A Textbook of Clinical Pharmacology and Therapeutics

OPIOIDS 161

increases, correlating with the high efficacy of repeated-dose
oralmorphine. Morphine-6-glucuronide is eliminated in the
urine, so patients with renal impairment may experience severe
and prolonged respiratory depression. The birth of opiate-
dependent babies born to addicted mothers demonstrates the
ability of morphineand its glucuronide to cross the placenta.

Drug interactions

• Morphineaugments 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

Diamorphineis diacetylmorphine. Its actions are similar to
those of morphine, although it is more potent as an analgesic
when given by injection. Diamorphinehas a reputation for
having a greater addictive potential than morphineand is
banned in the USA. The more rapid central effect of intravenous
diamorphinethan of morphine(the faster ‘buzz’), due to rapid
penetration of the blood–brain barrier, makes this plausible (see
below).Diamorphineis used for the same purposes as mor-
phine. It is more soluble than morphine, and this may be rele-
vant to limit injection volume (e.g. in epidural analgesia).

Adverse effects

The adverse effects of diamorphineare the same as those for
morphine.

Pharmacokinetics

Diamorphineis hydrolysed (deacetylated) rapidly to form
6-acetylmorphine and morphine, and if given by mouth owes
its effect entirely to morphine. Diamorphinecrosses 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 pethidineare similar to those of morphine. It
causes similar respiratory depression, vomiting and gastro-
intestinal 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. Pethidineis sometimes used in obstetrics
because it does not reduce the activity of the pregnant uterus,
butmorphineis 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 proconvul-
sant. The t1/2ofpethidineis three to four hours in healthy
individuals, but this is increased in the elderly and in patients

with liver disease. Pethidinecrosses the placenta and causes

respiratory depression of the neonate. This is exacerbated by

the prolonged elimination t1/2in neonates of about 22 hours.

Drug interactions

• Whenpethidineis 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. Fentanylis available as a transdermal

patch which is changed every 72 hours. They can be given

intrathecally and via patient-controlled devices.

TRAMADOL

Use

Tramadolis widely used for moderate to severe pain, includ-

ing 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 μreceptors

(opioid action) and partly by enhancing amine (5HT and cat-

echolamine) transmission (and hence gating mechanism) by

blocking neuronal amine re-uptake.

Adverse effects

These differ from pure opioid agonists, including less respira-

tory depression, constipation and abuse potential. Diarrhoea,

abdominal pain, hypotension, psychiatric reactions, as well as

seizures and withdrawal syndromes have been reported.

METHADONE

Use

Methadonehas very similar actions to morphine, but is less

sedating and longer acting. Its main use is by mouth to replace

morphineordiamorphinewhen these drugs are being with-

drawn in the treatment of drug dependence. Methadonegiven

once daily under supervision is preferable to leaving addicts to

seekdiamorphineillicitly. Many of the adverse effects of opioid

abuse are related to parenteral administration, with its attend-

ant risks of infection (e.g. endocarditis, human immunodefi-

ciency 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 follow-

ing oral administration reduces the reward and reinforcement

of dependence. The relatively long half-life reduces the inten-

sity of withdrawal and permits once-daily dosing under super-

vision.Methadoneis also becoming more widely used in the

treatment of chronic or terminal pain patients where its add-

itional property of being an NMDA antagonist may be helpful.