by the International Narcotics Control Board, which

indicated that few countries served as major supplier of ephedrine

to other countries. Often, there is a large gap between the amount

required for legitimate use and the amount imported into these

countries reflecting diversion for abuse. Some ephedrine, traded in

dosage forms, is used as a precursor to synthesize methamphetamine.

5. Therapeutic usefulness

Ephedrine is used widely as a bronchodilator in the symptomatic

treatment of reversible bronchospasm which may occur in association

with asthma, bronchitis, emphysema, and other obstructive pulmonary

diseases. Hypotension and shock have been treated with parenteral

ephedrine through its actions producing cardiac stimulation and

vasoconstriction. Less common indications include obesity, motion

sickness and enuresis.

The commonality of ephedrine use as a medicine is indicated by

the fact that 92% of the countries which responded to the WHO

questionnaire (46/50) indicated therapeutic use of ephedrine. This

figure suggests that ephedrine is used therapeutically in many

countries in the world. Some of these countries have indicated a

large number of pharmaceutical products containing ephedrine on the

market, often as combination products.

6. Recommendation

On the basis of the available information concerning its

pharmacological profile, dependence potential and actual abuse, the

public health and social problems associated with the abuse of

ephedrine are assessed to be significant. The current problem

appears to be particularly serious in certain African countries. On

this basis, it is recommended that l-ephedrine and the racemate be

placed in Schedule IV of the Convention on Psychotropic Substances,

1971. The d-isomer, which is significantly less potent than the l-

isomer, need not be controlled. In making this recommendation, it is

noted that ephedrine combination products would be eligible for

exemption according to the 1971 Convention.

It is further noted that there are overlapping jurisdictions

concerning the 1971 Convention and the 1988 UN Convention Against

Illicit Traffic in Narcotic Drugs and Psychotropic Substances, which

may make full effective international regulations of ephedrine

difficult. The interrelationship and interpretation of these

conventions needs clarification by appropriate international bodies,

including the International Narcotics Control Board and the World

Health Organization. In addition, it is recommended that these

bodies develop ways to alert Member States which export

pharmaceutical formulations of ephedrine, that these preparations

have the potential for abuse and use as a precursor.

B. Notification Regarding the Proposal of the Government of Spain

Reference: NAR/CL.17/1998 CU 98/214

TLAB/CSSS/302/98

UNDCP 42nd CND

WHO/ECDD 31 (1971C)

The Secretary-General of the United Nations presents his compliments

to the Secretary of State of the United States of America and has

the honour to refer to his note NAR/CL.4/1997 of 28 May 1997, by

which he transmitted a notification received from the Government of

Spain pursuant to article 2, paragraph 1 of the Convention on

Psychotropic Substances, 1971. In its notification the Government of

Spain informed the Secretary-General that it was of the opinion that

Schedules I and II of the 1971 Convention should be amended to

include: (a) isomers, except were expressly excluded, of substances

listed in those Schedules, whenever the existence of such isomers is

possible; (b) esters and ethers of substance in those Schedules,

except where included in another Schedule, whenever the existence of

such esters or ethers is possible; (c) salts of those esters, ethers

and isomers, under the conditions stated above, whenever the

formation of such salts is possible; and (d) a substance resulting

from modification of the chemical structure of a substance already

in Schedule I or II and which produces pharmacological effects

similar to those produces by the original substances.

[[Page 1631]]

The Secretary-General also transmitted a copy of that

notification to the World Health Organization (WHO), in accordance

with the provision of article 2, paragraph 2 of the Convention, for

consideration by the thirty-first meeting of the WHO Expert

Committee on Drug Dependence in 1988.

In accordance with the provision of article 2, paragraph 4, of

the Convention, the World Health Organization has transmitted to the

Secretary-General, by a noted dated 30 September 1988, its

assessment and recommendation in response to the proposal made by

the Government of Spain. Those recommendations read as follows:

(i) WHO does not recommend to amend Schedule I and Schedule II

of the 1971 Convention, to extend international controls

collectively to esters, ethers, and analogues of controlled

substances;

(ii) with regard to isomers, WHO recommends that a phrase could

be added for substances in Schedule I of the 1971 Convention. That

phrase would read as follows: ``The stereoisomers, unless

specifically excepted, of substance in this Schedule, whenever the

existence of such stereoisomers is possible within the specific

chemical designation'', and

(iii) with regard to stereoisomers of the substances in Schedule

II, III and IV of the 1971 Convention, WHO recommends that

interpretation guidelines should be developed by the International

Narcotic Control Board in collaboration with the World Health

Organization, in order to eliminate the confusion arising from

inconsistencies in the present nomenclature of the Schedules in the

1971 Convention.

In accordance with the provisions of article 2, paragraphs 1 and

4, of the Convention, the Secretary-General hereby transmits the

text of the notification as annex I to the present note.

The World Health Organization, in connection with the

notification has also submitted advance excerpts from the report of

the thirty-first meeting of the WHO Expert Committee on Drug

Dependence (23-26 June 1998), which examined the proposal of the

Government of Spain. The excerpts from that report are hereby

transmitted as annex II.

In accordance with the provision of article 2, paragraph 2 of

the Convention, the notifications from the Government of Spain and

from the World Health Organization will be brought to the attention

of the Commission on Narcotic Drugs at its next session in March

1999. Any action or decision taken by the Commission with respect to

this notification, pursuant to article 2, paragraph 5, of the

Convention, will be notified to States Parties in due course.

Article 2, paragraph 5, reads as follows:

``The Commission, taking into account the communication from the

World Health Organization, whose assessments shall be determinative

as to medical and scientific matters, and bearing in mind the

economic, social, legal, administrative and other factors it may

consider relevant, may add the substance to Schedule I, II, III or

IV. The Commission may seek further information form the World

Health Organization or from other appropriate sources.''

In order to assist the Commission in reaching a decision, it

would be appreciated if an economic, social, legal, administrative

or other factors the Government may consider relevant to the

recommendations made by the World Health Organization in response to

the proposal made by the Government of Spain could be communicated a

the latest by 4 January 1999 to the Executive Director of the Office

for Drug Control and Crime Prevention, c/o Commission and

Secretariat Services Section, P.O. Box 500, A-1400 Vienna, Austria,

fax: +43-1-26060-5885.

11 November 1998

NAR/CL.17/1998

Annex I

Annex I

Note dated 30 September 1998 addressed to the United Nations By the

World Health Organization

The World Health Organization presents its compliments to the

United Nations and has the honour to transmit, in accordance with

Article 2, paragraphs 1 and 4 of the Convention on Psychotropic

Substances, 1971, assessments and recommendation of the World Health

Organization, as set forth in Annex hereto, in response to the Note

Verbale of 15 May 1997 concerning the proposal by the Government of

Spain.

The World Health Organization avails itself of this opportunity

to present to the United Nations the assurance of its highest

consideration.

11 November 1998

NAR/CL.17/1998

Annex II

Annex II

Proposal of the Government of Spain

1. Outline of the Proposal

In 1997, the Spanish Government submitted a proposal to the

Secretary General of the United Nations to amend the 1971 Convention

on Psychotropic Substances by adding to Schedules I and II, the

chemical compositions of the isomers, esters and ethers of the

psychotropic substances already in these schedules, as well as any

modified chemical compounds producing effects similar to those

produced by the original substances (hereinafter referred to as

``analogues''). The Spanish proposal also recommends the inclusion

of the salts of the substances. However, the question of salts is

not addressed in the following section since the salts of the

substances listed in these Schedules are already under international

control. An in-depth analysis of potential advantages and

disadvantages of this proposal has led to the following conclusions.

2. Assessment and recommendation

With regard to the scheduling of analogues or ``any modified

chemical compounds producing effects similar to those produced by

the original substances'', extending controls collectively to these

groups of substances which are related to, but potential

pharmacologically different from, the substances in the two

Schedules may contradict the scheduling procedure stipulated in

Article 2 of the 1971 Convention on Psychotropic Substances which

requires WHO to evaluate individual problems, such as disagreements

among Parties concerning the precise scope of substances under

control. The same questions may arise concerning the scheduling of

esters and ethers. In addition, the advantages in terms of extended

scope of control would be rather limited. Though difficult to

evaluation, controlling analogues, esters and ethers is likely to

have a negative impact on legitimate industrial and research

activities involving these substances.

For these reasons, it is not recommend to amend Schedules I and

II of the 1971 Convention to extend international controls

collectively to esters, ethers and analogues of controlled

substances. It has been noted, however, that criminal activities

involving analogues of controlled substances can be controlled at

the national level, without extending unnecessary administrative and

regulatory controls to these substances used for legitimate

industrial and research purposes. In one country, this was achieved

by applying only criminal controls to certain specified acts

involving analogues. Governments having similar problems with

analogues should consider the desirability of adopting similar

selective control measures, an option which is not available under

the 1971 Convention once analogues have been scheduled.

In some countries, introducing national controls for new

analogues synthesized by clandestine laboratories is very difficult.

Ideally, a combination of national and international controls should

be developed concurrently. There is a need to expedite the critical

review of substance brought to the attention of WHO by governments.

With regard to isomers, a useful clarification could be provided

by introducing a modified qualifying phrase in the proposal of the

Spanish Government into Schedule I. The revised phrase to be added

to Schedule I would read as follows (addition underlined):

The stereoisomers, unless specifically excepted, of psychotropic

substance in this Schedule, whenever the existence of such

stereoisomers is possible within the specific chemical designation

in this Schedule.

This renders the proposal chemically precise and consistent with

the current interpretation of the Schedule. Hence the proposal could

provide an explicit clarification of the scope of controlled isomers

including racemates.

With regard to stereoisomers of the substances in Schedules II,

III and IV, the confusion arising from the inconsistencies in the

present nomenclature of the Schedules should be clarified by means

of interpretation guidelines to be developed by an appropriate

international body, such as the International Narcotics Control

Board, in collaboration with WHO.

C. Notification on Dihydroetorphine and Remifentanil

Reference: NAR/CL.16/1998 CU 98/213

TLAB/CSSS/301/98

UNDCP 42nd CND

WHO/ECDD 31 (1961C)

The Secretary-General of the United Nations presents his

compliments to the

[[Page 1632]]

Secretary of State of the United States of America and has the

honour to inform the Government that the World Health Organization

(WHO), pursuant to article 3, paragraphs 1 and paragraph 3 (iii), of

the Single Convention on Narcotic Drugs, 1961, and of that

Convention as amended by the 1971 Protocol, has notified the

Secretary-General by note dated 30 September 1998 that it is of the

opinion that 7,8-dihydro-7--[1-(R)-hydroxy-1-methylbutyl]-

6,14-endo-ethanotetrahydrooripavine (also known as dihydroetorphine)

and that 1-(2-methoxycarbonylethyl)-4-(phenylpropionylamino)-

piperidine-4-carboxylic acid methyl ester (also known as

remifentanil) should be included in Schedule I of the Convention.

In accordance with the provisions of article 3, paragraph 2, of

the Convention, the Secretary-General hereby transmits the text of

the notification as annex I to the present note.

The World Health Organization, in connection with the

notification has also submitted advance excerpts from the report of

the thirty-first meeting of the WHO Expert Committee on Drug

Dependence (23-26 June 1998), which reviewed these substances with a

view, inter alia, to possible international control. The excerpts

from that report concerning the two substances recommend for

scheduling, are hereby transmitted as annex II.

In accordance with the provisions of article 3, paragraph 2 of

the Convention, the notification from the World Health Organization

will be brought to the attention of the Commission on Narcotic Drugs

at its next session in March 1999 in accordance with article 3,

paragraph (iii), of the Convention.

Article 3, paragraph 3 (iii), reads as follows:

``If the World Health Organization finds that the substance is

liable to similar abuse and productive of similar ill effects as the

drugs in Schedule I or Schedule II or is convertible into a drug, it

shall communicate that finding to the Commission which may, in

accordance with the recommendation of the World Health Organization,

decide that the substance shall be added to Schedule I or Schedule

II.''

Any action or decision taken by the Commission with respect to

this notification, pursuant to article 3, paragraph 3 (iii), of the

Convention, will be notified to Governments in due course.

11 November 1998

NAR/CL.16/1998

Annex I

Annex I

Note dated 30 September 1998 addressed to the United Nations By the

World Health Organization

The World Health Organization presents its compliments to the

United Nations and has the honour to transmit, in accordance with

Article 3, paragraphs 1 and 3 (iii) of the Single Convention on

Narcotic Drugs, 1961, as amended by the 1972 Protocol Amending the

Single Convention on Narcotic Drugs, 1961, assessments and

recommendation of the World Health Organization, as set forth in the

annex hereto, concerning the proposed inclusion of dihydroetorphine

and remifentanil in Schedule I of the said Convention.

The World Health Organization avails itself of this opportunity

to present to the United Nations the assurance of its highest

consideration.

11 November 1998

NAR/CL.16/1998

Annex II

Annex II

Dihydroetorphine

1. Substance identification

Dihydroetorphine (CAS 14357-76-7) is chemically 7,8-dihydro-7-

-[1-(R)-hydroxy-1-methylbutyl]-6,14-endo-

ethanotetrahydrooripavine.

2. Similarity to known substances and effects on the central nervous

system

Dihydroetorphine is chemically similar to etorphine, which is in

Schedule I of the Single Convention on Narcotic Drugs, 1961.

Pharmacologically, animal studies indicate that dihydroetorphine is

a highly potent analgesic, with an analgesic efficacy of 6,000 and

11,000 times as potent as morphine in mice and rabbits,

respectively. In mice and rabbits, the peak analgesic effect was

attained 15 minutes after subcutaneous injection of

dihydroetorphine, and the duration of analgesic effect lasted 60-90

minutes, which was shorter than that of morphine (120-150 minutes).

Radioligand binding assay indicated that dihydroetorphine is a

selective mu-type opioid-receptor agonist.

3. Dependence Potential

Animal studies indicated that dihydroetorphine possessed a strong

psychological dependence potential, 5,000-10,000 times more potent

than morphine in self-administration tests in rats, 500 and 100

times more potent than morphine and heroin in self-administration

studies in monkeys, 8,000 and 1,000 times more potent than morphine

and heroin in drug discrimination studies in rats, respectively.

However, animal studies showed that the physical dependence-

producing properties of dihydroetorphine were relatively low. The

withdrawal syndromes caused by dihydroetorphine in mice jumping

tests were weaker than morphine. In monkey withdrawal precipitation

tests and abrupt withdrawal tests, withdrawal syndromes of

dihydroetorphine were significantly weaker than those of morphine.

4. Actual abuse and/or evidence of likelihood of abuse

Abuse of dihydroetorphine began soon after it was marketed in China

in 1992. Although indicated as an analgesic, it was also used as an

opiate withdrawal syndrome suppressing agent. Its abuse spread very

quickly in the country. Epidemiological studies have shown that

there were two reasons for starting to abuse dihydroetorphine -

iatrogenic and social. One group of abusers began to use the drug

for medical purposes but increased the doses because tolerance

developed quickly, and the potent dependence-producing properties of

dihydroetorphine played a dominant role in compelling the patient to

start abusing the drug. Opiate abusers were another group of people

who took the drug as a substitute for heroin because of its stronger

psychological dependence-producing properties, cheaper price, and

less strict control than heroin.

5. Therapeutic usefulness

Dihydroetorphine was registered in China in December 1992 for the

relief of acute severe pain. However, it is not useful as a drug for

substitution treatment of opioid withdrawal because of short

duration of action.

6. Recommendation

Dihydroetorphine is a potent mu-type opioid-receptor agonist. Based

on its pharmacological properties and dependence potential

demonstrated in animal studies, as well as its actual abuse observed

in China, it is estimated that dihydroetorphine is liable to similar

abuse and productive of similar ill effects as the drugs in Schedule

I of the Single Convention on Narcotic Drugs, 1961. It is therefore

recommended that dihydroetorphine be placed in Schedule I of this

Convention.

Remifentanil (INN)

1. Substance Identification

Remifentanil (CAS-132875-61-7), chemically 1-(2-

methoxycarbonylethyl)-4-(phenylpropionylamino)-piperidine-4-

carboxylic acid methyl ester, is also known as GI 87084X.

Remifentanil hydrochloride (CAS-132539-07-2) is also known as GI

87084B. There are no chiral carbon atoms in the molecule; so no

stereoisomers or racemates are possible.

2. Similarity to known substances and effects on the central nervous

system

Remifentanil is classified as a relatively selective mu-type opioid-

receptor agonist with a profile similar to fentanyl, alfentanil and

sufentanil, but with an ultra-short duration of action. Comparison

of potency in in vitro binding assays specific for the mu-type

opioid receptor has demonstrated similar potencies of remifentanil

and fentanyl. Remifentanil's analgesic potency was found as similar

to fentanyl, alfentanil and sufentanil in rats, mice and dogs.

In clinical pharmacology studies, remifentanil exhibited properties

(including adverse effects) that were similar to other fentanyl

analogues. The most serious adverse effects were attributable to its

mu-type opioid-receptor agonist properties and included

hyptotension, bradycardia, muscle rigidity and respiratory

depression.

3. Dependence potential

Withdrawal signs developed in rats following cessation of

remifentanil administration. Remifentanil substituted for morphine

in morphine-dependent withdrawn monkeys. Remifentanil was found

reinforcing in self-administration studies in monkeys.

In opiate-experienced nondependent human subjects, the very rapid

subjective peak effects of remifentanil were not significantly

different from those of fentanyl. In another study involving healthy

subjects, euphoria occurred at about the same incidence for

remifentanil as for fentanyl and alfentanil.

[[Page 1633]]

4. Actual abuse and/or evidence of likelihood of abuse

One case of remifentanil abuse and overdose by intra-nasal

administration occurred during the clinical study of the drug.

Remifentanil had been administered over a period of several weeks,

leading to an overdose resulting in loss of consciousness,

tachycardia, depressed respiration and seizures. Following emergency

room treatment, the patient recovered.

5. Therapeutic usefulness

Remifentanil is used as an analgesic during induction and

maintenance of general anesthesia, in postoperative anesthesia, and

in monitored anesthesia care. Remifentanil has been approved for

marketing in 17 countries.

6. Recommendation

Remifentanil is a short-acting mu-type opioid-receptor agonist.

Based on its pharmacological properties and dependence potential, it

is estimated that remifentanil is liable to similar abuse and

productive of similar ill effects as the drugs in Schedule I of the

Single Convention on Narcotic Drugs, 1961. It is therefore

recommended that remifentanil be placed in Schedule I of this

Convention.

III. Discussion

Although WHO has made specific scheduling recommendations for each

of the drug substances, CND is not obliged to follow the WHO

recommendations. Options available to the CND for substances considered

for control under the Psychotropic Convention include: (1) Acceptance

of the WHO recommendations; (2) acceptance of the recommendations to

control but control the drug substance in a schedule other than that

recommended; or (3) reject the recommendations entirely.

A. Ephedrine

Ephedrine has been recommended for control in Schedule IV of the

Psychotropic Convention. If ephedrine is controlled in Schedule IV, the

United States, as a signatory to the Convention would have to determine

what additional domestic controls, if any, may be needed to fulfill its

obligations.

The Convention requires licenses for manufacturers, distributors,

and those entities in the retail trade. In addition, Article 9 of the

Convention states that ``[t]he Parties shall require that substances in

Schedules II, III and IV be supplied or dispensed for use by

individuals pursuant to medical prescription only, except when

individuals may lawfully obtain, use, dispense or administer such

substances in the duly authorized exercise of therapeutic or scientific

functions.'' On the other hand, the WHO notification on ephedrine

states that ``in making this recommendation, it is noted that ephedrine

combination products would be eligible for exemption according to the

1971 Convention.'' The Psychotropic Convention does not mention

``combinations'' but the term ``preparations'' is defined under Article

1 as ``(i) any solution or mixture, in whatever physical state

containing one or more psychotropic substances, or (ii) one or more

psychotropic substances in dosage form.'' Under Article 3, paragraphs 2

and 3, a party may exempt a preparation from certain controls under the

Convention, including the prescription requirement, if the preparation

is compounded in such a way that it presents no, or a negligible, risk

of abuse.

Ephedrine is available in the United States as an ingredient in

over-the-counter (OTC) bronchodilator products and in certain OTC

hemorrhoid treatment products. Importantly, ephedrine has been

designated as a listed chemical under the CSA (21 U.S.C. 802(34)) and

is subject to regulations under 21 CFR 1309, 1310, and 1313 , which are

enforced by the Drug Enforcement Administration. Accordingly,

distribution of ephedrine single-entity products and certain

transactions involving ephedrine combination products are subject to

the recordkeeping, reporting, registration, and import/export

notification provisions of the CSA. These controls must be examined to

determine whether they enable the United States to fulfil its

obligations for ephedrine, should it be controlled under Schedule IV of

the Psychotropic Convention. Finally, it should be noted that under

Article 2, paragraph 7(d), of the Psychotropic Convention, a party may

notify the United Nations that, due to exceptional circumstances, it

will elect not to apply all of the provisions required by the

Convention.

B. Spanish Proposal on Isomers of Schedule I Substances

WHO has also recommended adding a phrase to Schedule I that would

``clarify'' that stereoisomers of psychotropic substances in Schedule I

of the Convention would be considered as Schedule I substances.

According to WHO, this is ``chemically precise and consistent with the

current interpretations of the Convention * * * [and] could provide an

explicit clarification of the scope of controlled isomers including

racemates.''

It should be noted that WHO is recommending a change in the wording

of the list of substances controlled in Schedule I. A similar change

was approved by the Commission on Narcotic Drugs in 1977 which modified

the Schedules to state, ``[a]lso under international control are the

salts of the substances listed in these Schedules, whenever the

existence of such salts is possible.'' Adding such a statement about

stereoisomers, as WHO has recommended, should not have a significant

impact on the scope of control of psychotropic substances.

Domestically, under the CSA, stereoisomers are automatically subject to

control when a substance is added to Schedule I.

C. Dihydroetorphine and Remifentanil

Dihydroetorphine is a hydrogenated derivative of etorphine and a

potent -opioid-receptor agonist used as a short-acting

analgesic in China. It is not marketed in the United States, but it is

considered a Schedule II narcotic substance under the CSA because it is

a thebaine derivative. Remifentanil is a selective -opioid-

receptor agonist of the fentanyl group. Remifentanil is approved in the

Unites States as an anesthetic and is controlled domestically as a

narcotic in schedule II of the CSA. As such, no additional controls

will be necessary to fulfil U.S. obligations if remifentanil is

controlled under Schedule I of the Single Convention.

FDA, on behalf of the Secretary of HHS, invites interested persons

to submit comments on the United Nations notifications concerning these

drug substances and WHO's recommendations on stereoisomers pursuant to

the proposal from the Government of Spain. FDA, in cooperation with the

National Institute on Drug Abuse, will consider the comments on behalf

of HHS in evaluating the WHO scheduling recommendations. Then, under

section 811(d)(2)(B) of the CSA, HHS will recommend to the Secretary of

State what position the United States should take when voting on the

recommendations at the CND meeting in March 1999. Comments regarding

the WHO recommendations for control of substances under the Single

Convention will also be forwarded to the relevant agencies for

consideration in developing the U.S. position regarding narcotic

substances at the CND meeting.

IV. Submission of Comments and Opportunity for Public Meeting

Interested persons may, on or before February 10, 1999, submit to

the Dockets Management Branch (address above) written comments

regarding this notice. FDA does not presently plan to hold a public

meeting. If any person believes that, in addition to its written

comments, a public meeting would

[[Page 1634]]

contribute to the development of the U.S. position on the substances to

be considered for control under the Psychotropic Convention, a request

for a public meeting and the reasons for such a request should be sent

to Nicholas P. Reuter (address above) on or before January 26, 1999.

The short time period for the submission of comments and requests for a

public meeting is needed to assure that HHS may, in a timely fashion,

carry out the required action and be responsive to the United Nations.

Comments are to be identified with the docket number found in brackets

in the heading of this document. Received comments may be seen in the

Dockets Management Branch (address above) between 9 a.m. and 4 p.m.,

Monday through Friday.

Dated: January 4, 1999.

William K. Hubbard,

Associate Commissioner for Policy Coordination.

[FR Doc. 99-448 Filed 1-8-99; 8:45 am]

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