Subjective
and objective symptoms in relation to plasma
methadone concentration in methadone
patients
Hiltunen AJ, Lafolie P, Martel J, Ottosson
EC, Boreus LO, Beck O, Borg S, Hjemdahl P.
Source
Department of Clinical
Neuroscience, St Göran's Hospital,
Karolinska Institute, Stockholm, Sweden.
Abstract
Two rating scales, which were originally
developed for measurements of objective and
subjective signs of opiate withdrawal, were used
to evaluate potential estimates (correlates) of
methadone effects in relation to plasma
methadone concentrations. Patients participating
in our regular methadone maintenance treatment
project were studied during 24 h after the
intake of the daily methadone dose. Methadone
concentrations in plasma were compared to the
subjective (estimated by the patients) and
objective (estimated by the investigator) signs
of the drug effects before, and 2.5, 5, 9 and 24
h after intake of methadone. Some new items
possibly related to rising methadone
concentrations were added to the subjective
scale. Results indicated that, for subjective
ratings, the majority of the items investigated
corresponded well with the plasma methadone
concentrations. The most significant
associations were found for the following items:
low psychomotor speed, alertness, running nose,
yawning and anxiety. For objective
ratings, only the items rhinorrhea, piloerection
and signs of anxiety were significantly
associated with the methadone concentrations.
These rating scales may, together with plasma
methadone determinations, be of considerable
value when making dose adjustments for methadone
maintenance patients. Further work is, however,
needed to establish concentration-effect
relationships.
Introduction
The need for reliable evaluation of opiate
withdrawal symptoms has resulted in the
development of several rating scales, e.g. the
Himmelsbach scale (Himmelsbach 1941), and the
Addiction Research Center Inventory (Haertzen
1965; Haertzen and Meketon 1968). Recently,
Handeisman and co-workers (Handeisman et al.
1987) presented two rating scales designed to
reflect common psychic, motoric and autonomic
signs and symptoms of opiate withdrawal, i.e.
the objective opiate withdrawal scale (OOWS) and
the subjective opiate withdrawal scale (SOWS).
When these scales were utilized to detect opiate
withdrawal, significantly higher SOWS and OOWS
scores were observed in patients admitted to a
detoxification ward before, compared to after,
receiving methadone. Their results further
indicated that addicts may still experience
subjective symptoms in the absence of any
observable objective signs of opiate withdrawal
(Handelsman et al. 1987).
In research on methadone maintenance
treatment, little attention has focussed on
detecting objective signs and subjective
symptoms of how well daily methadone doses have
been adjusted to the patients'needs. Methadone
dosages have usually been adjusted on the basis
of conventional clinical parameters, often
combined with measurements of plasma methadone
concentrations. There is a recommended plasma
concentration range of 2OO-4OO ng/ml (Holmstrand
et al. 1978; Dole 1991; Loimer and Schmid 1992),
but this has not been valiadated against
symptoms in the patients. The purpose of the
present study was to develop a rating procedure
for above purposes by testing the suitability of
already established scales (SOWS and OOWS). As
high levels of the subjective symptoms may be
associated with low levels of objective symptoms
(Koib and Himmelsbach 1938; Handelsman et al.
1987), the SOWS scale seemed particularly
interesting. As this scale exclusively reflects
symptoms associated with the withdrawal state
(i.e. too low or descending methadone
concentrations), we decided to add new items
into the SOWS scale, which were designed to
reflect drug effects associated with ascending
methadone concentrations. This modified SOWS
scale was evaluated in relation to plasma
methadone concentrations during the absorption
and distribution phases of the drug after a dose
of methadone during methadone maintenance
treatment. In the first part of the study, the
interest was focussed on how well global SOWS
and OOWS ratings were related to the methadone
concentrations. The second part of the study
concerns the influence of methadone
concentrations on separate items, with the aim
to decide which possibly irrelevant items might
be excluded from the scales.
Discussion
The usefulness of two opiate withdrawal
rating scales was investigated in the present
study in order to evaluate relationships between
symptoms and plasma methadone concentrations.
Items expected to reflect decreasing symptoms
during rising concentrations of methadone were
added into a modified SOWS scale. The results
show that plasma methadone concentrations
correlated well with estimates made by patients
participating in our methadone maintenance
program. Most of the studied items were
significantly correlated to the methadone
concentration, including the new items in the
modified SOWS scale. On the contrary, only a few
of the items of the objective scale (OOWS) were
correlated to methadone concentrations. The
results seem to apply to both in- and
out-patients, since no differences were found
between the two groups.
The effects of varying methadone
concentrations during the day are smaller than
during methadone abstinence and, consequently,
more difficult to quantitate. Handeisman and
co-workers (1987) pointed out that addicts may
experience subjective symptoms in the absence of
any observable objective signs of opiate
withdrawal when methadone is withdrawn. In
agreement with this, we found that fewer items
on the objective scale than on the subjective
scale were correlated to methadone
concentrations. Rhinorrhea, piloerection and
anxiety were, however, still associated with the
plasma methadone concentrations, and these items
can be used in the further development of the
rating scale. Somewhat surprisingly, mydriasis
could not be correlated to the plasma methadone
concentration. However, such measurements would
have to be performed under highly standardized
conditions to be used quantitatively.
One possible explanation for the excellent
results of the present study might be the
expectation effect, or demand characteristics
(Kazdin 1980). Subjects may be influenced by the
cues from the experimental situation so that
they respond in a certain way independently of
the experimental manipulation. Our patients
probably knew the expected effects of their
ordinary methadone dose during the next 24 h.
Our ten in-patients could also have overrated
changes due to an interest in raising their
methadone doses, since these patients were being
dose-adjusted at the time. However, this is
unlikely to be the sole explanation for our
results since, i) the out-patients already were
dose-adjusted and wellfunctioning, and ii)
results in the SOWS and OOWS scales corresponded
well, although the OOWS scale generally had less
power to detect changes.
Daily variations of plasma methadone
concentrations seem to reflect some degree of
abstinence at the end of the dosage interval,
since descending concentrations resulted in
increased ratings of anxiety, nausea, running
nose, irritability and tearing eyes. The newly
inserted items (modified SOWS), on the other
hand, mostly reflect positive effects or
overdosing of methadone, since the majority of
the correlations are positive rather than
negative (Table 2). The strongest positive
associations were shown with items alertness,
clear-thinking, relaxation and carefree.
Methadone maintenance treatments is, by
definition, a substitution treatment which
should not be overdosed (leading to "positive"
opiate effects) or underdosed (leading to
abstinence and craving). Thus, optimal dosing is
important. More careful assessment with the
scales used presently may improve the basis for
methadone dosing.
Results in the present study indicate that
subjective ratings of individual patients
reflect the plasma methadone concentrations
during a dose interval at steady state. Clinical
implications of these results may include an
adjustment of the methadone dose to each
individual by obtaining a balance between
abstinence and overdosing variables. By making a
profile of the ratings, it may be possible to
determine whether a balance exists, or whether
methadone is either overdosed or underdosed. It
remains to be shown if these or other scales can
predict the dosage requirements of methadone
patients by assessments of symptoms at "trough
levels" (predosing) in relation to plasma
concentrations. Such an association would be
clinically important and add information of
value for the evaluation of plasma methadone
effect relationships.
