4. Opiates / Opioids

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

mean any drug that acts at the opioid receptor

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

μ (mu), κ (kappa) and δ (delta OP3, OP2 and OP1 receptors superseded by MOP (μ-opioid peptide receptor, with endomorphins as natural ligands), DOP (δ- delta opioid peptide receptor, with enkephalins as natural ligands), KOP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

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

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.

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

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

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

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

: 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.

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.)

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.

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.

: 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.

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

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).

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.

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.

: 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

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)

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.

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.

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