4. Opiates / Opioids

Question 1

opiate

Answer 1

The word ‘opiate’, strictly defined, is any drug that is derived from the opium poppy

definition, however, morphine and codeine phosphate are classed
as opiates, whereas diamorphine (which is diacetylated morphine) is not

Question 2

opioid’

Answer 2

mean any drug that acts at the opioid receptor

Question 3

μ-agonists

Answer 3

All the pure μ-agonists have similar pharmacodynamic effects; their differences are
primarily pharmacokinetic.

Question 4

Opioid receptors

Answer 4

μ (mu), κ (kappa) and δ (delta
OP3, OP2 and OP1 receptors

superseded
by MOP (μ-opioid peptide receptor, with endomorphins as natural ligands), DOP (δ-
delta opioid peptide receptor, with enkephalins as natural ligands), KOP (κ-opioid
peptide receptor, with dynorphins as natural ligands) and NOP (nociceptin/orphanin
FQ peptide receptor, with orphanin FQ as its natural ligand

Question 5

Effects

Answer 5

they inhibit intracellular adenyl cyclase via G protein coupling,
they hyperpolarize cell membranes by facilitating the opening of postsynaptic
potassium channels and they inhibit neurotransmitter release by decreasing
the function of voltage-gated calcium channels

Question 6

Different Fx based on receptor

Answer 6

MOP (μ-) receptors are believed to
mediate not only analgesic effects but also respiratory depression

KOP (κ-) receptors
have more spinal and peripheral than central analgesic effects, as do the DOP (δ)
receptors

NOP receptor is the most recently identified, and investigation
has concentrated on its analgesic effects and its apparent neural processing of
factors such as drug tolerance, reward and addiction.

Question 7

Opioid actions

Answer 7

: these are almost too well known to repeat, but, to summarize,
opioids have a mixture of inhibitory and excitatory effects

Question 8

Inhibitory actions

Answer 8

sedation;
anxiolysis,
analgesia,
respiratory depression
(including inhibition of the respiratory response to hypoxia),
inhibition of cough
loss of vascular smooth muscle tone

Question 9

Excitatory effects

Answer 9

miosis
(stimulation of the Edinger–Westphal nucleus),

nausea and vomiting
via direct actions at the chemoreceptor trigger zone,

ADH release from the posterior pituitary,

urinary retention
enhanced detrusor muscle tone,

bronchoconstriction
increase in smooth muscle tone

constipation
increased activity in the circular muscle of the bowel
which prevents effective peristalsis

Question 10

Other effects

Answer 10

include histamine release,
pruritus (which may not be mediated by μ-receptors, as it is not reliably
reversed by naloxone)

chest-wall rigidity.

This is associated with rapid injection of the more potent short-acting opioids
but can occur with all of this class of drug.

One possible explanation for the phenomenon is that it is due to the simultaneous
inhibition of GABA release in the striatum of the basal ganglia together with a
simultaneous but transient increase in dopamine production

Question 11

Morphine

Answer 11

: this can be given by various routes.

There is a range of reported bioavailability:
100% (i.m.),
20–40% (oral),
35–70% (rectal).

It is not always appreciated that it takes some time for a bolus intravenous dose
to reach its maximal effect.

Unlike all the other major opioids,
at 20 minutes the drug has reached only 80% of its peak effect.

Morphine is metabolized in the liver to morphine-6-glucuronide (5–15%),

which is more potent than the parent compound
(its precise relative potency has not been quantified
because studies have looked at different aspects of
opioid effect rather than at analgesia alone),

and to morphine-3-glucuronide (50%),
which has no analgesic effects.

Question 12

Diamorphine

Answer 12

This is a semisynthetic derivative of morphine,

diacetylmorphine, which consists of two molecules of morphine.

The compound has no activity at μ-receptors until
it is metabolized to 6-monoacetylmorphine and thence to morphine
(both are active).

It is thus a prodrug with the same properties as morphine.

Some clinicians are convinced nonetheless that anecdotally
it is less emetic and more
euphoriant than morphine.

(When given intrathecally, its much higher lipid solubility does confer advantages.)

Question 13

Pethidine:

Answer 13

the side effect profile is very similar to that of morphine, but pethidine is
still regarded as an alternative opioid in patients who are intolerant of morphine.

It has a rapid onset of action, but its effects are shorter.

It differs in some other material respects.
One of its metabolites is norpethidine, which is a convulsant.

Prolonged or high-dose administration should therefore be avoided,
and it should be used with care in patients with renal impairment

One useful property is its ability to attenuate or abolish anaesthesia-induced
postoperative shivering (typically 25 mg by slow intravenous injection).

membrane stabilizer and has a local anaesthetic
effect.

Question 14

Fentanyl:

Answer 14

phenylpiperidine (like pethidine), which itself is the parent
compound of alfentanil and remifentanil.

Onset of effect is at 1–2 minutes,

with a peak action at 4–5 minutes and an
effective duration of action after a single bolus of
up to 30 minutes

highly lipid-soluble, and its metabolites are inactive.

It is a drug that accumulates when given by infusion
(or by repeated bolus injection);

its context-sensitive half-time (CSHT)
after 2 hours of constant infusion is 48 minutes,
which, after 8 hours of infusion, extends to 282 minutes.

Question 15

Alfentanil

Answer 15

: this is also a phenylpiperidine compound but with a shorter duration of
action than fentanyl.

After peaking at 1 minute after intravenous injection, its effects
last for only 5–10 minutes.

The drug accumulates when given by infusion, its CSHT
being 50 minutes after 2 hours.

Question 16

Remifentanil:

Answer 16

this is a phenylpiperidine ester

whose action is terminated by nonspecific tissue esterases.

Its main product of metabolism has minimal potency (<0.5%)

This gives it a short and predictable duration of action which is confirmed by its CSHT

It is effectively context-insensitive because the CSHT is 4.5 minutes after 2 hours of
infusion, and only 9.0 minutes after 8 hours

Its very rapid offset of action makes it
unsuitable for PCA for postoperative pain, but there are some obstetric anaesthetists
who advocate its use for labour analgesia. (Bolus doses 20–40 μg with a 2-minute
lockout. Associated problems include sedation and maternal desaturation.

One disadvantage
of high-dose remifentanil infusion is its potential to cause postoperative
hyperalgesia. This can be mitigated by low-dose ketamine, which suggests that the
hyperalgesia is mediated via NMDA receptor activation

Question 17

oxycodone

Answer 17

pure μ-agonists

(which has high oral bioavailability (up to 75%) and which is becoming more
popular for the treatment of postoperative pain).

Oxycodone has one weakly active
metabolite, oxymorphone. (The usual oral dose of oxycodone is 5–10 mg given 3–4-
hourly. There is also a sustained release preparation OxyContin; dose 10 mg 12-hourly).

Question 18

Tramadol:

Answer 18

Tramadol is a racemic mixture of R (+) and S (−) enantiomers,

of which the R (+) enantiomer has low initial activity at μ-receptors;

however, the higher affinity of its main metabolite (

ortho-desmethyltramadol) results in a sixfold increase in analgesic potency.

Question 19

Patient-Controlled Analgesia (PCA)

Answer 19

Advantages: PCA is popular with patients because of the autonomy and control that
it gives them, which makes it particularly useful in those who might otherwise be
reluctant to request analgesia and for those who dislike intramuscular injections. It is
popular with nurses for the same reasons, and because it can save nursing time. It is
popular with doctors because most PCA regimens by and large can cope with the
very wide variability that characterizes patients’ requirements for postoperative
opioids. As a generalization, it is efficacious and safe.

Question 20

Disadvantages

Answer 20

: it is important that a PCA does not lessen the direct personal contact
between the patient and nursing staff.

Electronic pumps can limit mobility, while
disposable devices lack the facility to track demand and the total analgesic dose
delivered.

Security can also be a problem. PCA is still a system that delivers bolus
doses, which results in peaks and troughs of effect. This can be overcome by adding a
background infusion, but potentially this is at the expense of safety

Question 21

Drugs used in PCA regimens:

Answer 21

Morphine is commonly used in PCA regimens
because it is seen to offer the best compromise between the combination of efficacy
and duration of action. A typical regimen is 1.0 mg bolus with a 5-minute lockout
time. Its pharmacokinetic profile, however, with the slow time to peak effect, suggests

The peak effect of fentanyl occurs around 4–5
minutes, and its duration of action of about 30 minutes makes this a suitable, and
underused agent (bolus doses of 10–20 μg; lockout time 5–10 minutes)

Question 22

Opioid-induced hyperalgesia (OIH):

Answer 22

paradoxical increased sensitivity
to pain in subjects given opioids

typically, although not exclusively, when
taking high doses over a prolonged period

High doses of intraoperative opioids can
also reduce nociceptive thresholds and cause secondary hyperalgesia

REmifentanil

because hyperalgesia
in the immediate post-operative period is associated with the development of
chronic post-surgery pain syndromes.

Question 23

Opioid-induced hyperalgesia (OIH):

Answer 23

paradoxical increased sensitivity
to pain in subjects given opioids

typically, although not exclusively, when
taking high doses over a prolonged period

High doses of intraoperative opioids can
also reduce nociceptive thresholds and cause secondary hyperalgesia

REmifentanil

because hyperalgesia
in the immediate post-operative period is associated with the development of
chronic post-surgery pain syndromes.

Question 24

OIH Moa

Answer 24

The precise mechanisms have not been elucidated

alteration of the opioid receptor itself such that the G-protein secondary
messenger systems described undergo a switch from an inhibitory to an excitatory
coupled mod

down-regulation
of glutamate transport at spinal cord level.

descending inhibitory serotoninergic pathways may become pro-nociceptive