Clinical Pharmacology and Therapeutics

OPIOIDS 161
increases, correlating with the high efficacy of repeated-dose
oral morphine. Morphine-6-glucuronide is eliminated in the
urine, so patients with renal impairment may experience severe
and prolonged respiratory depression. The birth of opiatedependent
babies born to addicted mothers demonstrates the
ability of morphine and its glucuronide to cross the placenta.
Drug interactions
• Morphine augments other central nervous system
depressants.
• Morphine should not be combined with MAOIs.
• Opioid (μ) receptor antagonists (e.g. naloxone) are used in
overdose.
DIAMORPHINE (‘HEROIN’)
Use
Diamorphine is diacetylmorphine. Its actions are similar to
those of morphine, although it is more potent as an analgesic
when given by injection. Diamorphine has a reputation for
having a greater addictive potential than morphine and is
banned in the USA. The more rapid central effect of intravenous
diamorphine than of morphine (the faster ‘buzz’), due to rapid
penetration of the blood–brain barrier, makes this plausible (see
below). Diamorphine is used for the same purposes as morphine.
It is more soluble than morphine, and this may be relevant
to limit injection volume (e.g. in epidural analgesia).
Adverse effects
The adverse effects of diamorphine are the same as those for
morphine.
Pharmacokinetics
Diamorphine is hydrolysed (deacetylated) rapidly to form
6-acetylmorphine and morphine, and if given by mouth owes
its effect entirely to morphine. Diamorphine crosses the
blood–brain barrier even more rapidly than morphine. This
accounts for its rapid effect when administered intravenously
and hence increased abuse potential compared with morphine.
PETHIDINE
Use
The actions of pethidine are similar to those of morphine. It
causes similar respiratory depression, vomiting and gastrointestinal
smooth muscle contraction to morphine, but does
not constrict the pupil, release histamine or suppress cough. It
produces little euphoria, but does cause dependence. It can
cause convulsions. Pethidine is sometimes used in obstetrics
because it does not reduce the activity of the pregnant uterus,
but morphine is often preferred. Delayed gastric emptying
(common to all opioids) is of particular concern in obstetrics,
as gastric aspiration is a leading cause of maternal morbidity.
Pharmacokinetics
Hepatic metabolism is the main route of elimination.
Norpethidine is an important metabolite since it is proconvulsant.
The t 1/2 of pethidine is three to four hours in healthy
individuals, but this is increased in the elderly and in patients
with liver disease. Pethidine crosses the placenta and causes
respiratory depression of the neonate. This is exacerbated by
the prolonged elimination t 1/2 in neonates of about 22 hours.
Drug interactions
• When pethidine is given with monoamine oxidase
inhibitors, rigidity, hyperpyrexia, excitement, hypotension
and coma can occur.
• Pethidine, like other opiates, delays gastric emptying, thus
interfering with the absorption of co-administered drugs.
ALFENTANYL, FENTANYL AND REMIFENTANYL
Use
These are derivatives of pethidine. They are more potent but
shorter-acting and are used to treat severe pain or as an
adjunct to anaesthesia. Fentanyl is available as a transdermal
patch which is changed every 72 hours. They can be given
intrathecally and via patient-controlled devices.
TRAMADOL
Use
Tramadol is widely used for moderate to severe pain, including
post-operative pain. It can be administered by mouth, or
by intramuscular or intravenous injection
Mechanism of action
Tramadol works partly through an agonist effect at μ receptors
(opioid action) and partly by enhancing amine (5HT and catecholamine)
transmission (and hence gating mechanism) by
blocking neuronal amine re-uptake.
Adverse effects
These differ from pure opioid agonists, including less respiratory
depression, constipation and abuse potential. Diarrhoea,
abdominal pain, hypotension, psychiatric reactions, as well as
seizures and withdrawal syndromes have been reported.
METHADONE
Use
Methadone has very similar actions to morphine, but is less
sedating and longer acting. Its main use is by mouth to replace
morphine or diamorphine when these drugs are being withdrawn
in the treatment of drug dependence. Methadone given
once daily under supervision is preferable to leaving addicts to
seek diamorphine illicitly. Many of the adverse effects of opioid
abuse are related to parenteral administration, with its attendant
risks of infection (e.g. endocarditis, human immunodeficiency
virus or hepatitis). The object is to reduce craving by
occupying opioid receptors, simultaneously reducing the
‘buzz’ from any additional dose taken. The slower onset following
oral administration reduces the reward and reinforcement
of dependence. The relatively long half-life reduces the intensity
of withdrawal and permits once-daily dosing under supervision.
Methadone is also becoming more widely used in the
treatment of chronic or terminal pain patients where its additional
property of being an NMDA antagonist may be helpful.