- Email: [email protected]
or abuse
Drug and Alcohol
Dependence,
Elsevier
Publishers
Scientific
FENETYLLINE:
17 ( 1986) Ireland
THERAPEUTIC
GERFRIED KRISTEN, SCHLICHTEGROLL*
Degussa Pharma Gruppe, Main-i (F.R.G.)
ANNELIES
259-27
1
259
Ltd.
USE, MISUSE AND/OR ABUSE SCHAEFER
Chemiewerk
Homburg,
and ANSGAR
Daimlerstrasse
VON
25, D-6000
Frankfurt/
SUMMARY
Fenetylline (CAPTAGON@) is included in a list of compounds to be considered by a World Health Organization (WHO) Expert Committee in April 1985 for possible international scheduling under the Convention on Psychotropic Substances, 1971. For over 23 years, this central stimulant has been used therapeutically in hyperkinetic children and other indications in place of amphetamines and other central stimulants with higher risk levels. In good correspondence with recent animal data fenetylline also shows significant qualitative and quantitative differences compared to amphetamine in man. It has few adverse side effects, a lower abuse potential and little actual abuse compared to amphetamine. Thus its benefit/risk assessment is substantially more favourable than that of other central stimulants. For proper therapeutic use of the substance, prescription status is or should be required by national authorities. Key words: Fenetylline - Amphetamine ratio - Misuse, Abuse - Hyperkinesis
- Therapeutic
uses -
Benefit/risk
INTRODUCTION
Fenetylline was originally developed by Degussa’s drug research department as part of an investigational program on theophylline derivatives, particularly concerned with the cardiovascular, pulmonary and central nervous system (CNS) effects of these substances. Fenetylline clearly exhibits central stimulant activity. However, early studies strongly suggested that fenetylline may differ from classical CNS stimulants of the amphetamine type in terms of potency, mode of action and the type and incidence of side effects. Thus, there were indications that the compound may offer decided advantages over available therapeutic modalities.
*To
whom
correspondence
should
be addressed.
0376-8716/86/$03.50 o Elsevier Scientific Publishers Ireland Printed and Published in Ireland
Ltd
In 1961, Degussa AG (Pharmaceutical Division/Homburg) introduced fenetylline into the Federal Republic of Germany as a 50-mg tablet. In 1964, Degussa requested prescription status to assure that the drug was used only under medical supervision. Thus, fenetylline can be dispensed only pursuant to a medical prescription in the F.R.G. Some early metabolic and pharmacological studies suggested that fenetylline might be similar to amphetamine; these early studies may be subject to some scrutiny. Nevertheless, largely on the basis of these early findings and because no investigational new drug application (IND)/(NDA) was submitted to the Food and Drug Administration (FDA) and thus no medical use established in the United States. In 1981 fenetylline was placed in Schedule I of the Controlled Substances Act of the United States. More recent preclinical investigations argue strongly against the assumption that fenetylline is similar to amphetamine. In particular, recent pharmacological, pharmacokinetic and metabolic results strongly disagree with early assumptions that the pharmacology of fenetylline is essentially that of amphetamine [l--3; Nissen, unpublished report). Moreover, there is a substantial body of information from human studies and extensive therapeutic experience with the drug which attest to its therapeutic usefulness and demonstrate that the compound exhibits substantial differences from amphetamines in terms of benefit/risk ratio. THERAPEUTIC
EFFICACY.
ADVERSE
EFFECTS
AND
ABUSE
Medical effects. In psychological and psychomotor tests Janke and Boss [ 41 found that 50 mg of fenetylline improved mental and psychomotor performance 1 h after oral administration (Fig. 1). In addition, the compound has been shown to have a mood-improving effect which clearly differs from that of other centrally acting stimulants. Based on the literature, the stimulating activity of fenetylline proved to be distinctly lower in intensity than that of caffeine, methylphenidate and methamphetamine [ 41. Other authors [ 5-81 agree with the results of these investigations and describe fenetylline’s action as improving mood as well as increasing productivity and the ability to concentrate. Similar results were found in a 1984 investigation [2] conducted by the Institute for Occupational Physiology, Technical University of Munich, using a double-blind, placebo-controlled crossover design. It was concluded that fenetylline significantly improves psychomotor and mental performance. No instances of an abnormal or exaggerated sense of well-being were observed after fenetylline intake in any of the clinical studies. The typical ‘euphoria’ classically associated with amphetamine-type compounds did not occur with fenetylline. After ingesting fenetylline subjects were described as being in a well-balanced emotional state (Figs. 1 and 2) [ 4,5]. Indications. Fenetylline is typically prescribed in place of amphetamines and other centrally acting stimulants. Its effects make the drug particularly
261
*
a *p
<
b
d
0.06
Fig. 1. Effect of 50 mg fenetylline hydrochloride administered orally to 20 human volunteers on adjective check list scores [4]. W, placebo; q, fenetylline. (a) sociable; (b) emotionally; (c) purposeful; (d) in good mood; (e) psychic and motor activity.
for use in the following indications : hyperkinesia in children (minimal brain dysfunction syndrome) [ 9-11; Nissen and Matussek, unpublished report; Nissen, unpublished report]. - narcolepsy [ 8,12-151. - lack of drive, particularly in the elderly, patients with and without organic diseases, e.g. parkinsonism, apoplexy, etc. [5--8,16,17; Brix and Werner, unpublished report]. - lack of drive following severe illness, surgery, [7,16-191 as well as head injuries [l&20,21]. Fenetylline is especially advantageous in the treatment of hyperkinetic children where it replaces centrally (CNS) acting stimulants, such as methylphenidate and methamphetamine, which present greater risks and have suitable
-
262 + 80 70 60 50 Q )_ z a
I
40 30 20 101
O-1 IO209 30-
-
40. 509 60-
P
30
so
80
MO
FENETYLLINE
+p
of 30, 50, and 80 mg fenetylline hydrochloride to questionnaire scores [4 1. emotional stability;
+,
higher abuse potential, This has been found in one of the leading European hospitals in this field (Nissen and Matussek, unpublished report; Nissen, unpublished report). Other therapeutic alternativeswould be neuroleptics or antidepressants which have more adverse effects. Fenetylline’s efficacy in hyperkinesia has been demonstrated in a double-blind study [91. It is of equal importance in the treatment of narcolepsy and epileptic absences. In
263
these cases the drug not only improved vigilance but also substantially decreased paroxysms [ 14 ; Bauman and Tomka, unpublished report]. The only therapeutic alternatives for these indications are CNS stimulants with a higher risk level. The same consideration applies to adjuvant therapy in Parkinson’s disease in which CNS stimulants are widely used. Since fenetylline was introduced into therapy some 23 years ago a very long therapeutic experience attests to its safety and efficacy in addition to the above mentioned more recent studies and data. Benefit/risk assessment. When making a benefit/risk assessment, it should be stressed that results from clinical trials and more than 23 years of therapeutic experience with fenetylline have detected no adverse effects on hepatic and renal functions, on blood pressure, or on the hemogram (Figs. 3 and 4) [ 5-7,201. Furthermore, there is no indication of the occurrence of pulmonary hypertension [ 221. The only adverse reactions reported with therapeutic doses of fenetylline are occasional palpitation, vertigo, dryness of mouth, gastric complaints, and other minor sympathomimetic or unspecific effects [ 5,7,8]. Following
160140’
. . . . . . . . n.
..1......-
130-
a
SYSTOLIC
120llOlooao-
*
80,
_-___-_-
-a
DIASTOLIC-
7030609
DIFFERENCE
m
1
1
0
8
WEEKS
Fig. 3. Mean blood pressure of 21 persons without circulatory disturbances before (0) and 8 weeks after oral administration of 50 mg fenetylline hydrochloride b.i.d. (morning and afternoon) [ 221.
‘64
Schellong-Test SE FORE
12
PULSE
110 10
SYSTOLIC
QO 80
DIASTOLIC
70 00 3 1
3
0
120
6 0
MINUTES SYSTOLIC
AFTER
110 100 90
PULSE
80
DIASTOLIC
70 60 I I
I
1
3
I
6.
MINUTES
Fig. 4. Mean heart rate and blood pressure values of 17 patients with orthostatic dysregulation before and 10 days after oral administration of 50 mg fenetylline hydrochloride b.i.d. [6 1.
fenetylline intake in the late afternoon or evening (which is not recommended) some early sleep disturbances have been reported [ 5,7-9,161. If the contraindications and precautions defined in fenetylline’s labelling are observed, the drug has proved to be reliable and safe. DIFFERENCES
BETWEEN
FENETYLLINE
AND AMPHETAMINES
Several significant differences have been observed clinically regarding the effects and adverse reactions of fenetylline on the one hand and amphetamine or methamphetamine on the other (Table I).
265
TABLE
I
COMPARISON OF SIDE EFFECTS OF AMPHETAMINE OR METHAMPHETAMINE AND FENETYLLINE IN THERAPEUTIC DOSAGES [ 51 Amphetamine or methamphetamine
Fenetylline
Blood pressure Appetite Fine motor activity
Increase Reduced Tremor
Mood
‘Euphoria’
Small decrease Practically not influenced Extremely seldom small tremor at higher dosages Well-balanced emotional state
Post-medication decrease performance Enhanced effect by caffeine Subjective feeling of restlessness Early sleep disturbances
in Significant
Not observed
Existent
Existent
Rather frequently Frequently
Seldom Seldom
(1) Fenetylline does not influence, or only slightly affects, appetite [ 5-7, 91. Psychological studies have shown that fenetylline barely differs from placebo with regard to the desire for food while anorectics markedly reduce that desire (Fig. 5) [ 231. (2) In contrast to amphetamine and caffeine, fenetylline does not interfere with fine motor activity [4]. In three different psychomotor tests (target pointing, finger dexterity, tremor measurement) fenetylline even improved performance [ 11. (3) In a double-blind crossover study in which the MAO-B inhibitor, selegiline, and fenetylline were compared to placebo with regard to their influence on the psychomotor efficiency of human volunteers, it could be seen that fenetylline improves all parameters (motor reaction time, mental processing, and control errors) [ 21. (4) At therapeutic dosages, amphetamine-type stimulants produce symptoms, such as post-medication decrease in performance associated with hangover effects, tendency to collapse, motor restlessness, insomnia, tremor and rapid changes of mood or jumping from one idea to another. Fenetylline has rarely been found to produce these effects with therapeutic dosages E5,71. (5) Fenetylline antagonize alcohol-induced depression of the patellar reflexes [24]. Thus, its mode of action on the neuromuscular system is apparently different from that of amphetamine. This could explain the beneficial effect of fenetylline on fine muscle control (i.e. reduction of tremor). (6) Fenetylline is better tolerated than amphetamine and other CNS stimulants (Figs. 3 and 4, Table I) [see also Ref. 31.
266
APPETITE SCORE Ub
rs
3.6 t
3.4
K w
3.2.
= (1
3.0.
:
2.8.
> J-
2.6’
cn z
2.4.
: t
2.2’
P
M
F
Fig. 5. Mean questionnaire scores on activity preference, ‘desire for food’, in 16 human subjects following oral administration of placebo, mefenorex (40 mg) and fenetylline (50 mg) [23]. P, placebo; M, mefenorex (40 mg); F, fenetylline (50 mg).
These differences between fenetylline and amphetamine correspond well with recent findings in animal experiments [3,25]. Thus, it might be expected that fenetylline might also differ from amphetamine with respect to abuse potential. ABUSE
POTENTIAL
Fenetylline is also clearly different from other CNS stimulants in terms of its abuse potential. This has been shown in tests involving self-administration in monkeys [26; Hoffmeister, unpublished report] as well as in the above mentioned human pharmacological studies and in over 23 years of therapeutic experience. The psychostimulant activity of fenetylline is described as a sense of well-balanced positive emotional tone and not as passively experienced elation [4,5]. A few authors [ 7,271 have noted that
267
fenetylline may have some abuse potential. As far as known, this appears, in large measure, to be attributable to the drive-promoting action of fenetylline which may help individuals already abusing drugs to overcome hangover and fatigue. Notably, there are two former narcotic abusers described in the literature who denied experiencing any euphoric effect from fenetylline [27]. Fenetylline has not been reported as being used as a primary drug of abuse. No physical and no evident psychological withdrawal symptoms have been causally linked to cessation of chronic intake of fenetylline. Finaliy, in 16 cases when fenetylline was replaced by placebo, 10 patients either did not notice the substitution or accepted the ‘less strong Captagon’ with little complaint (case histories). Results are not available on the remaining six cases. In summary, there is sufficient evidence to conclude that fenetylline has a low potential for abuse compared to amphetamine and other classical CNS stimulants. ACTUAL
ABUSE
A total of 118 cases (Table II) of abuse of fenetylline has been reported to the manufacturer by various sources in the F.R.G. since the drug was marketed in 1961 up to October 1983. Twenty-seven of these cases occurred prior to April 1964 when medical prescription became obligatory. Since then an average of only about 5 cases/year of fenetylline abuse has been reported. These figures have been compiled from data supplied by the Bundesgesundheitsamt, the Drug Committee of the German Chamber of Physicians and from direct notifications to the manufacturer. They do not include reports from police or any other authorities. It was found that polydrug abusers were involved in 37 cases. In some instances patients have received fenetylline pursuant to a medical prescription and inappropriately continued at increased dosage levels. This drug misuse could be dealt with through educational actions informing physicians and patients about appropriate prescribing and use. The manufacturer is not aware of any reports involving possible parenteral use or abuse of fenetylline. Degussa has investigated reported cases of fenetylline abuse in the United States. Until October 1983, only three emergency room reports were uncovered under the Drug Abuse Warning Network system. Fenetylline is not marketed in the U.S.A. Nevertheless, there have been various reports of seizures, mainly of counterfeit fenetylline tablets, or preparations containing substances purported to be fenetylline, including falsified packaging characteristics, in some countries. Degussa Pharma is eager to work with the appropriate authorities to halt any such diversion. To support these efforts the manufacturer has introduced an improved packaging code. DISCUSSION
AND CONCLUSIONS
A summary of data on the efficacy and safety of fenetylline, including information on abuse potential and actual abuse, has been presented. Degussa encourages national regulatory authorities to require prescription
268 TABLE
II
REPORTS OF CAPTAGON@ 1961) TO OCTOBER 1983 Period of reporting
CAPTAGON@ No. of reported cases I total)
1962 1963 Until April 1964 Until medical prescription became obligatory until 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 Until October 1983 Total
ABUSE
4 18 5
FROM
DATE
Persons working in health professions
No. of suspected cases
-
Cases in connection with incurred criminal liabilitya
2 8
1 3 4
10
-
1 2
-
4
-
-
3 1 2 3
-
1
-
2 3 4 8 4 11 2
118
15, _
4 5 8 15 7 8 2 1 3 -
-
(JULY
abuse
27
-
OF INTRODUCTION
2 1 2 1 1
-
-
24
18
17
aThese are subjects who could possibly be characterized criminal liability after a single intake of a high dose.
as dealers or having incurred
before fenetylline may be-dispensed to help ensure that it is used properly. Degussa has placed carefully worded notes of precaution in its instructions for use in order that the physician and the patient are made aware that longterm therapy is to be avoided and so-called ‘drug holidays’ of several weeks are to be observed. During the past 23 years, it has been found that the
269
abuse potential and the actual abuse of fenetylline in the F.R.G. and in other countries has been low compared to that of amphetamine-type stimulants. Subjecting fenetylline to stringent international scheduling would probably result in physicians prescribing other substances, such as the amphetamines, neuroleptics, or antidepressants, for medical conditions for which fenetylline is indicated. Experience has shown that these latter substances either have high abuse potential, are actively sought by drug abusers, and/or have more serious adverse effects than fenetylline. For example, these are amphetamine-like effects or, in the case of neuroleptics, can be long-term consequences, such as tardive dyskinesia. Medical effects. Presently fenetylline is used in Germany and other European countries for the following therapeutic indications: - hyperkinesia in children (minimal brain dysfunction syndrome) - narcolepsy - lack of drive, especially in elderly patients, and for other special conditions (after severe illness, surgery, and head injuries). Clinical trials and more than 23 years of therapeutic experience have detected no adverse drug-related effects on hepatic and renal functions, pulmonary circulation or hemogram and blood pressure. The only adverse effects reported after therapeutic doses have been minimal and have included palpitation, vertigo, and other minor sympathomimetic or unspecific effects. Psychological tests in healthy volunteers have shown stimulating and mood improving effects distinctly lower in intensity than those of caffeine and other central stimulants, such as methylphenidate and methamphetamine. These effects were not accompanied by the typical euphoria classically associated with amphetamine-type compounds. Other important differences in the profiles of activity exhibited by fenetylline and amphetamine-type stimulants support the contention that fenetylline also differs from amphetamine-type stimulants in terms of its abuse potential. These differences include: In human studies No arrhythmias or increase in blood pressure in contrast to amphetamine which has both effects. No post-medication effects in therapeutic dosages like amphetamine and other CNS stimulants. Inhibiting effects against alcohol-induced depression of patellar reflexes in contrast to amphetamine (see animal studies also Ref. 3). No interference and even significant improvement of fine motor activity and psychomotor performance with fenetylline in contrast to amphetamine and caffeine. No, or only slight, anorectic activity with fenetylline in contrast to other centrally acting stimulants. In animal studies Earlier as well as recent
[3,25]
animal studies show marked differences
270
between fenetylline and amphetamine. These differences were observed particularly in motor activity, interaction with compounds which induce loss of righting reflex, food intake, toxicity in grouped animals, adverse effects, and development of tolerance. Moreover, fenetylline inhibits various effects of amphetamine, e.g. hexobarbital induced loss of righting reflex and aggregate induced toxicity. These different profiles of activity observed are not consistent with the assumption that the pharmacological and therapeutic effects of fenetylline are identical to or due to those of amphetamine. Nor are the findings consistent with the concept that fenetylline is primarily a prodrug of amphetamine and/or theophylline even though relatively small amounts of amphetamine can be detected in urine and plasma after fenetylline administration to humans. On the other hand, in several tests fenetylline acts more like theophylline. Evidence for fenetylline’s low abuse potential has been reported by Hoffmeister [ 261. His studies showed that cocaine-dependent monkeys would self-administer cocaine, amphetamine and phenmetrazine in contrast to fenetylline which exhibited much weaker reinforcing properties, similar only to those of saline. Furthermore, very little actual abuse has been reported to the manufacturer by various sources in Germany: 118 cases since launching the drug in July 1961 up to October 1983 and, since medical prescription became obligatory in 1964, an average of about 5 cases of abuse per year. These figures do not include reports from police or other authorities. The actual abuse found could be attributed in part to use by alcohol and drug addicts to overcome hangover or fatigue. Fenetylline has not been reported as a primary drug of abuse. In addition, no physical or evident psychological withdrawal symptoms have been reported following cessation of chronic fenetylline administration. We are aware, however, that there are reports of the appearance of counterfeited CAPTAGON@ packages and tablets containing fenetylline or other stimulating substances in some countries, including the F.R.G. Degussa has, therefore, introduced a new packaging code which will provide better protection against these imitations. On a voluntary basis, Degussa maintains close contact with the relevant authorities in Germany (Federal Health Office = BGA, Federal Criminal Office = BKA, Drug Commission of the Federal Chamber of Physicians). It is also regularly filing reports in the F.R.G. on any information received on both abuse and adverse effects involving fenetylline. Thus, in view of fenetylline’s therapeutic efficacy, low incidence of adverse side effects and low abuse potential, its benefit/risk assessment is substantially more favourable than that of most other centrally acting stimulants .
271
REFERENCES 1 W. Janke and P. Netter, in: L. Tent, Erkennen, Wollen, Handeln, Festschrift fur Heinrich Diiker zum 80. Geburtstag, Verlag fur Psychologie, Dr. C.J. Hogrefe, Gottingen, Toronto, Zurich, 1981, pp. 404-423. 2 W. Miiller-Limmroth, Arzneim.-Forsch., 35 (1985) 998. 3 B. Nickel et al., Drug Alcohol Depend., 17 (1986) 235. 4 W. Janke and H. Boss, Arzneim.-Forsch., 11 (1961) 783. 5 H.H. Borger, Med. Welt, 9 (1962) 493. 6 F. Lang, Wiener Med. Wochenschr., 111 (1961) 900. 7 H. Linke, Arztl. Praxis, 13 (1961) 1868. 8 A. Simko, Med. Welt, 48 (1965) 2712. 9 F. Bahr, R. Llanos and N. Matussek, Pharmakopsychiatr. Neuropsychopharmakol., 3 (1970) 60. 10 E. Berger, Minimale cerebrale Dysfunktion bei Kindern, Verlag Huber, Bern, Stuttgart, Wien, 1977, p. 172. 11 B. Mangold, Prax. Kinderpsychol. Kinderpsychiatr., 24 (1975) 185. 12 H. Cramer, Dtsch. Arzteblatt, 73 (1976) 21. 13 H. Grosch, Z. Allg. Med. (Landarzt) 47 (1971) 1837. 14 R. Schiffter, Ther. G., 120 (1981) 898. 15 U.J. Jovanovic, Arzneim.-Forsch., 20 (1966) 206. 16 M. Domenach, Cah. Med. Lyon., 42 (1966) 489. 17 S. Dornbusch, Med. Klin., 58 (1963) 256. 18 W. Dietner, Arzt. Praxis, 15 (1963) 985. 19 M. Texier d’Arnoult, Cah. Med. Lyon., 42 (1966) 943. 20 M. Choppy et al., Therapie, 21 (1966) 215. 21 C. Lapras and J. Robert, Cah. Med. Lyon., 42 (1966) 727. 22 I. Raisp, Zdrav. Vestn., 40 (1971) 3. 23 P. Netter et al., Arzneim.-Forsch., 28 (1978) 1310. 24 H. Joachim and J. Hochreuther, Blutalkohol, 14 (1977) 19. 25 W. Dimpfel et al., Arzneim.-Forsch., 1986 (in press). 26 F. Hoffmeister, Psychopharmacology, 72 (1980) 41. 27 H. Grahmann and F. Reimer, Nervenarzt, 36 (1965) 227.
Dependence,
Elsevier
Publishers
Scientific
FENETYLLINE:
17 ( 1986) Ireland
THERAPEUTIC
GERFRIED KRISTEN, SCHLICHTEGROLL*
Degussa Pharma Gruppe, Main-i (F.R.G.)
ANNELIES
259-27
1
259
Ltd.
USE, MISUSE AND/OR ABUSE SCHAEFER
Chemiewerk
Homburg,
and ANSGAR
Daimlerstrasse
VON
25, D-6000
Frankfurt/
SUMMARY
Fenetylline (CAPTAGON@) is included in a list of compounds to be considered by a World Health Organization (WHO) Expert Committee in April 1985 for possible international scheduling under the Convention on Psychotropic Substances, 1971. For over 23 years, this central stimulant has been used therapeutically in hyperkinetic children and other indications in place of amphetamines and other central stimulants with higher risk levels. In good correspondence with recent animal data fenetylline also shows significant qualitative and quantitative differences compared to amphetamine in man. It has few adverse side effects, a lower abuse potential and little actual abuse compared to amphetamine. Thus its benefit/risk assessment is substantially more favourable than that of other central stimulants. For proper therapeutic use of the substance, prescription status is or should be required by national authorities. Key words: Fenetylline - Amphetamine ratio - Misuse, Abuse - Hyperkinesis
- Therapeutic
uses -
Benefit/risk
INTRODUCTION
Fenetylline was originally developed by Degussa’s drug research department as part of an investigational program on theophylline derivatives, particularly concerned with the cardiovascular, pulmonary and central nervous system (CNS) effects of these substances. Fenetylline clearly exhibits central stimulant activity. However, early studies strongly suggested that fenetylline may differ from classical CNS stimulants of the amphetamine type in terms of potency, mode of action and the type and incidence of side effects. Thus, there were indications that the compound may offer decided advantages over available therapeutic modalities.
*To
whom
correspondence
should
be addressed.
0376-8716/86/$03.50 o Elsevier Scientific Publishers Ireland Printed and Published in Ireland
Ltd
In 1961, Degussa AG (Pharmaceutical Division/Homburg) introduced fenetylline into the Federal Republic of Germany as a 50-mg tablet. In 1964, Degussa requested prescription status to assure that the drug was used only under medical supervision. Thus, fenetylline can be dispensed only pursuant to a medical prescription in the F.R.G. Some early metabolic and pharmacological studies suggested that fenetylline might be similar to amphetamine; these early studies may be subject to some scrutiny. Nevertheless, largely on the basis of these early findings and because no investigational new drug application (IND)/(NDA) was submitted to the Food and Drug Administration (FDA) and thus no medical use established in the United States. In 1981 fenetylline was placed in Schedule I of the Controlled Substances Act of the United States. More recent preclinical investigations argue strongly against the assumption that fenetylline is similar to amphetamine. In particular, recent pharmacological, pharmacokinetic and metabolic results strongly disagree with early assumptions that the pharmacology of fenetylline is essentially that of amphetamine [l--3; Nissen, unpublished report). Moreover, there is a substantial body of information from human studies and extensive therapeutic experience with the drug which attest to its therapeutic usefulness and demonstrate that the compound exhibits substantial differences from amphetamines in terms of benefit/risk ratio. THERAPEUTIC
EFFICACY.
ADVERSE
EFFECTS
AND
ABUSE
Medical effects. In psychological and psychomotor tests Janke and Boss [ 41 found that 50 mg of fenetylline improved mental and psychomotor performance 1 h after oral administration (Fig. 1). In addition, the compound has been shown to have a mood-improving effect which clearly differs from that of other centrally acting stimulants. Based on the literature, the stimulating activity of fenetylline proved to be distinctly lower in intensity than that of caffeine, methylphenidate and methamphetamine [ 41. Other authors [ 5-81 agree with the results of these investigations and describe fenetylline’s action as improving mood as well as increasing productivity and the ability to concentrate. Similar results were found in a 1984 investigation [2] conducted by the Institute for Occupational Physiology, Technical University of Munich, using a double-blind, placebo-controlled crossover design. It was concluded that fenetylline significantly improves psychomotor and mental performance. No instances of an abnormal or exaggerated sense of well-being were observed after fenetylline intake in any of the clinical studies. The typical ‘euphoria’ classically associated with amphetamine-type compounds did not occur with fenetylline. After ingesting fenetylline subjects were described as being in a well-balanced emotional state (Figs. 1 and 2) [ 4,5]. Indications. Fenetylline is typically prescribed in place of amphetamines and other centrally acting stimulants. Its effects make the drug particularly
261
*
a *p
<
b
d
0.06
Fig. 1. Effect of 50 mg fenetylline hydrochloride administered orally to 20 human volunteers on adjective check list scores [4]. W, placebo; q, fenetylline. (a) sociable; (b) emotionally; (c) purposeful; (d) in good mood; (e) psychic and motor activity.
for use in the following indications : hyperkinesia in children (minimal brain dysfunction syndrome) [ 9-11; Nissen and Matussek, unpublished report; Nissen, unpublished report]. - narcolepsy [ 8,12-151. - lack of drive, particularly in the elderly, patients with and without organic diseases, e.g. parkinsonism, apoplexy, etc. [5--8,16,17; Brix and Werner, unpublished report]. - lack of drive following severe illness, surgery, [7,16-191 as well as head injuries [l&20,21]. Fenetylline is especially advantageous in the treatment of hyperkinetic children where it replaces centrally (CNS) acting stimulants, such as methylphenidate and methamphetamine, which present greater risks and have suitable
-
262 + 80 70 60 50 Q )_ z a
I
40 30 20 101
O-1 IO209 30-
-
40. 509 60-
P
30
so
80
MO
FENETYLLINE
+p
of 30, 50, and 80 mg fenetylline hydrochloride to questionnaire scores [4 1. emotional stability;
+,
higher abuse potential, This has been found in one of the leading European hospitals in this field (Nissen and Matussek, unpublished report; Nissen, unpublished report). Other therapeutic alternativeswould be neuroleptics or antidepressants which have more adverse effects. Fenetylline’s efficacy in hyperkinesia has been demonstrated in a double-blind study [91. It is of equal importance in the treatment of narcolepsy and epileptic absences. In
263
these cases the drug not only improved vigilance but also substantially decreased paroxysms [ 14 ; Bauman and Tomka, unpublished report]. The only therapeutic alternatives for these indications are CNS stimulants with a higher risk level. The same consideration applies to adjuvant therapy in Parkinson’s disease in which CNS stimulants are widely used. Since fenetylline was introduced into therapy some 23 years ago a very long therapeutic experience attests to its safety and efficacy in addition to the above mentioned more recent studies and data. Benefit/risk assessment. When making a benefit/risk assessment, it should be stressed that results from clinical trials and more than 23 years of therapeutic experience with fenetylline have detected no adverse effects on hepatic and renal functions, on blood pressure, or on the hemogram (Figs. 3 and 4) [ 5-7,201. Furthermore, there is no indication of the occurrence of pulmonary hypertension [ 221. The only adverse reactions reported with therapeutic doses of fenetylline are occasional palpitation, vertigo, dryness of mouth, gastric complaints, and other minor sympathomimetic or unspecific effects [ 5,7,8]. Following
160140’
. . . . . . . . n.
..1......-
130-
a
SYSTOLIC
120llOlooao-
*
80,
_-___-_-
-a
DIASTOLIC-
7030609
DIFFERENCE
m
1
1
0
8
WEEKS
Fig. 3. Mean blood pressure of 21 persons without circulatory disturbances before (0) and 8 weeks after oral administration of 50 mg fenetylline hydrochloride b.i.d. (morning and afternoon) [ 221.
‘64
Schellong-Test SE FORE
12
PULSE
110 10
SYSTOLIC
QO 80
DIASTOLIC
70 00 3 1
3
0
120
6 0
MINUTES SYSTOLIC
AFTER
110 100 90
PULSE
80
DIASTOLIC
70 60 I I
I
1
3
I
6.
MINUTES
Fig. 4. Mean heart rate and blood pressure values of 17 patients with orthostatic dysregulation before and 10 days after oral administration of 50 mg fenetylline hydrochloride b.i.d. [6 1.
fenetylline intake in the late afternoon or evening (which is not recommended) some early sleep disturbances have been reported [ 5,7-9,161. If the contraindications and precautions defined in fenetylline’s labelling are observed, the drug has proved to be reliable and safe. DIFFERENCES
BETWEEN
FENETYLLINE
AND AMPHETAMINES
Several significant differences have been observed clinically regarding the effects and adverse reactions of fenetylline on the one hand and amphetamine or methamphetamine on the other (Table I).
265
TABLE
I
COMPARISON OF SIDE EFFECTS OF AMPHETAMINE OR METHAMPHETAMINE AND FENETYLLINE IN THERAPEUTIC DOSAGES [ 51 Amphetamine or methamphetamine
Fenetylline
Blood pressure Appetite Fine motor activity
Increase Reduced Tremor
Mood
‘Euphoria’
Small decrease Practically not influenced Extremely seldom small tremor at higher dosages Well-balanced emotional state
Post-medication decrease performance Enhanced effect by caffeine Subjective feeling of restlessness Early sleep disturbances
in Significant
Not observed
Existent
Existent
Rather frequently Frequently
Seldom Seldom
(1) Fenetylline does not influence, or only slightly affects, appetite [ 5-7, 91. Psychological studies have shown that fenetylline barely differs from placebo with regard to the desire for food while anorectics markedly reduce that desire (Fig. 5) [ 231. (2) In contrast to amphetamine and caffeine, fenetylline does not interfere with fine motor activity [4]. In three different psychomotor tests (target pointing, finger dexterity, tremor measurement) fenetylline even improved performance [ 11. (3) In a double-blind crossover study in which the MAO-B inhibitor, selegiline, and fenetylline were compared to placebo with regard to their influence on the psychomotor efficiency of human volunteers, it could be seen that fenetylline improves all parameters (motor reaction time, mental processing, and control errors) [ 21. (4) At therapeutic dosages, amphetamine-type stimulants produce symptoms, such as post-medication decrease in performance associated with hangover effects, tendency to collapse, motor restlessness, insomnia, tremor and rapid changes of mood or jumping from one idea to another. Fenetylline has rarely been found to produce these effects with therapeutic dosages E5,71. (5) Fenetylline antagonize alcohol-induced depression of the patellar reflexes [24]. Thus, its mode of action on the neuromuscular system is apparently different from that of amphetamine. This could explain the beneficial effect of fenetylline on fine muscle control (i.e. reduction of tremor). (6) Fenetylline is better tolerated than amphetamine and other CNS stimulants (Figs. 3 and 4, Table I) [see also Ref. 31.
266
APPETITE SCORE Ub
rs
3.6 t
3.4
K w
3.2.
= (1
3.0.
:
2.8.
> J-
2.6’
cn z
2.4.
: t
2.2’
P
M
F
Fig. 5. Mean questionnaire scores on activity preference, ‘desire for food’, in 16 human subjects following oral administration of placebo, mefenorex (40 mg) and fenetylline (50 mg) [23]. P, placebo; M, mefenorex (40 mg); F, fenetylline (50 mg).
These differences between fenetylline and amphetamine correspond well with recent findings in animal experiments [3,25]. Thus, it might be expected that fenetylline might also differ from amphetamine with respect to abuse potential. ABUSE
POTENTIAL
Fenetylline is also clearly different from other CNS stimulants in terms of its abuse potential. This has been shown in tests involving self-administration in monkeys [26; Hoffmeister, unpublished report] as well as in the above mentioned human pharmacological studies and in over 23 years of therapeutic experience. The psychostimulant activity of fenetylline is described as a sense of well-balanced positive emotional tone and not as passively experienced elation [4,5]. A few authors [ 7,271 have noted that
267
fenetylline may have some abuse potential. As far as known, this appears, in large measure, to be attributable to the drive-promoting action of fenetylline which may help individuals already abusing drugs to overcome hangover and fatigue. Notably, there are two former narcotic abusers described in the literature who denied experiencing any euphoric effect from fenetylline [27]. Fenetylline has not been reported as being used as a primary drug of abuse. No physical and no evident psychological withdrawal symptoms have been causally linked to cessation of chronic intake of fenetylline. Finaliy, in 16 cases when fenetylline was replaced by placebo, 10 patients either did not notice the substitution or accepted the ‘less strong Captagon’ with little complaint (case histories). Results are not available on the remaining six cases. In summary, there is sufficient evidence to conclude that fenetylline has a low potential for abuse compared to amphetamine and other classical CNS stimulants. ACTUAL
ABUSE
A total of 118 cases (Table II) of abuse of fenetylline has been reported to the manufacturer by various sources in the F.R.G. since the drug was marketed in 1961 up to October 1983. Twenty-seven of these cases occurred prior to April 1964 when medical prescription became obligatory. Since then an average of only about 5 cases/year of fenetylline abuse has been reported. These figures have been compiled from data supplied by the Bundesgesundheitsamt, the Drug Committee of the German Chamber of Physicians and from direct notifications to the manufacturer. They do not include reports from police or any other authorities. It was found that polydrug abusers were involved in 37 cases. In some instances patients have received fenetylline pursuant to a medical prescription and inappropriately continued at increased dosage levels. This drug misuse could be dealt with through educational actions informing physicians and patients about appropriate prescribing and use. The manufacturer is not aware of any reports involving possible parenteral use or abuse of fenetylline. Degussa has investigated reported cases of fenetylline abuse in the United States. Until October 1983, only three emergency room reports were uncovered under the Drug Abuse Warning Network system. Fenetylline is not marketed in the U.S.A. Nevertheless, there have been various reports of seizures, mainly of counterfeit fenetylline tablets, or preparations containing substances purported to be fenetylline, including falsified packaging characteristics, in some countries. Degussa Pharma is eager to work with the appropriate authorities to halt any such diversion. To support these efforts the manufacturer has introduced an improved packaging code. DISCUSSION
AND CONCLUSIONS
A summary of data on the efficacy and safety of fenetylline, including information on abuse potential and actual abuse, has been presented. Degussa encourages national regulatory authorities to require prescription
268 TABLE
II
REPORTS OF CAPTAGON@ 1961) TO OCTOBER 1983 Period of reporting
CAPTAGON@ No. of reported cases I total)
1962 1963 Until April 1964 Until medical prescription became obligatory until 1964 1965 1966 1967 1968 1969 1970 1971 1972 1973 1974 1975 1976 1977 1978 1979 1980 1981 1982 Until October 1983 Total
ABUSE
4 18 5
FROM
DATE
Persons working in health professions
No. of suspected cases
-
Cases in connection with incurred criminal liabilitya
2 8
1 3 4
10
-
1 2
-
4
-
-
3 1 2 3
-
1
-
2 3 4 8 4 11 2
118
15, _
4 5 8 15 7 8 2 1 3 -
-
(JULY
abuse
27
-
OF INTRODUCTION
2 1 2 1 1
-
-
24
18
17
aThese are subjects who could possibly be characterized criminal liability after a single intake of a high dose.
as dealers or having incurred
before fenetylline may be-dispensed to help ensure that it is used properly. Degussa has placed carefully worded notes of precaution in its instructions for use in order that the physician and the patient are made aware that longterm therapy is to be avoided and so-called ‘drug holidays’ of several weeks are to be observed. During the past 23 years, it has been found that the
269
abuse potential and the actual abuse of fenetylline in the F.R.G. and in other countries has been low compared to that of amphetamine-type stimulants. Subjecting fenetylline to stringent international scheduling would probably result in physicians prescribing other substances, such as the amphetamines, neuroleptics, or antidepressants, for medical conditions for which fenetylline is indicated. Experience has shown that these latter substances either have high abuse potential, are actively sought by drug abusers, and/or have more serious adverse effects than fenetylline. For example, these are amphetamine-like effects or, in the case of neuroleptics, can be long-term consequences, such as tardive dyskinesia. Medical effects. Presently fenetylline is used in Germany and other European countries for the following therapeutic indications: - hyperkinesia in children (minimal brain dysfunction syndrome) - narcolepsy - lack of drive, especially in elderly patients, and for other special conditions (after severe illness, surgery, and head injuries). Clinical trials and more than 23 years of therapeutic experience have detected no adverse drug-related effects on hepatic and renal functions, pulmonary circulation or hemogram and blood pressure. The only adverse effects reported after therapeutic doses have been minimal and have included palpitation, vertigo, and other minor sympathomimetic or unspecific effects. Psychological tests in healthy volunteers have shown stimulating and mood improving effects distinctly lower in intensity than those of caffeine and other central stimulants, such as methylphenidate and methamphetamine. These effects were not accompanied by the typical euphoria classically associated with amphetamine-type compounds. Other important differences in the profiles of activity exhibited by fenetylline and amphetamine-type stimulants support the contention that fenetylline also differs from amphetamine-type stimulants in terms of its abuse potential. These differences include: In human studies No arrhythmias or increase in blood pressure in contrast to amphetamine which has both effects. No post-medication effects in therapeutic dosages like amphetamine and other CNS stimulants. Inhibiting effects against alcohol-induced depression of patellar reflexes in contrast to amphetamine (see animal studies also Ref. 3). No interference and even significant improvement of fine motor activity and psychomotor performance with fenetylline in contrast to amphetamine and caffeine. No, or only slight, anorectic activity with fenetylline in contrast to other centrally acting stimulants. In animal studies Earlier as well as recent
[3,25]
animal studies show marked differences
270
between fenetylline and amphetamine. These differences were observed particularly in motor activity, interaction with compounds which induce loss of righting reflex, food intake, toxicity in grouped animals, adverse effects, and development of tolerance. Moreover, fenetylline inhibits various effects of amphetamine, e.g. hexobarbital induced loss of righting reflex and aggregate induced toxicity. These different profiles of activity observed are not consistent with the assumption that the pharmacological and therapeutic effects of fenetylline are identical to or due to those of amphetamine. Nor are the findings consistent with the concept that fenetylline is primarily a prodrug of amphetamine and/or theophylline even though relatively small amounts of amphetamine can be detected in urine and plasma after fenetylline administration to humans. On the other hand, in several tests fenetylline acts more like theophylline. Evidence for fenetylline’s low abuse potential has been reported by Hoffmeister [ 261. His studies showed that cocaine-dependent monkeys would self-administer cocaine, amphetamine and phenmetrazine in contrast to fenetylline which exhibited much weaker reinforcing properties, similar only to those of saline. Furthermore, very little actual abuse has been reported to the manufacturer by various sources in Germany: 118 cases since launching the drug in July 1961 up to October 1983 and, since medical prescription became obligatory in 1964, an average of about 5 cases of abuse per year. These figures do not include reports from police or other authorities. The actual abuse found could be attributed in part to use by alcohol and drug addicts to overcome hangover or fatigue. Fenetylline has not been reported as a primary drug of abuse. In addition, no physical or evident psychological withdrawal symptoms have been reported following cessation of chronic fenetylline administration. We are aware, however, that there are reports of the appearance of counterfeited CAPTAGON@ packages and tablets containing fenetylline or other stimulating substances in some countries, including the F.R.G. Degussa has, therefore, introduced a new packaging code which will provide better protection against these imitations. On a voluntary basis, Degussa maintains close contact with the relevant authorities in Germany (Federal Health Office = BGA, Federal Criminal Office = BKA, Drug Commission of the Federal Chamber of Physicians). It is also regularly filing reports in the F.R.G. on any information received on both abuse and adverse effects involving fenetylline. Thus, in view of fenetylline’s therapeutic efficacy, low incidence of adverse side effects and low abuse potential, its benefit/risk assessment is substantially more favourable than that of most other centrally acting stimulants .
271
REFERENCES 1 W. Janke and P. Netter, in: L. Tent, Erkennen, Wollen, Handeln, Festschrift fur Heinrich Diiker zum 80. Geburtstag, Verlag fur Psychologie, Dr. C.J. Hogrefe, Gottingen, Toronto, Zurich, 1981, pp. 404-423. 2 W. Miiller-Limmroth, Arzneim.-Forsch., 35 (1985) 998. 3 B. Nickel et al., Drug Alcohol Depend., 17 (1986) 235. 4 W. Janke and H. Boss, Arzneim.-Forsch., 11 (1961) 783. 5 H.H. Borger, Med. Welt, 9 (1962) 493. 6 F. Lang, Wiener Med. Wochenschr., 111 (1961) 900. 7 H. Linke, Arztl. Praxis, 13 (1961) 1868. 8 A. Simko, Med. Welt, 48 (1965) 2712. 9 F. Bahr, R. Llanos and N. Matussek, Pharmakopsychiatr. Neuropsychopharmakol., 3 (1970) 60. 10 E. Berger, Minimale cerebrale Dysfunktion bei Kindern, Verlag Huber, Bern, Stuttgart, Wien, 1977, p. 172. 11 B. Mangold, Prax. Kinderpsychol. Kinderpsychiatr., 24 (1975) 185. 12 H. Cramer, Dtsch. Arzteblatt, 73 (1976) 21. 13 H. Grosch, Z. Allg. Med. (Landarzt) 47 (1971) 1837. 14 R. Schiffter, Ther. G., 120 (1981) 898. 15 U.J. Jovanovic, Arzneim.-Forsch., 20 (1966) 206. 16 M. Domenach, Cah. Med. Lyon., 42 (1966) 489. 17 S. Dornbusch, Med. Klin., 58 (1963) 256. 18 W. Dietner, Arzt. Praxis, 15 (1963) 985. 19 M. Texier d’Arnoult, Cah. Med. Lyon., 42 (1966) 943. 20 M. Choppy et al., Therapie, 21 (1966) 215. 21 C. Lapras and J. Robert, Cah. Med. Lyon., 42 (1966) 727. 22 I. Raisp, Zdrav. Vestn., 40 (1971) 3. 23 P. Netter et al., Arzneim.-Forsch., 28 (1978) 1310. 24 H. Joachim and J. Hochreuther, Blutalkohol, 14 (1977) 19. 25 W. Dimpfel et al., Arzneim.-Forsch., 1986 (in press). 26 F. Hoffmeister, Psychopharmacology, 72 (1980) 41. 27 H. Grahmann and F. Reimer, Nervenarzt, 36 (1965) 227.