Dextropropoxyphene
Dextropropoxyphene Hydrochloride
A white or almost white odourless crystalline powder. Ph.
Eur. solubilities are: very soluble in water; freely soluble in
alcohol, practically insoluble in ether. USP solubilities are:
freely soluble in water: Soluble in alcohol, in acetone, and in
chloroform: practically insoluble in ether. Store in airtight
containers and protect from light.
Dependence and Withdrawal
As for Opioid Analgesics, Dextropropoxyphene has been subject to
abuse.
Adverse Effects
As for Opioid Analgesics in general. In the
recommended dosage the adverse effects of dextro-
propoxyphene are less marked than those of mor-
phine. Gastro-intestinal effects, dizziness, and
drowsiness are the most common. Liver impairment
has been reported.
There are a disturbing number of fatalities from
either accidental or intentional overdosage with dex-
tropropoxyphene. Many reports emphasise the ra-
pidity with which death ensues; death within an
hour of overdosage is considered by some not to be
uncommon and can occur within 15 minutes. Over-
dosage is often complicated by patients also taking
alcohol and using mixed preparations such as dex-
tropropoxyphene with paracetamol or aspirin.
Symptoms of overdosage are similar to those of opi-
oid poisoning in general, but in addition patients
may experience psychotic reactions. There may be
cardiac conduction abnormalities and arrhythmias.
Dextropropoxyphene injections are painful and
have had a very destructive effect on soft tissues and
veins when dextropropoxyphene has been abused in
this way.
Anorectal reactions have followed the prolonged
use of suppositories containing dextropropoxy-
phene; reactions appear to be dose dependent.
Effects on the blood. A 12-year history of haemolysis and
subsequent significant haemolytic anaemia in an elderly
woman was associated with chronic, periodic, and occasion-
ally excessive intake of co-proxamol.
Effects on the ears. A report of complete nerve deafness
associated with chronic abuse of co-proxamol was made to
the UK Committee on Safety of Medicines.' The Committee
had received 2 other reports of permanent hearing loss attrib-
uted to co-proxamol abuse: transient hearing loss had also
been reported in 2 patients taking usual doses: 7 further re-
ports described tinnitus.
Effects on the liver. There have been occasional reports of
jaundice in patients taking dextropropoxyphene without para-
cetamol. Many of the 49 suspected hepatic reactions with
dextropropoxyphene reported lo the UK Committee on Safe-
ty of Medicines by 1985' had involved dextropropoxyphene.
in association with paracetamol: clinical features including
malaise, jaundice, raised serum transaminases. and some-
times fever, were however generally characteristic of dextro-
propoxyphene alone. Relapsing jaundice mimicking biliary
disease was attributable lo the dextropropoxyphene compo-
nent of co-proxamol in 3 patients' whereas there was no ab-
normality of liver function in 11 patients on long-term co-
proxamol analgesia'
Hypoglycaemia. References to a hypoglycaemic effect of
Dextropropoxyphene has been made in the literature.
Overdosage. There have been several reviews or retrospec-
tive studies of acute self-poisoning with dextropropoxy-
phene. At a symposium on the safety and efficacy of
dextropropoxyphene many of the participants dealt with the
problems of dextropropoxyphene overdosage, often in con-
junction with paracetamol and sometimes with alcohol. Pro-
found and even fatal CNS depression can develop rapidly as
a result of the dextropropoxyphene content and in many cases
death has occured within an hour. The quantity likely to be
fatal is small, Whittinston'' suggested that 15 tablets or less
of co-proxamol could lead to death and this is close to the
figure of 20 tablets suggested by Young and Lawson.: A number of
paper reviewed the cases of poisoning in different countries ;
one of these on poisoning in the USA demonstrated that the
incidence of dextropropoxyphene-associated deaths reached
a peak in 1977 and has been tailing since then at a rate that is
not matched by a decline in prescribing. Also Finkles could
not demonstrate a connection between the metabolite nordex-
tropropoxyphcne and the fatalities. However, nordextropro-
poxyphene. like dextropropoxyphene. is considered to have
local anaesthetic activity and Henry and Cassidy implicated
membrane stabilising activity as a major factor responsible
for the severe cardiac depressant effect of dextropropoxy-
Phene.
Treatment of Adverse Effects
As for Opioid Analgesics in general, p.68.
Rapid treatment of overdosage with naloxone and
assisted respiration is essential. Cardiac effects may
not be reversed by naloxone. Gastric lavage and ad-
ministration of activated charcoal may be of value
but dialysis is of little use.
Convulsions may require control with an anticon-
Vulsant , bearing in mind that the CNS depressant ef-
fects of dextropropoxyphene might be exacerbated
(see also under Interactions, below). Stimulants
should not be used because of the risk of inducing
convulsions.
Patients taking overdoses of dextropropoxyphene
with paracetamol will also require treatment for pa-
racetamol poisoning .
Precautions
As for Opioid Analgesics in general.
Abuse. There have been reports of the abuse of dextropro-
poxyphene.' and Lader' considered that the ready availability
of dextropropoxyphene made it liable to abuse although it
was a relatively weak opioid analgesic. However. Finkle
thought there was no evidence that dextropropoxyphene was
frequently associated with abuse, and Turner* concluded that.
although there was abuse potential, it was of relatively low
importance in terms of the community as a whole.
A severe withdrawal syndrome has been reported in one eld-
erly patient who covertly consumed a daily dose of dextropro-
poxyphene of I to 3 g for at least 12 months. The patient was
treated by a gradually decreasing dosage schedule of dextro-
of propoxyphene over 9 weeks.
Breast feeding. See under Pharmacokinetics, below.
Porphyria. Dextropropoxyphene has been associated with
clinical exacerbations of porphyria and is considered unsafe
in porphyric patients.
Interactions
For interactions associated with opioid analgesics.
See pentazocine.
Plasma concentrations of dextropropoxyphene are
increased by ritonavir , with a resultant risk of toxic-
ity; concomitant administration should be avoided.)
CNS depressants. including alcohol, may contribute
to the hazards of dextropropoxyphene. The convul-
sant action of high doses of dextropropoxyphene
may be enhanced by CNS stimulants.
Dextropropoxyphene interacts with several other
drugs through inhibition of liver metabolism. Drugs
reported to be affected include antidepressants , ben-
zodiazepines , beta blockers, carbamazepine , phenobarbitone,
phenytoin and warfarin.
Antimuscarinics. A suggested interaction between orphen-
adrine and dextropropoxyphene has been questioned.
Pharmacokinetics
Dextropropoxyphene is readily absorbed from the
gastro-intestinal tract, the napsylate tending to be
more slowly absorbed than the hydrochloride, but
both are subject to considerable first-pass metabo-
lism. Peak plasma concentrations occur about I to 2
hours after ingestion. It is rapidly distributed and
concentrated in the liver, lungs, and brain. About
80% of dextropropoxyphene and its metabolites are
reported to be bound to plasma proteins. Dextropro-
poxyphene crosses the placenta. It has been detected
in breast milk but some authorities consider that the
amount is too small to be harmful to a breast-fed in-
fant.
Dextropropoxyphene is N-demethylated to nordex-
tropropoxyphene (norpropoxyphene), in the liver. It
is excreted in the urine mainly as metabolites. It is
now recognised that dextropropoxyphene and nor-
dextropropoxyphene have prolonged elimination
half-lives: values of 6 to 12 hours and 30 to 36 hours.
respectively, have been reported. Accumulation of
dextropropoxyphene and its metabolites may occur
with repeated doses and nordextropropoxyphene
may contribute to the toxicity seen with overdosage.
Administration in the elderly. The elimination half-lives
of dextropropoxyphene and its metabolite nordextropropoxy-
phene were prolonged in healthy elderly subjects when com-
pared with young controls. After multiple dosing median
half-lives of dextropropoxyphene and nordextropropoxy-
phene were 36.8 and 41.8 hours respectively in the elderly
compared with 22.0 and 22.1 hours in the young subjects. In
this study there was a strong correlation between half-life of
nordextropropoxyphene and estimated creatinine clearance.
Administration in hepatic impairment. Plasma concen-
trations of dextropropoxyphene were higher in patients with
cirrhosis given the drug than in healthy controls whereas con-
centrations of nordextropropoxyphene were lower.
Administration In renal impairment. Higher and more
persistent plasma concentrations of dextropropoxyphene and
nordextropropoxyphene in anephric patients when compared
with healthy subjects were attributed to decreased first-
pass metabolism of dextropropoxyphene and decreased renal ex-
cretion of nordextropropoxyphene in the anephric patients.
Uses and Administration
Dextropropoxyphene is an opioid analgesic
structurally related to methadone. It has mild
analgesic activity and is administered by mouth as
the hydrochloride or napsylate to alleviate mild to
moderate pain. Unlike the laevo-isomer (levopro-
poxyphene. Dextropropoxyphene has little
antitussive activity.
Dextropropoxyphene is mainly used in conjunction
with other analgesics with anti-inflammatory and
antipyretic effects, such as aspirin and paracetamol.
In the UK the usual dose is 65 mg of dextropropox-
yphene hydrochloride or 1OO mg of the napsylate
given three or four times daily. In the USA similar
doses are given every 4 hours up to a maximum total
daily dose of 390 mg of the hydrochloride and
600 mg of the napsylate. Compounded preparations
of dextropropoxyphene hydrochloride ( I part) and
paracetamol (10 parts) have the British Approved
Name co-proxamol: a usual strength of this combi-
nation is dextropropoxyphene hydrochloride
32.5 mg with paracetamol 325 mg. Compounded
preparations of dextropropoxyphene napsylate and
paracetamol may be known in the USA as co-prox-
APAP.
In a detailed review of the analgesic effectiveness of dextro-
propoxyphene, Beaver' observed that. with respect to single
oral doses, the weight of evidence pointed to the recommend-
ed doses of dextropropoxyphene being no more and probably
less effective than usual doses of paracetamol. aspirin, or oth-
er NSAlDs, However, the comparative effectiveness may
vary substantially depending on the cause of the pain. When
it comes to comparative studies involving combinations of
dextropropoxyphene with other analgesics, findings are even
less clear-cut: there are studies showing, some benefit from
such a combination and others showing no benefit. The effec-
tiveness of co-proxamol (dextropropoxyphene with paraceta-
mol) has long been a matter of controversy yet despite this a
recent survey- conducted in 30 UK teaching hospitals found
that co-proxamol was the most widely used paracetamol-con-
taining analgesic. It was suggested that the popularity of co-
proxamol was purely down to prescribing habits passed on to
new medical staff, rather than hard evidence regarding effica-
cy. This view has been refuted by Sykes et all who say that a
large number of studies have demonstrated clear analgesic ef-
fects for dextropropoxyphene. However, any assumption that
jthe combination was widely used because it was more effec-
tive than paracetamol alone was not supported by a systemat-
ic overview of single dose studies by Li Wan Po and Zhang.J
They concluded that while co-proxamol was indeed an effec-
tive analgesic it was no better than paracetamol alone. While
the evidence from this and other systematic reviews indicate
that co-proxamol should be replaced by paracetamol alone for
acute pain the position for chronic use is considered to be not
so clear.