1979b). A selective increase in synaptic vesicular Mgrt-dependent ATPase activity
resulted during tolerance and depcndence development but synaptic plasma
membrane Mgtt-dependent ATPase and Na-, K+ activated ATPase activity were not
altered (Yamamoto, Harris, Loh & Way, 1977).
Like morphine, repeated intraventricular injections of ß-endorphin also resulted
in enhanced 4SCa++ uptake (Guerrero-Munoz et al., 1979c). Rats were rendered
tolerant by twice daily administration for three successive days of a high dose of
ß -endorphin (9 I-Jg in 5 lJ1 of saline) into a stainless steel cannula implanted in the
fourth ventricle. The Irrst dose produced catalepsy which diminished with each
successive adm inistration and was absent after the sixth and fmal dose.
Synaptosomal 45Ca++ uptake studies were performed 30 min after the last inject ion.
The results indicated that the development of tolerance to ß-endorphin was
accompanied by augmented 4SCa++ uptake by about 30%. This enhancement in
uptake was comparable to that with a nearly similar dose ofmorphine sulphate given
ß -ENDORPHIN IN PHYSICAL DEPENDENCE
Tolerance alterations in neuronal Ca++ and chronic opiate action
The evidence provided above support the thesis that tolerance to opiate action could
be the consequence ofcumulative Ca++ retention in the neurone which opposes acute
opiate action. As indicated by the studies on tolerant animals, the Ca++ is elevated at
nerve endings and the increase occurs selectively at synaptic vesicular sites. The
increase in neuronal Ca++ requires that more opiate be administered to lower Ca++ to
a level that produces analgesia. This Ca++ retention receptor (CRR) at the
synaptic plasma membrane and synaptic vesicles becomes activated to combine with
activated Ca++ (calmodulin) with the first opiate injection and becomes increasingly
prominent with each successive and increasing opiate dose. Thus, with increasing
increments of Ca++ retention, there is a proportionate increase in the amount of
opiate required to produce analgesia. This provides an amplification mechanism to
explain tolerance development as weil as the phenomenon of cross tolerance. With
elevated neuronal Ca++ levels, agents other than opiates which tend to decrease
neuronal Ca " would also ' be less effective . Thus, the analgetic response to La+++
(Harris, Loh & Way, 1976) and EGTA (Schrnidt & Way, 1979) in morphine after
development oftolerance is less than that in the normal state and this would explain
the cross tolerance of opiate-tolerant animals to these two agents.
Manipulations which tend to enhance acute opiate action could indirectly activate
Ca++ retention and thereby facilitate the development of .tolerance whereas the
reverse should inhibit tolerance development. Thus, EGTA which enhances acute
morphine action by reducing available Ca++ facilitates the development oftolerance,
whereas the injection of'Car" decreases the development oftolerance. Consistent with
these notions, it has been reported that Ca++ reduces tolerance development and it has
been found that slow infusion of EGTA intraventricularly in the rat enhances
tolerance development (Schmidt & Way, 1980).
The selective increase in synaptic vesicular Mgv'-dependent ATPase activity
accompanying the increase in synaptic vesicular Ca++ after tolerance and dependence
development is also compatible with the present hypothesis. As pointed out earlier, it
has been postulated that the acute effects of morphine may involve an inhibition of
neurotransmitter release due to depletion of vesicular Ca++. Since Mgv'-dependent
ATPase ofsynaptic vesicles appears to be important for both the uptake and release
of neurotransmitters, the increase in the activity of Mg++-ATPase after morphine
may reflect a homeostatic response to its chronic administration.
Evidence that this is astate wherein the exeitable effeets of elevated neuronal Ca++ on
neurotransmitter release is masked by the presenee of opiates was demonstrated in
to have largely disappeared from the body, not only was a hyperalgesie response
demonstrated to be present as evidenced by shortened tail-fliek lateney but sueh
animals also evideneed greater sensitivity to the hyperalgesie effeets of'Ca-t injeetion
than non-dependent animals (Sehmidt & Way, 1980). On the other hand as
demonstrated earlier (Harris et al., 1975a), a lowering of neuronal Ca++ with La+++,
like opiates, redueed the severity of aeute withdrawal and increased the dose of
naloxone required to preeipitate withdrawal jumping.
A testable hypothesis based on alterations in neuronal Cart has been provided that
appears to explain the pharmacological properties of opiates. Data cited to support
the arguments include the correlation ofin vitro and in vivo fmdings on neuronal Ca++
disposition with acute and chronic pharmacological actions concemed with
analgesia , tolerance and physical dependence in the intact animal. The hypothesis
can be subjected to further experimental validation and efforts are continuing
The above studies with ~endorphin also suggest so me approaches towar~s
assessing its possible functional role. As a neuromodulator, for example, can it
regulate neurotransmitter release by controlling neuronal Ca++? Can the ability to
accumulate Ca++ represent a homeostatic response to counteract continuous stress of
the endorphinergic system? These questions can only be answered by time and
A large portion ofthe studies described on ß-endorphin are supported by grants from
the National Institute on Drug Abuse (DA M037 and DA 01696).
Bradbury, A. F., Smyth, D. G. & Snell, C. R. (1976). C fragment oflipotropin has a high affmity
forbrain opiate receptors. Nature, 260,.793-795 .
Cardenas, H. L. & Ross, D. H. (1976). Calcium depletion of synaptosome s after morphine
treatment. Brit. J. Pharmac., 57, 521-526.
Catlin, D. H., Gorelick , D. A., Gerner, R. H., Hui, K. K. & Li, C. H. (1980). Clinical effects of
ß-endorphin infusions. Adv. Biochem. Psychopharmac., in press.
Celsen, B. & Kuschinsky, K. (1974). Effects of morphine on kinetics of [J4C)-dopamine in rat
striatal slices. Naunyn Schm iedeberg 's Arch. Pharm ac., 284,159-165.
Cox, B. M., Goldstein, A. & Li, C. H. (1976). Opioid activity ofa peptide p-lipotropin (61-91)
derived from fl-Iipotropin. Proc. Nat. Acad.Sei. USA, 73, 1821-1823.
Guerrero-Munoz, F., Cerreta, K. V., Guerrero, M. L. & Way, E. L. (1979a). Effect ofmorphine
on synaptosomal Ca++ uptake . J. Pharmac. exp. Ther., 209,132-136.
Guerrero-Munoz, F., Guerrero, M. & Way, E. L. (1979b). Effectofmorphine on calcium uptake
in Iysed synaptosomes. J. Pharmac. exp. Ther., 211, 370-374.
Guerrero-Munoz, F., Guerrero, M. L. & Way, E. L. (1979c). Effect of p -endorphin on Ca++
uptake in the brain. Science. 206, 89-91.
Harris, R. A., 1wamoto, E. T., Loh, H. H. & Way, E. L. (1975b). Analgetic effects oflanthanum:
cross tolerance with morphine. Brain Res., 100,221-225.
Harris, R. A., Loh, H. H. & Way, E. L. (1975a). Effects of divalent cations, cation chelators and
an ionophore on morphine analgesia and tolerance . J. Pharmac. exp. Ther., 195,488-498.
Harris, R. A., Loh, H. H. & Way, E. L. (1976). Antinociceptive effectsoflanthanum and cerium
in non-tolerant and morphine tolerant-dependent animals. J. Pharmac. exp. Ther., 196,
Harris , R. A., Yamamoto, H., Loh, H. H. & Way, E. L. (1977). Discrete changes in brain
calcium with morphine analgesia, tolerance-dependence, and abstinence. Lift Sci. , 20,
Henderson , G., Hughes, J. & Kosterlitz, H. W. (1975). The effects ofmorphine on the release of
noradrenaline from the cat isolated nicotating membrane and the guinea pig ileum
myoenteric plexus longitudinal muscle preparation. Brit.J. Pharmac.,53, 505-512.
Hu, J., Huidobro-Toro, J. & Way, E. L. (1980). Calcium antagonism of opiate action in the
non-tolerant and tolerant guinea pig ileum. In Endogenous and Exogenous Opiate
Agonists and Anlagonislsed . Way, E. L., pp, 263-266. Oxford: Pergamon Press.
Huidobro-Toro , J., Li, C. H. & Way, E. L. (1978). Single-dose tolerance to ant inocicept ion,
and dependence on p-endorphin in mice. Eur. J. Pharmac., 52,179-190.
Huidobro-Toro , J. & Way, E. L. (1979). Studies on the hyperthermic response of p-endorphin
in mice. J. Pharmac. exp. Ther., 211, 50-58.
ß-ENDORPHIN IN PHYSICAL DEPENDENCE 381
Iwamoto, T., Harris, R. A., Loh, H. H. & Way, E. L. (1978). Antinociceptive responses after
microinjection of morphine or lanthanum in discrete rat brain sites. J. Pharmac. exp .
Kolb, L. & Himmelsbach, C. K. (1938). Clinical studies of drug addiction, physical dependence,
withdrawal and recovery , Ann. J. Psychol.. 94, 759.
Li, C. H. & Chung, D. (1976). Isolation and structure of an untriakontapeptide with opiate
activity from camel pituitary glands. Proc. Nat. Acad. Sei. USA. 73, 1145-1148.
Loh, H. H., Brase, D. A., Sampath-Khanna, S., Mar , J. & Way, E. L. (l976a). p-endorphin in
vitro inhibition ofstriatal dopamine release. Nature. 264,367-368.
Loh, H. H., Tseng, L. F., Wei, E. & Li, C. H. (l976b). p-endorphin is a potent analgesic agent.
Proc. Nat . Acad. Sei. USA. 73, 2895-2898.
Paton, W. D. M. (1957). The action of morphine and related substances on contraction and on
acetylcholine output of co-axially stimulated guinea pig ileum . Brit. 1. Pharmac., 12,
Quock, C. P., Cheng, J., Chan, S. C. & Way, E. L. (1968). The abstinence syndrome in long-term
high dosage narcotic addiction. Brit. J. Addict.. 63, 261-270.
Schauman, W. (1957). Inhibition by morphine ofthe release ofacetylcholine from the intestine
ofthe guinea pig. Brit. J. Pharmac.. 12, 115-118.
Schmidt, W. K. & Way, E. L. (1980). Hyperalgesie etfects ofdivalent cations and antinociceptive
etfects of a calcium chelator in naive and morphine-dependent mice. J. Pharmac. exp .
Symposium on Regulation and Funct ion ofNeutral Peptides. Gardone Riviera, Brescia, in
Su, C. Y., Lin, S. H., Wang, Y. T., Li, C. H., Hung, L. H., Lin, C. S. & Lin, B. C. (1978). Etfects
of ß-endorphin on narcotic abstinence syndrome in man. Formosan med. J.. 77, 133-142.
Tseng, L F., Loh, H. H. & Li. C. H. (1976). p-endorphin. Cross tolerance to and cross physical
dependence on morphine. Proc. Nat. Acad. Sei. USA. 73,4187-4189.
Wei, E. & Loh, H. H. (1976). Physical dependence on opiate-like peptides. Science, 197,
Wei, E. T., Tseng, F., Loh , H. H. & Li, C. H. (1977). Comparison ofthe behavioral etfects of
ß-endorphin and enkephalin analogs . Lift Sei.. 21,321-328.
Yamamoto, H., Harris, R. A., Loh, H. H. & Way, E. L. (1977). Etfects of morphine tolerance
and dependence on Mgtt-dcpendent ATPase activity of synaptic vesicles. Lift Sci. , 20,
Yamamoto, H., Harris, R. A., Loh, H. H. & Way, E. L. (1978). Etfects of acute and chronic
treatments on calcium localization and binding in brain . J. Pharmac. exp . Ther.. 205,
Departm ents ofExperimental Alcohol and Drug Addiction Research,
The Psychiatrie Research Centre,
The present wave ofheroin abuse in Sweden has its roots in the 1960s. In the wake of
the epidemie of eentral stimulant abuse raw opium was introdueed in 1969, soon
followed by 'rnorphine base' , a einn amon like powder, whieh had to be dissolved in
eitrie or aseorbie aeid before injeetion . After abrief period with morphine tablets,
hero in was introdueed into the drug market in 1974. Th is esealation from less to
more eonee ntrated and pot ent eompounds has several negative eonsequenees.
Firstly, heroin is about three time s more potent than morphine. By virtue of its
higher lipid solubility it pen etrates more rapidly into the brain. Currentl y at least 60
young Swedes die every year in drug aeeidents. Secondly, hero in passes mueous
membranes more easily than morphine and ean thus be 'snorted' into the nasal
eavities and absorbed by thi s route. This use pattern has been reported in south
Sweden and in Stoekholm and faeilitates the progression into intravenous compulsive abuse.
A current, national ease fmding, survey found 3,291 persons using opi ate s
intravenously (Palrn , Olsson & Karl sson , 1980). The actual number may be higher.
The survey estimated the total to be between 7,500 and 10,000 intravenous addiets in
the whole of Sweden. The ineidenee of hero in add ietion in Sweden appears to be
about 50 per hundred thousand inhabita nts, mostl y eoneentrated in the urb an arcas.
This appears to be fairly mod est, in eomparison with estimates of, about 22 5 per
hundred thousand inhabitants mad e in the United States in 1977 (G reenwood &
Crider, 1978). Nevertheless the heroin abuse represent s a major negative health faetor
for thousands of young people in Sweden, to eommunities and to the soeiety.
Inereasing trends are also reported from other European countries, partieularl y West
Gerrnany, Ital y and The Netherlands.
M ETHADONE TR EA TMENT OF HEROI N A D DICT ION
Swedish methadone maintenance treatment (MMT)
MMT for chronic heroin addiction was introduced in Sweden by G unne in 1966 after
a visit to Dole and Nys wander, th e originators ofthis treatm ent method. The Swedish
treatment pro gramme is different from all other MMT prograrnmes in that , I) it has
been the only nat ion al prograrnme, 2) it has kept consta nt inta ke crite ria over the 14
yea rs it has been in operation , 3) a conside rable resea rch etTor t has been coupled to
the tre atment and 4) pa tients have been hosp ital ized for two to three months during
Since it has been the onl y programme in Sweden there has been no competition
between ind ividual ph ysician s and treatment programmes with ambulation of
pati ent s to those MMT programmes otTering the best ' terrns' regarding dose level,
take horn e pri vileges and so on . This has also made it possible to maintain inta ke
criteria constant over time and to make prospective evaluat ion of th e programme.
The detailed characterization of the tre ated population has been given elsewhere
(Holmstrand & Grönbl adh, 1975; Grönbladh & Holmstrand , 1977). Subjects from
th e whole of Sweden were referred to th e Psychi atrie Research Ce ntre in Uppsala
with the majority of pati ents coming from Stockholm. Between 1966-1979 , 170
subjects were accepted into the programme. Intake criteria were: l) age over 20 yea rs;
2) docurnentation, for exarnple. by hospital records, of mo re than four years
intravenous opi ate abuse; 3) evidence showing relapse after at least three completed
detoxifications; 4) ab sen ce of major psych iatric illness, for exarnple, psychosis; 5)
absence ofmixed abuse pattern .
After admission th e subjects were deto xified for one month and then ind uced into
MMT over a six week period, the usual fina l do se being 60-80 mg. During two to
three rnonths' hospital stay pat ient s and sta tTplanned for jobs, vocational training,
educa tio n and accommodation after disch arge. After leaving th e hospital the patients
received the ir methadone dose daily at th e local pharmacy.
The patients were continuo usly followed a nd aided by a treatment and follow up
team. Ran dom sampies of ur ine were tested for illicit drugs. The lon g hospitaliz ation
period permitted car eful cha racteri zat ion of th e pat ient fro m a sornatic, psychi atric
and soc ial viewpoint. The metab olic avai lability of a fou r bed wa rd permitted
familiar ize the pati ent with th e rul es and goals of the treatment programme.
The major results ofthe treatment programme are described belo w. From the total
int ake of 170 pat ients, 122 (72%) have shown successful reh abil itation. Out
ofth ese, 14% ha ve chosen to stop methadone and continue witho ut pharmacological
suppo rt. In 34 patients (20%) seve ra l intoxication ep isodes with other psychotropic
drugs or pri son sentences led to th e involuntary discharge fro m the programme.
These are regarded as treatment failures. Nine patients (5%) hav e died.
The employment situation is sho wn in Figure I. Of the retained population, 20 %
a re studying, 59% are gainfully employed and 14% seeking employment.
The etTect of MMT on th e pat ients work status is sho wn in Figure I. Before
treatment the patients had worked for an average oftwo weeks per year for two years
pr eceding intake in MMT. During treatment the employme nt rose to a
mean of32 week s per yea r in th e whole population after two yea rs.
T he results ofa controlled study (Gunne & Gr önbl adh , 1980) a re sho wn in Table I.
The patients (20-24 yea rs) were randomized bet ween a treatment gro up (TG)
receiving MMT and a control group (CG) otTe red alternat ive drug free treatments.
The two groups were comparable with a mean age of 22 .9 ± 3 (TG) and 22. 5 ± 1.2
(CG) years, documented histories of 6.6 ± 1.5 (TG) and 6.6 ± 1.2 (CG) yea rs of
intrave nous opiate ab use, history of relapses after 13.8 (TG) and 14.4 (CG) in pat ient
treatment episodes respective ly.
384 E. ÄNGGARD, M.-1. NILSSON, L. GRÖNBLADH & L.·M . GUNNE
Figure 1 Employment status for two years before and after MMT . The figures given are the
means ofthe individual numbers ofworking weeks per year.
Table 1 Two year results in eontrolled study ofMMT (Gunne & Gröbladh, 1980)
After a two year follow up 12/17 patients were drug free and doing weil in the TG
but only 1/17 patients were drug free in the CG. No patients died in the TG. Two
subjects died in the CG and an additional three subjects developed serious diseases
(sepsis, one patient; leg amputation, one patient and endocarditis, one patient). After
two years in the CG patients were eligible for admission into the TG. At this time
(spring 1980) eight subjects in the CG have chosen to do so (Table 2). Out ofthese, six
are doing weil. Ofthe remaining patients in the CG one is drug free, four are dead and
four are continuing heroin abuse with attendant poor health and criminality. The
results in the treatment group are comparable to those obtained in the whole (n=170)
treatment programme. The following conclusions can therefore be drawn about the
Protocol 11 M I I 150 Period I Period 2
Figure 2 Protocol to study adaptive ehanges in methadone (M) pharmaeokinetics during the
induetion phase. lntravenous pulse doses of deuterated methadone (M-d3) were given on day I
dose of M from 30-60 mg daily. Oata was used to ealculate biological availability, volume of
distribution and metabolie and renal c1earanees.
M ETH ADONE TREA TMENT OF HEROI N A DDICTION 385
I) For intravenous heroin add icts sat isfying the criteria for the prog ramme, the
Swedish MMT gives a 70-80% rehabilitation rate with attendant increases in social
productivity and decrease ofcriminality and mortality.
2) For intravenous heroin addi cts satisfying the criteri a but not receivin g treatrnent,
onl y 3% per year manage to leave the dru g career and the mortal ity rate is as high as
6% per year. The main alterna tives for these hard core addic ts seem to be prison ,
prostitution , drug abu se related disease and death.
One might question th e value and ethi cs of a controlIed study of MMT in Sweden ,
when ongo ing evaluation research showed good results (Figures 1-3) (Holmstrand &
Table 2 A controlled study ofMMT (Gunne & Grönbladh, 1980)
a Three subjects in prison, one subject had endocarditis
12 16 20 21, 28 32 36 ' 0 u: 1,8
Figure3 Plasma levels ofmethadone (0-0) and deuterated methadone (e-e) during period I in
Grönbladh, 1975; Grönbladh & Holmstrand, 1977) and the treatment modality is
accepted in man y other countries. The reason is the con siderable controve rsy around
MMT both in Sweden and elsewhere (Maddux & Bowden , 1972 ; Epstein, 1974).
Critics have c1aimed that young heroin abu sers will mature out of
th eir addictive life style anyway, that the efficacy ofMMT is onl y temporar y, that the
mortality ofMMT patients is as high as untreated addicts. Furthermore the risks with
illegal diversion ofmethadone have been pointed out and claims have been made that
the existence ofsubstitut ion treatment will decrease moti vation for other treatment
facilities, for example, therapeutic communities. In Norway MMT is not allowed.
In Denmark a less weil controlIed MMT programme based on pract ising ph ysicians,
is under pre ssure because of illegal diversion of methadone. In Sweden the issue is
very polarized with strong ideological overtones. The Swedish Board of Health and
Welfare has now appointed an expert committee, which later this year is expected to
give recommendations on whether or not MMT will be continued in Sweden.
Clearly MMT is a two-edged sword. A multitude of competing programmes with
too high intake rates, too low stafflpatient ratios, too loose int ake criteria and too
386 E. ÄN GGÄ RD. M.-1. NILSSON . L. G RÖN BLADH & L.-M. GUNNE
easy take horne pri vileges lead to treatment failures and possibly illegal methadone
diversion. On the other hand well structured and well controlled pro grammes
continue to give good results (Wilmarth & Goldstein, 1974). Th is should be no
surprise to the med ical cornmunity and to clinical pharmacologists. Just as any oth er
serious condition requiring drug therap y, heroin add iction develop s in phases and
involves populations with different pro gnosis. In the early pha ses dru g therapy is
on ly seldom indicated. Here a combinat ion of 'spontaneous' recovery and drug free
treatment modalities lead to a 50-60% rehabilitation rate in the first six years of the
addict life cycle. Later in the drug career, drug free treatment pro grammes seem to be
less effecti ve and less attractive to the add ict, who usually already has tried it and
failed . Also disea se and mortality increases in the remaining addict populat ion from
about 2% per year in the beginn ing of the drug career to over 10% per year after six
years. In thi s remaining population with poor progn osis a weIl str uctured MMT,
integ rating pharmacological , psychological and social support, is likely to give good
results as exemplified in this study.
The c1inical pharmacokinetics of MMT
Studies of the pharmacokinetics of methadone over recent years have revealed some
complexity. Earlier work using single doses have indicated a plasma half-life of 15 h
whereas the plasma half-life du ring chronic dosage was longer, about 25 h (lnturrisi
& Verebely, 1972a and b; Horns, Rado & Goldstein, 1975 ; Yereb ely, Volavka, Mule
& Resnick, 1975; Änggärd, Gunne, Holmstrand, McM ahon, Sandberg & Sulli van ,
1975; Olsen , Wendel, Livermore, Leger, Lynn & Gerber, 1977 ; Bellward, Warren.
Howald, Axelson & Abbot, 1977). Both animal and clinical data have indi cated the
development of dispositional tolerance to methadone during ma intenance treatment
(Masten, Pete rson , Burkhalter & Way, 1974; Yerebely er al.. 1975; Änggärd er al..
1975). Thus the ratio of the primary metabolite , 2-ethylidine-I,5-dimethyl-3,3-
diphenylp yrolidine (MI) to methadone in urine increased during the induction phase
and the steady state plasma level of methadone decreased. The dispositional
tolerance seems to be of clinical importance, since pat ients with low plasma levels of
methadone have a poorer record of rehabilitation tha n those with higher levels
(Holmstrand, Änggärd & Gunne, 1978). In the pre sent study pul se labelling with
deuterated methadone (Änggärd, Ni lsson, Holmstrand & Gunne, 1979) and ma ss
spectrometric analysis to study the adaptive changes in pharmacokinet ics during the
induction stage ofMMT has been employed.
" e 12 16 20 24 28 32 35 40 U 48
Figure4 Plasma levels of methadone (0 -0) and deuterated methadone (e -e) during period 2
METHADONE TREATMENT OF HEROIN ADDICTION 387
Twelve opiate addicts, 11 males and 1female , aged 25-30 years accepted for MMT,
volunteered to participate. Before MMT the subjects were hospitalized in the
metabolie ward and detoxified for one month. The duration of previous i.v. opiate
abuse was 5-9 years . Two protocols were used (Figure 2). In protocol 1, 30 mg of
(± )-methadone (M) was given throughout the course of the study. In protocol 11, 30
mg ofM was given for 10days followed by 60 mg ofM for the remaining period in the
M doses were given at 08 .00 h before normal breakfast. Serial blood sampies were
collected for 48 h following M-d3. Urine sampIes were collected in 8 h periods on
days 1-2 and days 24-26. Steady state (SS) blood sampies were taken at 07.00 h before
the morning dose . Mass fragmentographic analysis ofM and M-d3 in plasma and of
M and MI in urine were performed as descr ibed previously (Sullivan, MarshalI,
McMahon, Änggärd, Holmstrand & Gunne, 1975; Sullivan & Blake, 1972).
Biological availability (BA) was calculated with the trapezoidal rule using the area
under plasma concentration versus time curves (AUC) for M and M-d3 .
BA during SS was calculated using AUC during one dosage interval. Plasma half-lifes
(T'I,),volumes of distribution (Va), total body c1earance (Cs) and renal c1earance (CR)
were calculated according to standard pharmacokinetic procedures.
Figure5 The relationship between urinary pH and renal clearance of methadone in the
present study and in another study on pH-dependent elimination kinetics of methadone
(Nilsson et al..to be published).
The pharmacokinetic data are given in Table 3. Examples ofplasma concentration
curves during period land 2 are shown in Figures 3 and 4. The urinary pH was more
acid ic during the first days of induction, probably as a consequence of resp iratory
depression by M. This had an efTect on renal c1earance in some (for examples,
subjects 1,5,6,8,10 and 11). The renal c1earance of M was found to be increased below
pH 6 (Figure 5). Above pH6, renal c1earance was negligible in comparison with
I 5.85 98 40 3.37 70.5 12.0 6.89 67 38 3.74 82.4 6.34 z
2 5.76 106 23 4.83 143.0 11.4 6. 17 102 26 4.86 106.0 14.40 rVl
3 5.53 98 26 2.58 74.5 24 .0 5.94 99 40 4.17 78 .2 29 .90 Vl 0
4 5.82 73 23 3.35 120.0 20 .6 5.96 101 19 4.63 195.0 15.90 "7-
5 5.94 95 30 3.91 101.0 21.4 6.35 118 30 3.84 99. 1 6.52 r
6 6.25 36 39 3.68 68 .7 11.5 6.29 67 35 3.86 80 .2 5.00 0;0
7 5.77 97 34 4.65 109.0 33 .7 6.09 87 26 4.93 15 1.0 24.70 r;I>
8 5.78 106 19 3.40 149.0 19.0 7. 13 80 33 4.40 111.0 3.39 0
11 6.20 119 43 4.45 89 .7 28.9 6.09 92 43 3.27 68 .2 17.10
12 5.45 95 30 4.02 102.0 3 1.8 5.56 83 35 4.79 94 .8 20.60 0
METHADONE TREATMENT OF HEROIN ADDICTION 389
metabolie clearanee. During the period 2 toleranee had developed to the respiratory
depressant etTeet ofM and the urinary pH is in the range where it has no appreeiable
influenee on the elimination rate .
The steady state (SS) levels of the patients eould be predieted on the bas is of the
pharmaeokinetie data obtained on day I. The relationship between predieted and
observed SS levels are shown in Table 4.1t is seen that in four patients (1 ,7,9 and 10)
the SS levels were more than 30% lower than predieted. An example is shown in
Figure 6. In six patients (3,4 ,5,8 ,11 ,12) it was within 30% ofthe predieted and in one
patient (6) it was higher than predieted.
The design permitted the meehanism behind these ehanges in pharmaeokineties
during the induetion phase to be assessed (Table 4). In one subject (I) with lower
observed than predieted levels, the BA was found to be deereased. This indieates
that first pass metabolism might have been indueed by MMT. In three other subjeets
with lower than predieted SS level s in protoeol H, an inereased body clearanee eould
be explained by inereased metabolism. Sinee all patients with inereased metabolie
clearanee oeeurred in protoeol H the possibility exists that the indueed ehanges eould
__ - - - - - - - - - - - - - - - - - - Pr ed icte d
Figure 6 The relationship between predieted (- - -) and observed (e-e) plasma levels of
methadone in subjeet 7. Deuterated methadone was administered intravenously at the point
Table 4 Predicted and observed steady state plasma levels. Steady state plasma levels were
predicted on pharmaeokinetic data obtained on day \-2 .
Subject Predicted Observed Higher /lowe r
nmol mt:' nmol mr! than predicted
390 E. ÄNGGÄRD, M.-I. NILSSON, L. GRÖNBLADH & L.-M . G UNNE
place in about 25% ofthe patients. In c1inical experience the same proportion ofthe
subjects on MMT complain about feelings of abstinence,particularly during the last
12 h ofthe dosage intervaI. This interferes with the patients' rehabilitation etTorts and
may lead to intake of unprescribed drugs and relapse into opiate seeking behaviour.
The appropriate response of the physician to thedevelopment of self induction of
methadone metabolism is not self evident. An increase in the dose may temporarily
relieve the situation but after some time the patient has built up tolerance to the new
dose level and may now feel uncomfortable on the dose aga in . One possibility would
seem to be to shorten the dosage intervals to 12 h. This has however proved to be
unpractical in c1inical practice since the patient collects his medication daily at the
local pharmacy. If take-horne privileges are granted there is a risk for illegal
diversion of methadone. Another solution to this dilemma would be to transfer the
patient to I-acetyl-a-methadole (LAAM) (B1aine & Renault, 1976). This is a
methadone analogue which is also a precurser and becomes active only after the
N-demethylation to nor-LAAM and dinor-LAAM, two long-acting metabolites.
LAAM is however as yet only available as an experimental drug in the USA. For
patients developing metabolic tolerance to methadone, LAAM would appear to be
This work was supported by grants from the Swedish Medical Research Council
(B79-25X-048IO-04), the Swedish Academy of Pharmaceutical Seiences and from
the Delegation for Social Research (75/28 :5). Excellent technical assistance was
provided by Elisabeth Fredriksson and Kristina Stensjö.
Änggärd, E., Gunne, L.-M., Holmstrand, J., McMahon, R. E., Sandberg, Ci-G. & Sullivan, H.
R. (19 75). Disposition ofmethadone in methadone maintenance. Clin. Pharmac. Ther.. 17,
Änggärd, E., Nilsson, M.-I., Holmstrand, J. & Gunne, L.-M. (1979). Pharmacokinetics of
methadone maintenance. Pulse labeling with deuterated methadone in the steady state.
Eur. J. clin. Pharmac.. 16, 53-57.
Bellward, G. D., Warren, P. M., Howald, W., Axelson, J. E. & Abbot, F. S. (1974). Methadone
maintenance: Effectof urinary pH on renal clearance in chronic high and lowdoses. Clin.
Blaine, I. D. & Renault, P. F. (1976). 3x/week LAAM alternative to methadone. NIDA Res.
Epstein, E. 1.(1974). Methadone the forlorn hope. Public lnterest, 36, 3.
Greenwood, J. & Crider, R. (1978). Estimated number 0/ heroin addicts in 1977. Rockville,
Maryland, U.S.A.: National Institute on Drug Abuse.
Grönbladh , L. & Holmstrand, J. (1977). The Swedish methadone maintenance program
1967-1977. Läkartidningen, 74,4318-4322 .
Gunne , L.-M. & Grönbladh, L. (1980). The efficacy of methadone maintenance treatment.
L äkartidningen , 77, 227-230 .
Holmstrand, J., Anggärd, E. & Gunne, L.-M. (1978). Methadone maintenance: Plasma levels
and therapeutic outcome. Clin. Pharma c. Ther., 23,175-180.
Holmstrand, J. & Grönbladh, L. (1975). Methadone maintenance treatment of opiate abusers.
Horns, W. H., Rado, M. & Goldstein, A. (1975). Plasma levels and symptom complaints in
patients maintained on daily dosage of methadone hydrochloride. Clin. Pharmac . Ther.,
M ETHADONE TREATMENT OF HEROIN ADDICTION 391
Inturrisi, C. E. & Verebely, K. (l972a) . The levels of methadone in the plasma in methadone
maintenance. Clin. Pharmac. Ther., 13,633-637.
Inturrisi, C. E. & Verebely, K. (l972b) . Disposition ofmethadone in man after a single oral dose.
Clin. Pharmac. Ther.. 13,923-930.
Maddux, J. F. & Bowden, C. L. (1972). Crit ique of success with methadone maintenance
treatment. Am. J. Psychiat.. 129, 44ü-446.
Masten, L. W., Peterson , G. R., Burkhalter, A. & Way, E. L. (1974). Effect oforal administration
of meth adone on hepati c microsomal mixed function oxidase activity in mice. Life Sei; 14,
Olsen, G. D., Wendel , H. A., Livermore , J. D., Leger, R. M., Lynn, R. K. & Gerber, N. (1977).
Clinical effects and pharmacokinetics of racemic methadone and its optical isomers. Clin.
Palm , 8., Olsson, O. & Karlsson , C. (1980). Tungt narkotikamissbruk - en totalundersökning
1979. Report Ds 5: 5, Soeialdepartementet, Stockholm, Sweden (ISBN 91-38-05600-3).
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(1975). Mass fragmentographic determination of unlabeled and deuterium labeled
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programs in the U.S.A. WHO OjJset Publication no. 3.
H. SCHAEFER, w. SCHALLA &J. GAZITH
Centre International de Recherehes Dermatologiqu es
Dermat ology Clinic ofthe Free University 0/ Berlin ,
Skin is a highly differentiated, multi-functional and multi-Iayered organ and thus
susceptible to a variety of different types of diseases. This has resulted in the
development of a multitude of topical drugs, differing in their mode of action, their
ability to penetrate into the skin and in the way the skin reacts to them.
To obtain va lid and meaningful comparison s of the ph armacokinetics of different
drugs on and in the human skin, one ha s to be abl e to determine drug concentrations
The skin is a rather thin organ; 1 cm! of normal horny layer represents no more
than 1 mg tissue , while I crn- of epidermis amounts to about 10 mg, and I cm- ofthe
dermis may represent up to 200 mg tissue (mean values, wet weight), A 10-5 M
concentration of hydrocortisone, whi ch is relativel y high in both physiological and
pharmacological terms, represents only do se of5 ng in I cm- ofepidermis.
Radioactive labelling using materials of high specific activity is one of the few
methods that offers the sensitivity required for determination ofsuch small amounts
ofdrug, as was already stated by Malkinson (l968).
For mo st experiments, tritiated or carbon 14-labelled drugs were used. A specific
activity of 3-5 mCi mg- I for the tritiated drugs or 0.5-1 mCi mg-Iof 14C was sufficient
when a concentration ofO .I% drug in the preparation was employed . Before use , the
radio-labelled substances were checked for the presence of impurities and labile label
396 H. SCHAEFER , W. SCHALLA,J. GAZITH, G. STÜTTGEN & E. BAUER
The method is described in detail elsewhere (Wolf, 1940; Pinkus, 1951 ; Pinkus, 1952;
Zesch, Nordhaus & Schaefer, 1972; Schaefer, Zesch & St üttgen, 1977; Zesch &
Schaefer, 1973; Zesch & Schaefer, 1975).
Distribution in the horny layer
The horny layer is the main barrier against free diffusion of substances into the
organism. Because of this 'barrier' function, only small amounts of substances
succeed in permeating into the living layers ofthe skin and the organism, even when
large amounts come into contact with the skin surface. This permeation is a passive
diffusion process, there is no proof for any active transport mechanisms being
involved in percutaneous absorption. The whole of the horny layer is regarded as
being a rather homogenous penetration barrier.
This view of the penetration barrier as a property ofthe horny layer as a whole is
supported by the following experimental results. When the amount of substance is
measured in each single layer (Zesch et al., 1972), logarithmic curves are obtained for
most substances (Figures land 2) yielding in a halflogarithmic presentation straight
lines with a steep slope. Thus, the amount of penetrating substance decreases with
increasing depth in a logarithmic fashion , ranging mostly over 1.5 decades (Zesch et
al.. 1972). Applied to the horny layer, thisimplies that each single layer offers the
same resistance to penetration, the effect being cumulative throughout the stratum
Figure 1 Distribution of radioactivity in human homy layer after topical application of a
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