Pethidine Hydrochloride
A fine white odourless crystalline powder.
Ph. EU{. solubilities: very soluble in water, freely soluble in
alcohol: practically insoluble in ether. USP solubilities: very
soluble in water: soluble in alcohol: sparingly soluble in ether.
A 5% solution has a pH of about 5. Store in airtight contain-
ers. Protect from light.
Incompatibility. Solutions of pethidine hydrochloride are
acidic. They are incompatible with barbiturate salts and loss
of clarity was also observed in an early additive study with
other drugs including aminophylline. heparin sodium, itiethi-
cillin sodium, morphine sulphate, nitrofurantoin sodium,
phenytoin sodium, sodium iodide, sulphadiazine sodium, and
sulphafurazole diethanolamine. Colour change from pale yel-
low to light green occurred when solutions of minocycline
hydrochloride or tetracycline hydrochloride were mixed with
pethidine hydrochloride in 5% glucose injection. In the same
study an immediate precipitate occurred on admixture with
cefoperazone sodium or meziocillin sodium: with nafcillin
sodium an immediate cloudy appearance cleared on agitation.
Incompatibility has also been observed between pethidine hy-
drochloride and aciclovir sodium, imipenem, frusemide. li-
posomal doxorubicin hydrochloride and idarsbicin.
Solutions of cefazolin sodium and pethidine hydrochloride
mixed in 5% glucose injection turned light yellow after 5 days
storage at 25 the admixture was stable for at least 20 days at
4Β°.
Stability. Pethidine hydrochloride injection 100 mg per mL
was stable for at least 24 hours at room temperature when
diluted to a concentration of 300 mg per litre in glucose 5%
and 4% and in sodium chloride injection (0.9%) and sodium
chloride injection (0.9%) diluted I in 5.
Accelerated stability studies using elevated temperatures and
humidities to simulate tropical conditions classified pethidine
hydrochloride as a less stable drug substance. It was sug-
gested that during quality assurance of preparations contain-
ing pethidine hydrochloride particular attention should be
paid to their stability.
Dependence and Withdrawal
As for Opioid Analgesics. Doses of pethidine
as large as 3 or 4 g daily have been taken by addicts.
As tolerance to the CNS stimulant and antimus-
carinic effects is not complete with these very large
doses, muscle twitching, tremor, mental confusion,
dilated pupils, and sometimes convulsions may be
present.
Withdrawal symptoms appear more rapidly than
with morphine and are of shorter duration.
For the abuse of pethidine analogues, see under Pre-
Cautions.
Adverse Effects and Treatment
As for Opioid Analgesics in general.
The effects on smooth muscle may be relatively less
intense than with morphine and constipation occurs
less frequently. After overdosage, symptoms arc
generally similar to those of morphine poisoning.
However, stimulation of the CNS and convulsions
may also occur, especially in tolerant individuals or
following toxic doses by mouth: these have been at-
tributed mainly to the metabolite norpethidine. Lo-
cal reactions often follow injection of pethidine;
general hypersensitivity reactions occur rarely. The
intravenous administration of pethidine may result
in increased heart rate.
The incidence of adverse effects in hospitalized patients re-
ceiving pethidine was monitored by the Boston Collaborative
Drug Surveillance Program. Following pethidine by mouth
adverse reactions were reported in 16 of 366 patients and
mainly involved the gastro-intestinal tract. Following pethi-
dine by injection 102 of 3268 patients had adverse effects, the
central nervous system being involved in 38.
Effects on the cardiovascular system. Histamine release
was more frequent after pethidine than after morphine, fenta-
nyl, or sufentanil administered intravenously for the induc-
tion of anaesthesia.' Increased plasma-histamine
concentrations occurred in 5 of 16 patients given pethidine in
a mean dose of 4.3 mg per kg body-weight and were general-
ly accompanied by hypotension. tachycardia, erythema, and
increased plasma-adrenaline concentrations. Only I of 10
given morphine and none of those receiving fentanyl or suf-
entanil showed evidence of histamine release. All of the his-
tamine releasers were young women.
Effects on the nervous system. CNS excitatory effects of
pethidine such as tremors, muscle twitches, and convulsions
have been associated with toxic doses and have been attribut-
ed to the metabolite norpethidine. Accumulation of norpethi-
dine may occur if large doses of pethidine are repeated at
short intervals and is especially likely when renal function is
impaired.
Precautions
As for Opioid Analgesics in general.
It should also be given cautiously to patients with
supraventricular tachycardia or with a history of
convulsive disorders.
Abuse. A synthetic analogue of pethidine. MPPP ( I -methyl-
4-phenyl-4-propionoxypiperidineJ, manufactured illicitly for
recreational use, achieved notoriety when it was accidentally
contaminated with MPTP (l-methyl-4-phenyl-l,2,3,6-iel-
rahydropyridine) leading to an epidemic of parkin.sonism
among intravenous drug abusers. The World Health Organi-
zation has also identified another analogue. PEPAP ( I -phe-
nylethyl-4-phenyl-4-acetoxyptperidine) as being liable to
abuse.
Elderly. Pethidine had a slower elimination rate in elderly
compared with young patients and a reduction in total daily
dose might be necessary in elderly patients receiving repeated
doses of pethidine. Another study concluded that age-related
changes in disposition were not sufficient to warrant modifi-
cation of pethidine dosage regimens
Phaeochromocytoma. Pethidine provoked episodes of
hypertension in a patient with phaeochromocytoma. the effect
was suppressed by labetalol. Like other histamine-releasing
opioids. pethidine should be used with caution in such pa-
tients.
Pregnancy and the neonate. Pethidine is widely used for
analgesia during labour. It rapidly crosses the placenta and
like other opioid analgesics may cause respiratory depression
in the neonate although this may be less than with morphine.
Respiratory depression vanes according to the liming and
size of the maternal dose.
Fetal depression was not apparent when delivery occurred
within I hour of pethidine administration, but was present in
6 of 24 infants delivered I to 3 hours after injection and in ail
of 5 infants delivered 3 to () hours after injection.' Cooper et
al noted higher blood concentrations of pethidine in infants
delivered within I hour of a single dose of pethidine 150 mg
intramuscularly when compared with those born following
administration I to 4 hours before delivery. The role of pethi-
dine metabolites is not certain, but relatively little of a dose
might have been metabolised by the mother within I hour,
Hogg el al. " reported that neonates appeared able to ineiabo-
tise pethidine although probably more slowly than adults.
They also showed that the amounts of pethidine and norpethi-
dine excreted by the neonate increased significantly with the
mulernai dose-delivery interval for intervals of up to 5 hours
and considered that most of the placentally transferred pethi-
dine should be excreted by the third day. Elimination of pelhi-
dine took up lo 6 days in the neonates studied by Cooper ft
ul.' In another study.* depressed neonatal responses persisted
for the first 2 days of life; depression was dose-related being
greatest with the highest dose of pethidine f75 lo 150mg
within 4 hours of delivery).
Further references on the transplacental transfer of pethidine
can be found under Pregnancy in Pharmacokinetics, below
Neither psychological nor physical effects were found in 5-
ycar-old children of mothers who had received pethidine dur-
ing labour Neonatal behaviour does not appear to have been
affected significantly by pethidine. although it has been ac,
knowledge that the relationship between maternal analgesia
in labour and subsequent infant behaviour is by no means
simpler The results of early studies which suggested an ex-
cess of cases of cancer in children whose mothers received
pethidine during labour have been refuted by a more recent
and larger study.
Renal Impairment. Caution is necessary when pethidine is
given lo patients with renal impairment. Evidence of CNS ex-
citation. including seizures and twitches, in 2 patients with
renal insufficiency receiving multiple doses of pethidine was
altiibutcd to accumulation of the metabolite norpethidine,
lhey both had high norpethidine : pethidine plasma concen-
tration ratios
Interactions
For interactions associated with opioid analgesics.
Very severe reactions, including coma. severe respi-
ratory depression, cyanosis, and hypotension have
occurred in patients receiving MAOls (including
moclobemide) and given pethidine. There are also
reports of hyper excitability, convulsions, tachycar-
dia. hyperpyrexia, and hypertension. Pethidine
should not be given to patients receiving MAOls or
within 14 days of their discontinuation. Concurrent
administration of pethidine and phenothiazines has
produced severe hypotensive episodes and may pro-
long the respiratory depression due lo pethidine.
Plasma concentrations of pethidine are increased by
ritonavir, with a resultant risk of toxicity: concomi-
tant administration should be avoided.
Barbiturate. Opioid analgesics and barbiturates can be ex-
pected to have additive CNS depressant effects. Prolonged se-
dation with pethidine in the presence of phenobarbitone has
also been attributed to induction of N-demethylation of pethi-
dine, resulting in the enhanced formation of the potentially
neurotoxic metabolite norpethidine.
Histamine H-2 Antagonists. Cimetidine reduced the clear-
ance and volume of distribution of pethidine in healthy sub-
jects, whereas ranitidine did not.
MAOls. Some of the most serious interactions involving
pethidine have been with non-selective MAOls and have been
manifest as enhanced depressant effects or hyper excitability
(see above). However, a life-threatening interaction has also
been reported between pethidine and selegiline, a selective
monoamine oxidase type B inhibitor. Also, symptoms sug-
gestive of a mild serotonin syndrome developed in a 73-year-
old woman taking moclobemide (a reversible inhibitor of
monoamine oxidase), nontriptyline, and lithium after she was
given pethidine intravenously.
Phenothiazines. Prochlorperazine prolonged the respirato-
ry depressant effect of pethidine in healthy subjects.' En-
hanced CNS depression and hypotension were reported when
healthy subjects were given chlorpromazine in addition to
pethidine: there was evidence of increased W-demethylation
of pethidine.
Phenytoin. The hepatic metabolism of pethidine appears lo
be enhanced by phenytoin. Concomitant administration re-
sulted in reduced half-life and bioavailability in healthy sub-
jects: blood concentrations of norpethidine were increased.'
Pharmacokinetics
Pethidine hydrochloride is absorbed from the gas-
tro-intestinal tract, but only about 50% of the drug
reaches the systemic circulation because of first-
pass metabolism. Absorption following intramuscu-
lar injection is variable. Peak plasma concentrations
have been reported I to 2 hours after oral adminis-
tration. It is about 60 to 80% bound to plasma pro-
teins.
Pethidine is metabolised in the liver by hydrolysis to
pethidinic acid (meperidinic acid) or demethylation
to norpethidine (normeperidine) and hydrolysis to
norpethidinic acid (normeperidinic acid), followed
by partial conjugation with glucuronic acid. Nor-
pethidine is pharmacologically active and its accu-
mulation may result in toxicity. Pethidine is reported
to have a plasma elimination half-life of about 3 to 6
hours in healthy subjects: the metabolite norpethi-
dine is eliminated more slowly, with a half-life re-
ported to be up to about 20 hours. Both pethidine
and norpethidine appear in the cerebrospinal fluid.
At the usual values of urinary pH or if the urine is
alkaline, only a small amount of pethidine is excret-
ed unchanged; urinary excretion of pethidine and
norpethidine is enhanced by acidification of the
urine. Pethidine crosses the placenta and is distribut-
ed into breast milk.
Administration. The elimination half-life of pethidine was
prolonged and plasma clearance decreased when given pen-
operatively compared with postoperatively.
During labour the pharmacokinetics of pelhidine may depend
on the method of administration, in a comparison of intra-
muscular injection at different sites, absorption of pethidine
from the gluteus muscle was impaired and the deltoid muscle
was preferred.2 i
No statistically significant differences were found in pharma-
cokinetic parameters for deltoid and gluteal intramuscular in-
jections in elderly postoperative patients' However,
substantial interpatient variability was noted for both sites.
and the authors suggested that more rapid and predictable
routes such as intravenous injection may be more appropriate
for postoperative use in the elderly.
Administration in hepatic impairment. The terminal
half-life of pethidine was prolonged to about 7 hours in cir-
rhotic patients compared with 3 hours in healthy subjects and
was attributed to impairment of the drug-metabolising activi-
ty of the liver. Another study concluded that although im-
paired hepatic metabolism might confer relative protection
from norpethidine toxicity in patients with cirrhosis, there
might be an increased risk of cumulative toxicity because of
slow elimination of the metabolite.
Administration in renal impairment. Plasma protein
binding of pethidine was reported to be decreased in renal dis-
ease and ranged from 58.2% in healthy subjects lo 31.8% in
anuric patients. The same workers also reported impaired
elimination of pethidine in patients with renal dysfunction. ~
Pregnancy. Some references to the pharmacokinetics of
pethidine during labour are given below.
Uses and Administration
Pethidine hydrochloride, a phenylpiperidine deriva-
tive, is a synthetic opioid analgesic that acts
mainly as a n opioid agonist. Pethidine is used for
the relief of most types of moderate to severe acute
pain including the pain of labour. It is more lipid sol-
uble than morphine and has a less potent and shorter
lasting analgesic effect; analgesia usually lasts for 2
to 4 hours. Its short duration of action and accumu-
lation of its potentially neurotoxic metabolite nor-
pethidine on repeated administration make it
unsuitable for the management of chronic pain.
Pethidine has a weaker action on smooth muscle
than morphine and its lower potential to increase bil-
iary pressure makes it suitable when opioid analge-
sics are required to manage pain associated with
biliary colic and pancreatitis. It is also used as pre-
operative medication and as an adjunct to anaesthe-
sia. It has been given with phenothiazines such as
promethazine to achieve basal narcosis. Pethidine
has little effect on cough or on diarrhoea.
For the relief of pain, pethidine hydrochloride is giv-
en in doses of 50 to 150 mg by mouth every 4 hours.
It may also be given by intramuscular or subcutane-
ous injection in doses of 25 to 100 mg and by slow
intravenous injection in doses of 25 to 50 mg repeat-
ed after 4 hours. For postoperative pain the subcuta-
neous or intramuscular doses may be given every 2
to 3 hours if necessary. In children, doses of 0.5 to
2 mg per kg body-weight may be given by mouth or
by intramuscular injection.
In obstetric analgesia 50 to 100 mg may be given by
intramuscular or subcutaneous injection as soon as
contractions occur at regular intervals. This dose
may be repeated after I to 3 hours if necessary up to
a maximum of 400 mg in 24 hours.
For pre-operative medication 25 to 100 mg may be
given intramuscularly or subcutaneously about I
hour before operation: children may be given 0.5 to
2 mg per kg. As an adjunct to nitrous oxide-oxygen
anaesthesia 10 to 25 mg may be given by slow intra-
venous injection.
Administration. In addition to conventional routes of ad-
ministration pethidine has been given epidurally and in-
irathecally. It has also been given intravenously and
intranasally by patient-controlled analgesia. However, some
consider that the use of pethidine should be avoided in pa-
tient-controlled analgesia because of the increased risk of
norpethidine-induced seizures' (see also under Effects on the
Nervous System, above).
Eclampsia and pre-eclampsia. See Lytic Cocktails under
Sedation, below.
Pain. Pethidine may be preferred to morphine when rapid
control of acute pain is required. It is widely used in obstetrics to control the pain of labour and for postoperative pain relief following caesarean section or other surgical procedures.
In a study of patients with intractable pain the minimum ef-
fective analgesic blood concentration ranged from 100 to
S20 ng per mL (median 250 ng per mL) in 15 of 16, the re-
maining patient failed to obtain analgesia with pethidine. Ad-
ditional measures were considered necessary' if the minimum
effective concentration exceeded 400 ng per mL.
Pethidine has traditionally been given by intermittent intra-
muscular injection in the treatment of acute pain but incon-
sistent pain relief can be expected because of fluctuating
blood-pethidine concentrations:' continuous intravenous in-
fusion might be more effective for acute pain. For reference
to various routes of administration, see Administration,
above.
SICKLE CELL CRISIS Concern has been expressed over the con-
linued use of pethidine for analgesia in painful crises in sick-
le-ceH disease. Control of pain may be inadequate and doses
commonly used to manage crises may lead to accumulation
of the neuroexcitatory metabolite of pethidine and precipitate seizures.see also under Effects on the Nervous System
above.
Sedation. Some references to the use of pethidine for endos-
copy are given below.
LYTIC COCKTAILS Lytic cocktails consisting of chlorpro-
Mazine, pethidine. and/or promethazine have been given in-
travenouslv in some countries for the management of pre-
eclampsia and imminent eclampsia. However, the use of
phenothiazines is generally not recommended late in preg-
nancy. The more usual treatment of pre-eclampsia and ec-
lampsia is primarily aimed at reducing hypertension.
Lytic cocktails have also been used for sedation and analgesia
in paediatnc patients, generally by the intramuscular route.
although intravenous injections have also been used. Howev-
er there is a high rate of therapeutic failure as well as serious
adverse effects with such combinations, and the American
Academy of Pediatrics' has recommended that alternative
sedatives and analgesics should be considered; guidelines
have been drawn up should it be appropriate to use a lytic
cocktail. Lytic cocktails are not the most appropriate means
of sedation for short procedures since patients must be moni-
lored for approximately one hour before the procedure while
the drugs lake effect, and for even longer during the recovery
period
Shivering. For reference to the use of pethidine in the man-
agement of shivering associated with anaesthesia, see under
Adverse Effects of General Anaesthetics, p.1219. Pethidine
has also been used lo treat amphotericin-induced shaking
chills.