Abstract
Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Since pain is so highly subjective, it may also be described as being what the patient says it is.
Pain is defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage. Since pain is so highly subjective, it may also be described as being what the patient says it is.
Pain may be classified according to its presumed aetiology. Nociceptive pain is the result of the stimulation of nociceptors by noxious stimuli, whilst neuropathic pain is the result of dysfunction of the nervous system. These may exist together as mixed pain. There is also visceral pain, the clearest example being that associated with gallstones.
An alternative classification is based on chronicity. The point at which acute pain becomes chronic has been suggested at about 12 weeks or when the pain is no longer thought to be due to the initial insult.
Physiology
Nociceptive impulses are triggered by the stimulation of nociceptors that respond to chemical, mechanical or thermal damage. The chemical mediators that initiate (H+, K+, acetylcholine, histamine, serotonin (5-HT), bradykinin) and sensitise (prostaglandins, leukotrienes, substance P, neurokinin A, calcitonin gene-related peptide) the nociceptors are legion. Two types of primary afferent fibres exist:
small myelinated Aδ fibres (diameter 2–5 µm) that conduct sharp pain rapidly (40 m.s−1)
unmyelinated C fibres (diameter < 2 µm) that conduct dull pain slowly (2 m.s−1). These fibres enter the dorsal horn of the spinal cord and synapse at different sites (Aδ at Rexed laminae II and V; C at Rexed laminae II). The substantia gelatinosa (lamina II) integrates these inputs, from where second-order neurones form the ascending spinothalamic and spinoreticular pathways on the contralateral side. Descending pathways and the larger Aβ fibres conducting ‘touch’ stimulate inhibitory interneurones within the substantia gelatinosa and inhibit C fibre nociceptive inputs. This forms the basis of the ‘gate theory’ of pain (Figure 10.1).
Figure 10.1 Principle of the gate theory of pain within the dorsal horn of the spinal cord. (a) Pain mediated via C fibres passes through the gate centrally; (b) the gate is shut as Aβ fibres stimulate inhibitory interneurones (i) and by descending pathways, preventing the central passage of pain (ii).
Pain may be modified by altering the neural pathway from its origin at the nociceptor to its interpretation within the central nervous system (CNS). The commonly used agents are discussed below under the following headings:
Opioids and related drugs
Non-steroidal anti-inflammatory drugs (NSAIDs)
Other analgesics.
Opioids and Related Drugs
The term ‘opiate’ refers to all naturally occurring substances with morphine-like properties, while ‘opioid’ is a more general term that includes synthetic substances that have an affinity for opioid receptors. Opioids are basic amines.
Receptor Classification
Classical receptor classification, that is, kappa and delta, was based on either the name of the agonist that acted at that receptor, mu (µ) – morphine, kappa (κ) – ketcyclazocine or the location of the receptor, delta (δ) – vas deferens. The latest reclassification is listed in Table 10.1 and includes an additional non-classical receptor, NOP, which was discovered at the time of receptor cloning. It is known as the nociceptin/orphanin FQ peptide receptor.
| Receptor | Effects |
|---|---|
| MOP, µ, mu | analgesia, miosis, euphoria, respiratory depression, bradycardia, inhibition of gut motility |
| KOP, κ, kappa | analgesia, sedation, miosis |
| DOP, δ, delta | analgesia, respiratory depression |
| NOP | anxiety, depression, appetite modulation |
Both receptor types are serpentine (i.e. span the membrane seven times) and are linked to inhibitory G-proteins so that when stimulated by an appropriate opioid agonist (e.g. morphine to µ) the following sequence occurs: voltage-sensitive Ca2+ channels are closed, hyperpolarisation by K+ efflux and adenylase cyclase inhibition lead to reduced cAMP. These processes result in inhibition of transmitter release between nerve cells.
MOP or µ-Receptor
The µ-receptor is located throughout the CNS including the cerebral cortex, the basal ganglia, the spinal cord (presynaptically on primary afferent neurones within the dorsal horn) and the periaqueductal grey (as the origin of the descending inhibitory control pathway). Apart from analgesia, µ-receptor stimulation produces wide-ranging effects including respiratory depression (by reducing chemoreceptor sensitivity to carbon dioxide), constipation (reduced secretions and peristalsis) and cardiovascular depression.
KOP or κ-Receptor
The original κ-receptor agonist was ketocyclazocine, which demonstrated a different set of effects when compared with µ-receptor stimulation. The main advantage of κ-receptor stimulation relates to a lack of respiratory depression, although κ-agonists do seem to have µ-antagonist effects thus limiting their use.
DOP or δ-Receptor
The δ-receptor was the first to be cloned and is less widely spread throughout the CNS. Like µ-receptors, when stimulated they inhibit neurotransmitter release. It may also be involved in regulating mood and movement.
NOP-Receptor
When stimulated by nociceptin/orphanin FQ the NOP receptor produces effects similar to µ-receptor stimulation. It acts at both spinal and supraspinal levels to produce hyperalgesia at low doses but analgesia at high doses. NOP-receptor antagonists produce long-lasting analgesia and prevent morphine tolerance, and may be useful in the future.
Morphine
Morphine is a naturally occurring phenanthrene derivative. It has a complex structure (Figure 10.2) and is the reference opioid with which all others are compared. It is a µ-receptor agonist (see Table 10.2).
Presentation and Uses
Morphine is formulated as tablets, suspensions and suppositories, and as slow-release capsules and granules in a wide range of strengths. The oral dose of morphine is 5–20 mg 4-hourly. The parenteral preparation contains 10–30 mg.ml−1 and may be given intravenously or intramuscularly. The intramuscular dose is 0.1–0.2 mg.kg−1 4-hourly. Intravenous morphine should be titrated to effect, but the total dose is similar. It should be noted that these doses are only guidelines and the frequency of administration and/or the dose may have to be increased. The subcutaneous route is usually avoided due to its relatively low lipid solubility and therefore slow absorption. Delayed respiratory depression following intrathecal or epidural administration may occur and is again due to its relatively low lipid solubility.
Effects
Analgesia – particularly effective for visceral pain while less effective for sharp or superficial pain. Occasionally increased doses may be required but this is usually due to a change in pathophysiology rather than dependence.
Respiratory depression – the sensitivity of the brain stem to carbon dioxide is reduced following morphine while its response to hypoxia is less affected. However, if the hypoxic stimulus is removed by supplementary oxygen then respiratory depression may be potentiated. The respiratory rate falls more than the tidal volume. Morphine is anti-tussive. It may precipitate histamine release and bronchospasm.
Nausea and vomiting – the chemoreceptor trigger zone is stimulated via 5-HT3 and dopamine receptors. The cells within the vomiting centre are depressed by morphine and do not stimulate vomiting.
Central nervous system – sedation, euphoria and dysphoria occur with increasing doses.
Circulatory – morphine may induce a mild bradycardia and hypotension secondary to histamine release and a reduction in sympathetic tone. It has no direct myocardial depressant effects.
Gut – morphine constricts the sphincters of the gut. Constipation results from a state of spastic immobility of the bowel. Whilst the sphincter of Oddi is contracted by morphine thereby raising the pressure within the biliary tree, the clinical significance of this is unknown.
Histamine release – reducing the rate of administration will help to limit histamine-induced bronchospasm and hypotension. Histamine release may result in a rash and pruritus but this may be reversed by naloxone.
Pruritus – most marked following intrathecal or epidural use. However, this does not appear to be due to histamine release and is generally not associated with a rash. Paradoxically, antihistamines may be effective treatment for pruritus, possibly as a result of their sedative effects.
Muscle rigidity – occasionally, morphine (and other opioids) can precipitate chest wall rigidity, which is thought to be due to opioid receptor interaction with dopaminergic and GABA pathways in the substantia nigra and striatum.
Miosis – due to stimulation of the Edinger–Westphal nucleus, which can be reversed by atropine.
Endocrine – morphine inhibits the release of adrenocorticotrophic hormone (ACTH), prolactin and gonadotrophic hormones. Antidiuretic hormone (ADH) secretion is increased and may cause impaired water excretion and hyponatraemia.
Urinary – the tone of the bladder detrusor and vesical sphincter is increased and may precipitate urinary retention. Ureteric tone is also increased.
Kinetics
When given orally morphine is ionised in the acidic gastric environment (because it is a weak base, pKa = 8.0) (see Table 10.3) so that absorption is delayed until it reaches the relatively alkaline environment of the small bowel where it becomes unionised. Its oral bioavailability of 30% is due to hepatic first-pass metabolism. Its peak effects following intravenous or intramuscular injection are reached after 10 and 30 minutes, respectively, and it has a duration of action of 3–4 hours. It has been given by the epidural (2–4 mg) and intrathecal (0.2–1.0 mg) routes but this has been associated with delayed respiratory depression.
| Elimination half-life (min) | Clearance (ml.min−1.kg−1) | Volume of distribution (l.kg−1) | Plasma protein-bound (%) | pKa | Percentage unionised (at p. 7.4) | Relative lipid solubility (from octanol:water coefficient) | |
|---|---|---|---|---|---|---|---|
| Morphine | 170 | 16 | 3.5 | 35 | 8.0 | 23 | 1 |
| Pethidine | 210 | 12 | 4.0 | 60 | 8.7 | 5 | 30 |
| Fentanyl | 190 | 13 | 4.0 | 83 | 8.4 | 9 | 600 |
| Alfentanil | 100 | 6 | 0.6 | 90 | 6.5 | 89 | 90 |
| Remifentanil | 10 | 40 | 0.3 | 70 | 7.1 | 68 | 20 |
Morphine concentration in the brain falls slowly due to its low lipid solubility, and consequently plasma concentrations do not correlate with its effects.
Morphine metabolism occurs mainly in the liver but also in the kidneys. Up to 70% is metabolised to morphine 3-glucuronide which appears to have effects on arousal and is possibly a µ-receptor antagonist. The other major metabolite is morphine 6-glucuronide, which is 13 times more potent than morphine and has a similar duration of action. They are both excreted in urine and accumulate in renal failure. Morphine is also N-demethylated. Neonates are more sensitive than adults to morphine due to reduced hepatic conjugating capacity, and in the elderly peak plasma levels are higher due to a reduced volume of distribution.
Diamorphine
Diamorphine is a diacetylated morphine derivative with no affinity for opioid receptors. It is a prodrug whose active metabolites are responsible for its effects. It is said to be approximately twice as potent as morphine (see Table 10.4).
| Route | Potency ratio with oral morphine | Equivalent dose to 10 mg oral morphine | |
|---|---|---|---|
| Codeine phosphate | po | 0.1 | 100mg |
| Dihydrocodeine | po | 0.1 | 100mg |
| Tramadol | po | 0.15 | 67mg |
| Tapentadol | po | 0.4 | 25mg |
| Oxycodone | po | 1.5 | 6.6mg |
| Morphine | po | 1 | 10mg |
| Morphine | im / iv / sc | 2 | 5mg |
| Diamorphine | im / iv / sc | 3.3 | 3mg |
Presentation and Uses
Diamorphine is available as 10 mg tablets and as a white powder for injection containing 5, 10, 30, 100 or 500 mg diamorphine hydrochloride, which is readily dissolved before administration. It is used parenterally for the relief of severe pain and dyspnoea associated with pulmonary oedema at 2.5–10 mg. It is used intrathecally (0.1–0.4 mg) and via the epidural route (1–3 mg) for analgesia where, due to a higher lipid solubility, it is theoretically less likely to cause delayed respiratory depression when compared with morphine.
Kinetics
Owing to its high lipid solubility diamorphine is well absorbed from the gut but has a low oral bioavailability due to an extensive first-pass metabolism. Its high lipid solubility enables it to be administered effectively by the subcutaneous route. Once in the plasma it is 40% protein-bound. It has a pKa = 7.6 so that 37% is in the unionised form at p. 7.4. Metabolism occurs rapidly in the liver, plasma and CNS by ester hydrolysis to 6-monoacetylmorphine and morphine, which confer its analgesic and other effects. The plasma half-life of diamorphine itself is approximately 5 minutes.
It produces the greatest degree of euphoria of the opioids and subsequently has become a drug of abuse.
Codeine
Codeine (3-methylmorphine) is 10 times less potent than morphine and not suitable for severe pain. The oral and intramuscular adult dose is 30–60 mg. Its use in children younger than 12 years has been restricted because of reports of morphine toxicity. The intravenous route tends to cause hypotension, probably via histamine release, and is therefore avoided. It has been suggested codeine acts as no more than a prodrug for morphine.
Uses
In addition to its analgesic uses it is used as an antitussive, antidiarrhoeal, hypnotic and anxiolytic.
Kinetics
Due to the presence of a methyl group that reduces hepatic first-pass metabolism the oral bioavailability of codeine (50%) is slightly higher than that of morphine.
A small proportion (5–15%) of codeine is eliminated unchanged in the urine while the remainder is eliminated via one of three metabolic pathways in the liver. The predominant metabolic pathway is 6-hydroxyglucuronidation to codeine-6-glucuronide, although 10–20% undergoes N-demethylation to norcodeine, and up to 15% undergoes O-demethylation to morphine. A number of other metabolites, such as normorphine and hydrocodone, have also been identified. Of these metabolites only morphine has significant activity at µ-receptors. O-demethylation is dependent on the non-inducible CYP2D6, which exhibits genetic polymorphism so that poor metabolisers experience little pain relief. The frequency of poor metabolisers varies and is estimated at 9% of the UK population but 30% in the Hong Kong Chinese population. Fast metabolisers will generate increased amounts of morphine with its attendant side effects. This has lead to its restriction for children below 12 years.
Dihydrocodeine
Dihydrocodeine is a synthetic opioid, which is structurally similar to codeine but is very approximately twice as potent. It has an oral bioavailability of about 20%. While very little research has been completed on dihydrocodeine it does appear to have a greater efficacy than codeine for the µ receptor and as such is less dependent on CYP2D6 for its effects, making it more predictable than codeine. Its metabolic pathways are analogous to those of codeine (see Figure 10.3).
Fentanyl
Fentanyl is a synthetic phenylpiperidine derivative with a rapid onset of action. It is a µ-receptor agonist and as such shares morphine’s effects. However, it is less likely to precipitate histamine release. High doses (50–150 µg.kg−1) significantly reduce or even eliminate the metabolic stress response to surgery but are associated with bradycardia and chest wall rigidity.
Presentation
Fentanyl is prepared as a colourless solution for injection containing 50 µg.ml−1, as transdermal patches that release between 25 and 100 µg per hour for 72 hours and as lozenges releasing 200 µg–1.6 mg over 15 minutes.
Uses
Doses vary enormously depending on the duration of analgesia and sedation required. For pain associated with minor surgery, 1–2 µg.kg−1 is used intravenously and has a duration of about 30 minutes. Higher doses are generally required to obtund the stimulation of laryngoscopy. High doses (50–100 µg.kg−1) are used for an opioid-based anaesthetic (although a hypnotic is also required), and here its duration of action is extended to about 6 hours. Following prolonged administration by continuous infusion only its elimination half-life is apparent, leading to a significantly prolonged duration of action.
Fentanyl has also been used to augment the effects of local anaesthetics in spinal and epidural anaesthesia at 10–25 µg and 25–100 µg, respectively. Its high lipid solubility ensures that a typical intrathecal dose does not cause delayed respiratory depression as it diffuses rapidly from cerebrospinal fluid (CSF) into the spinal cord. This contrasts with morphine, which enters the spinal cord slowly, leaving some to be transported in the CSF by bulk flow up to the midbrain. However, respiratory depression is observed when epidural fentanyl is administered by continuous infusion or as repeated boluses.
Kinetics
Fentanyl’s onset of action is rapid following intravenous administration due to its high lipid solubility (nearly 600 times more lipid-soluble than morphine). However, following the application of a transdermal patch, plasma levels take 12 hours to reach equilibrium. At low doses (< 3 µg.kg−1 intravenous) its short duration of action is due solely to distribution. However, following prolonged administration or with high doses, its duration of action is significantly prolonged as tissues become saturated. Its clearance is similar to and its elimination half-life is longer than that of morphine, reflecting its higher lipid solubility and volume of distribution. Fentanyl may become trapped in the acidic environment of the stomach where more than 99.9% is ionised. As it passes into the alkaline environment of the small bowel it becomes unionised and, therefore, available for systemic absorption. However, this is unlikely to raise systemic levels significantly due to a rapid hepatic first-pass metabolism, where it is N-demethylated to norfentanyl, which along with fentanyl is further hydroxylated. These inactive metabolites are excreted in the urine.
Alfentanil
Alfentanil is a synthetic phenylpiperidine derivative. It is a µ-receptor agonist but with some significant differences from fentanyl.
Presentation and Uses
Alfentanil is presented as a colourless solution containing 500 µg or 5 mg.ml−1. For short-term analgesia it is used in boluses of 5–25 µg.kg−1. It is also used by infusion for sedation where its duration of action is significantly prolonged.
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