- Introduction : Tramadol is considered
an analgesic with a potency about 1/10 that of
morphine. Because of its reduced magnitude in
inducing side-effects such as respiratory
depression and obstipation when given in
equieffective doses of standard opioids like
morphine or pethidine (Houmes et al., 1992,
Sunshine, 1994; Barsoum, 1995), it became a
popular analgesic for various painful conditions
(Moore and McQuay, 1997). The compound is
advocated since it lacks addiction liability
(Preston et al., 1991) and docs not result in
the development of an acute abstinence syndrome
when the specific opiate antagonist naloxone is
given (Barth et cil., 1987). Therefore, tramadol
is considered a nonscheduled analgesic which is
widely used as an analgesic in treating painful
conditions where strong opioids are not required
(Moore and McQuay, 1997).
-
- Although this compourid is also recommended
for the long-term alleviation of chronic
musculoskeletal or myofascial pain, little is
known about its potential side-effects when
taken for a longer period of time when the drug
is stopped abruptly. This is of special interest
since some papers have reported on an abuse
potential (Liu et al., 1999; Jensen. 1997)
respiratory depression (Barnung et cil.,
1997« Sachdeva and Jolly, 1997), cerebral
depression (Riedel and Stockhausen, 1984; Sticht
et al., 1997) and even fatal outcome when
tramadol was given in conjunction with a
benzodiazepine (Michaud et al., 1999). We would
like to report on a case where
opioïd-like withdrawal symptoms
developed following abrupt cessation of intake
of tramadol.
-
- PATIENT HISTORY:
- The patient is a 45-year-old caucasian
female who had no previous history of
musculoskeletal pain when being admitted to the
pain clinic. She demonstrated classical symptoms
of fibrornyalgia such as insomnia, and evoked
pain sensations when administering pressure to
at least 12 tender points. Intermittently she
also complained of cephalalgia at the
occipital-temporal area and had a mean VAS of
7.7. The patient did not respond to classical
antidepressive therapy with amyltriptiline given
for 1 week, and showed only little relief
following injection of a local anaesthetic
(lidocaine) into tender points. However, she
expressed significant relief following the
intake of tramadol liquid, instant release at a
dose of 50-100 mg. Usually taken every day in
the morning for the past 12 months. Pain relief
lasted over the whole day and no other
medication was taken apart from this analgesic,
except that the patient was taking milk thistle
as a remedy 'to support her liver function'.
Side-effects were intermittently experienced by
the patient consistmg of some sedation and
drowsiness, which were noted shortly after
medication intake. These sideeffects however,
did not affect her activities and concentration
at work. Within the last 3 months, however, she
frequently noted nausea shortly after intake,
following a dally dose of tramadol of at least
100 mg.
-
- Whilst on vacation in a foreign country, she
ran out of tramadol. After a week, she developed
marked and long standing pain at her back with a
VAS of 7.5, making it impossible for her to
walk. Seeking medical advice by a general
practioner involved in pain therapy in a major
US city, and since she had not experienced a
similar type of back pain in the past, a
specific COX-2 class inhibitor (celecoxib) was
prescribed in a dose of 200 mg/day. Although
this inedication did result in a moderate relief
from a VAS 6.5 to 4.0 within the following 2
days, the patient now additionally developed
restless leg syndrome. This resulted in a
significant disruption of sleep pattern
throughout the whole night. In order to help her
gain some night rest and to ease the
accompanying.cramp-like pain sensations in her
legs, a moderate dose of the benzodiazepine
lormetazepam (NoctamideO 0.5 mg/day) was given.
This medication resulted in sleep and some
relief of the cramps and the restless legs.
-
- However, within the following hours
additional symptoms were noted: (1) slight
mydriasis, (2) a depressive mood, together with
(3) moderate tremor and (4) repetitive
yawning and sneezing. Additionally, (5) a
moderate tachycardia of 95/min accompanied by
(6) a slightly elevated BP of 145/90 mmHg was
noted. Also, there was (7) an increased feeling
of thirst, (8) a feeling of tension within the
whole body and (9) heat waves taken off by cold
sensations were experienced. Psychologically,
(10) aggressiveness together with an increased
level of nervousness was noted and the patient
complained of (l1) migrating pain over the whole
body with intermittent bouts of cephalalgia and
nausea which was later followed by (12)
intra-abdominal cramps with diarrhoea.
-
- The clinical picture was not that of an
excerbation of fibromyalgia for which tramadol
was introduced, as the patient had never before
experienced a similar symptomatology. Also, the
patient's history and examination had ruled out
another type of musculoskeletal disorder, mild
lupus erythematosus, a beginning polyarticular
osteoarthritis, rheumatoid arthritis,
polyrnyalgia rheumatica, an acute or chronic
infection or a hypermobility syndrome. These
possibilities were ruled out since body
temperature and blood tests revealed no
pathology. Also, renal and liver function were
normal as there was no elevated creatinine
and/or transaminase level. Therefore, an
acute abstinence syndrome was diagnosed
(Jasinski, 1977) and the patient treated with a
selective peripherally acting antidiarrhoeal
(loperamide 4 mg/day) in order to stop
intraabdominal cramps and diarrhoea. This was
accompanied by an increased intake of fluids of
up to 3 l/day while the patient remained on the
benzodiazepine lormetazepam (Noctamide(W 0.5
mg/day) in order to treat insomnia. The restless
leg syndrome and her muscle pain was
successfully treated with dextromethorphan
(2x5Omg/ day). For the alleviation of the
excruciating headaches and nausea, sumatriptan
was given nasally (20 mg/day). Ail these
medications resulted in an alleviation of the
symptoms within 3 days and within 1 week the
patient recovered uneventfully with no further
sequelac.
-
- DISCUSSION
- This report is, to our knowledge, the first
observation of a patient who took the instant
release formulation of the analgesic tramadol on
a dally base for over 1 year, developing an
abstinencelike syndrome after cessation of the
drug Tramadol, which is a non-scheduled class
drug, is cited to be a mixed analgesic agent as
it mediates its action partly via the opiate
receptor system and partly via an activation of
the descending serotinergic/noradrenergic
inhibitory system (Desmeules et al., 1996). As
to the mode of action of these abstinence-like
symptoms, the oploidlike action of the compound
had to be taken into consideration.
-
- This is corroborated by the following:
- (1) The observed symptoms were
characteristic following long-term use of a
classical opioldtype analgesic being stopped
abruptly (Jasinski, 1977).
-
- (2)The parent compound tramadol shows very
little affinity to the opiold receptor site.
However, aside from its activity to inhibit
noradrenaline and serotonine re-uptake, the
pharmacologically active metabolite M1
(0desmethyltramadol) has a 300-fold higher
affinity to the opioid receptor (Raffa et al.,
1992). Although affinity does not equate with
intrinsic activity, and the opiold moiety of the
M1 metabolite of tramadol is in dispute,
numerous studies have suggested that it is this
metabolite which plays an important part in
mediating analgesla via interaction with the
opiold receptor (Raffa el al., 1992; Miranda and
Pinardi, 1998).
-
- (3) The use of tramadol over more than 1
year, as in our patient, eventually may have
resulted in a build up of the active metabolite
M1 in peripheral tissue sites such as skin,
muscles, fat and connecting tissue, which do not
participate in the mediation of effects but in
fact may act as a reservoir. This assumption is
corroborated by forensic data where tramadol was
involved in an overdose fatality (Moore et al.,
1999), suggesting that a build-up of tramadol
and/or its metabolite within peripheral tissues
following long-term use does occur. Data with
other analgesics and their build-up in
peripheral tissues further supports this
possibility (Taeger, 1981). It therefore is
conceivable that with the discontinuation of the
drug, levels of the parent compound tramadol
and/or its metabolite M1 slowly declined,
followed by reduced binding to the opiold
receptor. This resulted in the developinent of a
classical abstinence-like syndrome only after 1
week. Although our data are not in rapport with
other data from patients who developed no
abstinence after having recelved tramadol for 3
weeks followed by naloxone (Richter et aL,
1985), there is no follow-up data in patients
who were treated for more than 3 weeks and where
drug intake was stopped abruptly.
-
- (4)The phenomenon of physical dependence of
this analgesic has been noted in animal models
(Yanagita, 1978; Miranda and Pinardi, 1998) and
also in humans (Meyer et al., 1997, Liu et al-
1999). While being minor when compared to other
oploids, reinforcing properties may became
evident when tramadol was given at doses of 1
mg/kg (Villareal and Seevers, 1968).
-
- (5)Abstinence symtoms did pot develop within
the first day after cessation of intake in our
patient. In spite of the fact that elimination
of tramadol and its metabolites is primarily by
renal excretion (Lintz, 1990), elimination
half-life. for tramadol is 4.9 h while its
metabolite M1 is 6.7h after a single dose (Liao
and Nayak, 1992). This at least suggests some
difference in the elimination half-lives between
the parent compound and its metabolite. This is
is further substantiated by the fact that after
a single intravenous dose of 100 mg of tramadol,
the parent compound is excreted renally by 17.8%
while that of MI by only 6.3% (Lintz, 1990).
Since our patient had taken multiple doses over
a period of at least 12 months, such small
differences between parent compound and its
metabolite following a single dose may become
pronounced after multiple dosing over a long
period of time. Thus, high concentrations of M1
in body tissues, as demonstrated in a case of
fatal overdose (Moore et ai., 1999), and at the
receptor site, are followed by a slow decline
resulting in the appearance of abstinence-like
symptoms only after 1 week.
-
- Of unique interest was the appearance of the
restless le- syndrome (RLS), which is
characterized by ill-defined, deep-seated and
unpleasant sensations in the legs inducing an
irresistible urge to move, vath symptoms
occurring during periods of immobility. The RLS
has been related to alterations in tryptophan
and serotonin metabolism (Sandyk and Fisher,
1988, Sandyk, 1992). Since tramadol, unlike
morphine, codeine and other oploids, inhibits
the neuronal re-uptake of noradrenaline and
serotonin (Raffa et al., 1992, Reimanil and
Hennies, 1994) it is likely that longterm use
may result in a monoaminergic withdrawal of 5-HT
at the spinal cord level, with ensuing
peripheral sensory symptoms such as back pain
and RLS. In the absence of clear understanding
of the disorder's pathophysiology, treatment of
RLS has been largely empirical and reports have
quoted that the precursor of serotonin, ie.
tryptophan, attenuated symptoms of RLS and
insomnia (Sandyk, 1986).
-
- One might argue that the medication with
dextromethorphan was not the appropriate agent
to treat RLS but since dextromethorphan is an
opioid-like agent of the morphinane series,
which is used as a cough suppressant and does
not lead to addiction (Jaffe and Martin, 1990),
it also has been shown to act as an
NMDA-receptor antagonist (Dickenson, 1994). It
therefore seemed appropriate to use this ligand
as musculoskeletal pain together with an
increased NMDA-activity are involved in opioid
dependency (Manning et cil., 1996).
-
- In summary, we have presented a case
of an acute abstinence-like syndrome in a
patient having taken the centrally active, mixed
analgesic tramadol for over 1 year followed by a
sudden abstinence of intake. Although abstinence
symptomatology was opiold-like in appearance, it
lacked the psychological urge for continuation
of intake whichis typical for an opiate such as
morphine (Richter et al., 1985, Preston et aL,
199 1). The low abuse potential makes the
compound less prone to act as a reinforcer and
less likely to be a drug which will gain
attention by the drug community. Nevertheless,
patients having taken the drug for a longer
period of time should be informed not to
abruptly stop intake as typical opioid-like
abstinence symptoms are likely to develop.
-
- Philibert
C, Sauveplane K, Pinzani-Harter V et al. Le
bâillement: de la physiologie à la
iatrogénie. La lettre du pneumologue.
2011;14(5):168-172
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