Physiology and pharmacology of pain

The International Association for the Study of Pain (IASP) defines pain as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage’. It is clear from this definition that the degree of tissue damage and perception of pain are not necessarily correlated.

Pain perception is a complex phenomenon, involving sensory, emotional and cognitive processes. Thus, although analgesic drugs can be effective in relieving both acute and chronic pain, other factors may also need to be addressed. Modulating patient expectation can have a major effect on perceived pain, reflecting the importance of communication and explanation for both acute and chronic pain management.

Mechanisms of pain

To manage pain effectively, it is important to have a good understanding of the underlying pain pathways and how these may be modulated at different concentrations by analgesic agents. Melzack and Wall, in their gate control theory of pain, introduced the concept in the 1960s that there was the potential for modulation of pain and nociception on many levels. This moved away from the Descartian philosophy that pain was a sensation transmitted from the periphery to central areas in the brain. High threshold nociceptors (non-specialised bare nerve endings) are activated by a noxious stimulus, with subsequent generation of action potentials. These are transmitted along nerve fibres (primary afferent neurons), predominantly unmyelinated C fibres and small myelinated Aδ fibres ( Table 6.1 and Fig. 6.1 ). The nerve cell bodies are located in the dorsal root ganglia (sympathetic neuronal cell bodies are also found here), where the sensory nerve fibres enter the dorsal aspect of the spinal cord. The first central synapses of sensory neurons are found in Rexed's laminae (I–X), with their exact location being dependent on nerve fibre type. The substantia gelatinosa (comprising mainly laminae II) and lamina V are where nociceptive inputs are normally processed. The majority of second-order projection neurons cross to form the lateral spinothalamic tract, with a smaller number of fibres ascending on the side of origin. The neurobiology of the pain pathway ( Fig. 6.2 ) changes in response to tissue injury and also in response to treatment. For example, if an individual is taking opioids long term, his or her responses to pain and analgesics will be modified. This is at least partly because of alterations in pain pathway neurobiology: the neurotransmitters released and their target receptors may both change ( Table 6.2 ). Furthermore, the surrounding milieu is important, particularly the peripheral and central immune responses to inflammation (see below).

Table 6.1

Classification of nerve fibres

Data from Erlanger J & Gasser HS. Electrical Signs of Nervous Activity. Philadelphia, 1937; From Colvin L.A., and Fallon M.T., Pain physiology in anaesthetic practice, In Hardman J.G., et al. Oxford Textbook of Anaesthesia, 2017.

Fibre type	Conduction velocity (ms ^–1 )	Diameter (µm)	Function
Large, myelinated
Aα	70–120	12–20	Proprioception, motor
Aβ	30–70	5–12	Light touch, pressure
Aγ	15–30	3–6	Motor to muscle spindles
Small, myelinated
Aδ	12–30	2–5	Pain (‘first’ pain, e.g. pin prick), cold, touch
B	3–15	<3	Preganglionic autonomic
Unmyelinated
C	0.5–2	0.4–1.3	Pain: ‘second’ pain (e.g. slow, burning), temperature, postganglionic sympathetic fibres

Fig. 6.1, An outline of peripheral to central pain pathways. ACC, Anterior cingulate gyrus; DRG, dorsal root ganglion; GABA, gamma-aminobutyric acid; IC, insular cortex; NGC, nucleus gigantocellularis; NRM, nucleus raphe magnus; PAG, periaqueductal grey matter; PFC, prefrontal cortex; RVM, rostral ventromedial medulla; S1, primary somatosensory cortex; S2, secondary somatosensory cortex; SDH, spinal dorsal horn.

Fig. 6.2, Basic pain pathway. PAG, Periaqueductal grey matter; RVM, rostroventral medulla.

Table 6.2

Some of the neurotransmitters and receptors important in nociceptive processing, with changes in particular pain states

Neurotransmitter/agonist	Receptor	Comments
Amino acids
Glutamate	AMPA	Excitatory; fast synaptic transmission; permeable to cations such as Ca ²⁺ and Na ⁺ .
	NMDA	Excitatory; normally blocked at resting membrane potential by Mg ²⁺ . Activated by repeated high-intensity stimulation; involved in central sensitisation and wind-up; permeable to cations such as Ca ²⁺ and Na ⁺ .
	Metabotropic	Depending on site, may be excitatory or inhibitory. Linked to G proteins; at least three different groups (mGLuRI–III) may decrease glutamate release.
Glycine		Inhibitory.
GABA		Inhibitory.
Neuropeptides
Substance P	Neurokinin	One of the first neuropeptides shown to be involved in nociceptive processing; NK antagonists had limited analgesic effect in clinical trials; some antiemetic activity; G protein–coupled receptor; increases in inflammatory conditions; decreases in nerve injury.
CGRP		Inhibits SP breakdown and thus prolongs its duration of action; increases in inflammatory conditions; decreases in nerve injury.
CCK	CCKRs1–8	Excitatory; clinical trials of antagonists.
Thermal sensation and pain
Heat >42°C, capsaicin	TRPV1	Activated by noxious heat; topical capsaicin (low-dose cream or high-dose patch) used in chronic pain (cream: osteoarthritis; patch: neuropathic pain); selectively desensitises subset of C fibres expressing TRPV1 receptor.
Cool (8°C–28°C), menthol (in low concentrations)	TRPM8	Activated by non-noxious cold (cooling); increased expression of receptor in chronic pain; analgesic effect by receptor activation.

AMPA, α-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid; CCK, cholecystokinin; CGRP, calcitonin gene–related peptide; GABA, γ-aminobutyric acid; M, melastatin; NK, neurokinin; NMDA, N -methyl- d -aspartate; SP, substance P; TRP, transient receptor potential; V, vanilloid.

Central sensitisation may occur; this is amplification of peripheral input caused by glutamate activating the N -methyl- d -aspartate (NMDA) receptor (a non-selective cation channel that is normally blocked by a Mg ²⁺ ion) in a voltage-dependent manner ( Fig. 6.3 ). With increased and repeated noxious stimulation, more glutamate is released from primary sensory neurons. This results in increases in postsynaptic effects, including unblocking of the NMDA receptor (see Chapter 4 ). This can occur rapidly and is seen in many different pain states. Activation of the NMDA receptor triggers a number of downstream events within the postsynaptic neuron. There is the potential for developing novel analgesics that target specific parts of this pathway (see Table 6.2 ).

Fig. 6.3, Mechanisms of central sensitisation. NMDA, N -methyl- d -aspartate; NR, NMDA receptor (subunits).

Inflammation

The classical combination of rubor (redness), calor (heat), tumor (swelling) and dolor (pain) may occur in response to tissue injury or as part of a more general inflammatory process (e.g. inflammatory arthropathies such as rheumatoid arthritis). Peripheral changes occur with the release of a host of proinflammatory mediators including cytokines and chemokines, leading to peripheral sensitisation, where there is a decrease in nociceptor activation threshold and increased primary afferent drive. Fig. 6.4 outlines some of the peripheral processes involved in inflammatory pain. More recently, the importance of CNS changes has been emerging, with central inflammatory processes modulating pain neurobiology. Alterations in number, size and function of both astrocytes and microglial cells have been found, which may contribute to the development and maintenance of chronic pain syndromes.

Fig. 6.4, Mechanisms of peripheral sensitisation. ATP, Adenosine triphosphate; Na v , Na + channel; NGF, nerve growth factor.

Neuropathic pain

If nerve injury occurs, neuropathic pain may result, with characteristic changes in neurotransmitters and receptors, alterations in electrical activity and a shift to a hyperexcitable state. These include the following:

Changes in Na ⁺ channel subtypes in the peripheral nervous system, with spontaneous generation of action potentials in the absence of noxious stimulation. This may be the mechanism of the spontaneous pain often found in neuropathic pain syndromes.
Alterations in the balance between the descending inhibitory pathways and pronociceptive pathways, with amplification of pain signals from the spinal cord.
Alterations in the balance of neurotransmitters – for example, downregulation of substance P and calcitonin gene–related peptide (CRGP) and increases in dynorphin.

Visceral pain

Whereas somatic pain usually follows a fairly precise somatotopic map, visceral pain is much more diffuse. Visceral hyperalgesia can develop in chronic pain states such as chronic pancreatitis and irritable bowel syndrome. As with somatic pain, there are many points along the pain pathway between periphery and the brain where changes can occur in sensory processing alongside modulation from inflammatory mediators, particularly in the gut mucosa and immune system. Neuroimaging studies in patients with chronic visceral pain from irritable bowel syndrome have shown increased activity in brain areas involved in affective and cognitive processing, such as the dorsolateral and ventrolateral prefrontal cortices.

Pharmacology of analgesic drugs

The ideal analgesic drug should relieve pain with minimal adverse effects. However, patients continue to suffer pain despite the wide range of analgesics available. When devising a management plan for both acute and chronic settings, it may be helpful to use balanced or multimodal analgesia . These terms refer to the use of combinations of drugs acting by different mechanisms or at different sites within the pain pathway. Analgesic combinations may have additive or synergistic actions. This allows reductions in dose and adverse effects. Effective and repeated assessment is essential in determining optimal analgesic management ( Table 6.3 ).

Table 6.3

Approach to multimodal analgesia

Analgesic	Mode of action	Use in acute pain	Use in chronic pain	Comments
Paracetamol	Poorly understood; COX inhibition?	Yes – oral, rectal or intravenous.	Yes – reduce dose in frail elderly.	May be synergistic with some other analgesics (e.g. codeine); antipyretic.
NSAIDs	Reduce inflammatory response.	Yes.	Caution with long-term use, particularly for adverse cardiovascular side effects.	COX-2 selective drugs may have better GI profile; all can impact on renal function, especially if fluid depleted.
Opioids	Main analgesic action is via µ-opioid receptor, with inhibitory effects at spinal and supraspinal levels.	Yes – often by parenteral route if oral not available.	Very limited evidence of long-term efficacy, with increasing concerns about harms.	Harms from long-term use include addiction, tolerance, misuse, endocrine dysfunction, increased fracture risk. Major increase in prescribing for chronic pain over last 10–20 years.
Local anaesthetics	Interrupt neuronal transmission via Na ⁺ channel block.	Yes – very useful for perioperative pain control, with opioid-sparing effect; some evidence for intravenous use, although potential safety issues from toxicity.	Specific interventions, to allow peripheral and regional nerve blocks.	Via neuraxial route; can be useful in the management of cancer pain (especially movement-related pain).
Adjuvants/ antineuropathic agents	Depends on agent (e.g. TCAs): likely to increase descending inhibition; gabapentinoids reduce excitatory synaptic activity, probably via reduced release of glutamate.	Gabapentinoids – variable evidence from systematic reviews of efficacy as an opioid-sparing technique.	Yes – for neuropathic pain.	CNS effects often additive with opioids. Need dose titration to effect, with onset of analgesia consequently taking a number of weeks.

Opioids

Opioids are the most commonly used analgesics for the treatment of moderate to severe pain. Despite this, there are still major gaps in our knowledge of their clinical pharmacology; the choice of drug and dose is largely empirical. Although they may be highly effective, control of dynamic (pain on movement) or incident (breakthrough) pain may be poor and side effects a significant problem. The term opioid refers to all drugs, both synthetic and natural, that act on opioid receptors. Opiates are naturally occurring opioids derived from the opium poppy papaver somniferum. A variety of different opioids are available, but morphine is the most widely used. Incomplete cross-tolerance occurs between opioids, so an alternative should be tried if morphine is poorly tolerated. There is increasing evidence that individual analgesic response and adverse effect profile are both partly related to genetic make-up. Differences in single nucleotide polymorphisms (SNPs) almost certainly contribute to this variability in response between different opioids, with potential candidate genes including ABCB1 (encoding p-glycoprotein, a membrane transporter), STAT6 (signal transducer and activator of transcription 6) and β-arrestin (intracellular protein involved in receptor internalisation).

Dose conversion between different opioids is an inexact science; suggested equianalgesic doses ( Table 6.4 ) are based on relative potencies, often derived from studies not designed for dose equivalence calculations.

Table 6.4

Suggested equi-analgesic doses for opioids

Opioid	~ EQUI-ANALGESIC DOSE
Opioid	Parenteral	Oral
Morphine	10 mg	30 mg
Meperidine (pethidine)	100 mg	300 mg
Oxycodone	15 mg	20 mg
Fentanyl	100 µg	NA
Hydromorphone	1.5 mg	7.5 mg
Methadone	1–10 mg	10 mg (use with caution)
Codeine	N/A	200 mg

This is a guide only, and careful assessment of individual factors must be considered when transferring between opioids, particularly at higher doses. Methadone may be particularly problematic, because of its long half-life and inter-individual variability.

N/A, Not applicable.

Mechanism of action

Opioid receptors belong to the G protein–coupled family of receptors that have seven transmembrane domains, an extracellular N-terminal and an intracellular C-terminal. Activation results in changes in enzyme activity such as adenylate cyclase or alterations in calcium and potassium ion channel permeability (see also Chapter 1 ).

Opioid receptors were originally classified by pharmacological activity in animal preparations and later by molecular sequence. The three main receptors were classified as µ (mu), or OP3; κ (kappa), or OP1; and δ (delta), or OP2. More recently, an opioid-like receptor, the NOP (or nociceptin/orphanin FQ) receptor, has been identified. Receptor nomenclature has changed several times in the last few years; the current International Union of Pharmacology (IUPHAR) classifications are MOP (µ), KOP (κ), DOP (δ) and NOP (nociceptin/orphanin FQ peptide) receptors ( Table 6.5 ).

Table 6.5

Classification of opioid receptors as defined by the International Union of Pharmacology

Receptor	Previous classifications	Endogenous ligand	Site
MOP	Mu (µ); OP3	Endomorphin 1 and 2; met-enkephalin	Pre- and postsynaptic neurons in spinal cord, periaqueduct grey matter, limbic system, caudate putamen, thalamus, cerebral cortex; peripheral inflammation.
KOP	Kappa (κ); OP2	Dynorphin A and B; β-endorphin	Cerebral cortex, nucleus accumbens, nucleus raphe magnus (midbrain), hypothalamus, spinal cord.
DOP	Delta (δ); OP1	Leu- and met-enkephalins; β-endorphin	Olfactory centres, cerebral cortex, nucleus accumbens, caudate putamen, spinal cord, some limited distribution in areas involved in nociception.
NOP	Nociceptin/orphanin FQ; ORL-1	Nociceptin/orphanin FQ (nociceptin)	Nucleus raphe magnus, spinal cord, afferent neurons, peripheral immune cells.

Opioid receptors are distributed widely in both central and peripheral nervous systems, and this explains their widespread effects, both therapeutic and adverse. Complex interactions at various receptors underlie the different effects of currently available opioids. Several endogenous neuropeptide ligands are active at opioid receptors (see Table 6.5 ); they function as neurotransmitters, neuromodulators and neurohormones. The endogenous tetrapeptides endomorphins 1 and 2 are potent agonists acting specifically at the MOP receptor; they play a role in modulating inflammatory pain.

The analgesic action of morphine and most other opioids is related mainly to agonist activity at the MOP receptor. Unfortunately, many of the unwanted effects of opioids are also related to MOP agonism. At a cellular level, MOP receptor activation has an overall inhibitory effect via (1) inhibition of adenylate cyclase; (2) increased opening of potassium channels (hyperpolarisation of postsynaptic neurons, reduced synaptic transmission); and (3) inhibition of calcium channels (decreases presynaptic neurotransmitter release).

Some opioids or their metabolites also have activity at other receptors; for example, methadone acts at the NMDA receptor. These particular actions are discussed for individual agents later in this chapter. The more general effects of opioids are described in this section.

Analgesic action

MOP, and to a lesser extent KOP, receptor agonists produce analgesic effects, as does activation of spinal DOP receptors in certain situations. Opioids should be titrated against pain; if higher than necessary doses are given, respiratory depression and excessive sedation may result. If the pain is incompletely opioid responsive, as may occur with neuropathic pain, care must be taken with dose titration, and a detailed reassessment of analgesic response is essential. Opioids exert their analgesic effect by:

supraspinal effects in the brainstem, thalamus and cortex, in addition to modulating descending systems in the midbrain periaqueductal grey matter, nucleus raphe magnus and the rostral ventral medulla;
inhibitory effects within the dorsal horn of the spinal cord both pre- and postsynaptically; and
a peripheral action in inflammatory states: MOP receptors modulate immune function, and nociceptors are important in regulating peripheral sensitisation.

Central nervous system

Opioids have much wider ranging effects than simply analgesia. These include effects on the CNS, cardiovascular, GI, endocrine and immune systems ( Table 6.6 ).

Table 6.6

Non-analgesic effects of opioids

Effect	Comment
Sedation	Additive with other CNS depressant drugs. There is a dose-related reduction in minimum alveolar concentration (MAC) for volatile anaesthetics, though there is a floor to this effect. Opioids alone do not act as reliable anaesthetic agents.
Sleep	Interfere with rapid-eye-movement sleep with EEG changes (includes progressive decrease in EEG frequency; production of δ waves; burst suppression is not seen, even with large doses).
Mood	Significant euphoria is uncommon when used to treat pain. Dysphoria (possibly via a KOP receptor action) and hallucinations (often visual) can occur.
Miosis	KOP receptor effect on the Edinger–Westphal nucleus of the oculomotor nerve.
Tolerance (increasing doses to achieve the same effect)	Can occur acutely or chronically. At a cellular level, there is a progressive loss of active receptor sites combined with uncoupling of the receptor from the guanosine triphosphate (GTP)–binding subunit. NMDA receptor and intracellular second messenger systems are also involved, with a rationale for use of ketamine in acute tolerance.
Physical dependence	NOT addiction; physical symptoms occur with opioids cessation or in the case of precipitated withdrawal by administering an opioid antagonist. Includes anxiety, myalgia, hydrosis, GI upset.
Addiction	Craving for continued use, despite evidence of harm. Complex mechanisms, possibly involving the reward systems.
Opioid-induced hyperalgesia	This is a paradoxical response where an increase in opioid dose results in hyperalgesia. It may be part of the spectrum of opioid toxicity or can occur in isolation. It has been found to occur after systemic administration of potent short-acting opioids such as remifentanil but can occur with any opioid.
Respiratory depression	Particularly occurs in the elderly, neonates and when given without titrating effect to analgesic response; less problematic in chronic use (tolerance). Increased risk if nociceptive input is reduced or removed, such as after a nerve block. Sensitivity to CO ₂ is reduced (MOP effect) via depression of neuronal sensitivity (ventral medulla).
Airway/cough reflex	Suppress stress response to laryngoscopy and airway manipulation; suppress cough activity and mucociliary function. This may cause inadequate clearing of secretions and hypostatic pneumonia.
Gastrointestinal	Nausea and vomiting (may be mediated both centrally and peripherally: direct effect on the chemoreceptor trigger zone; delay in gastric emptying). Increased gastrointestinal muscle tone and decreased motility. Constipation common (direct action on opioid receptors in gut smooth muscle); increase in biliary pressure with gallbladder contraction.
Cardiovascular	Some opioids are associated with bradycardia. If normovolaemic, no significant cardiovascular depressant effect, unless histamine release occurs. There is no direct effect on cerebral autoregulation, although an increase in P a co ₂ from respiratory depression may increase cerebral blood flow. Opioids decrease central sympathetic outflow, which can manifest as haemodynamic compromise, especially with rapid intravenous bolus. QTc prolongation with some opioids (e.g. methadone). Increased risk of myocardial infarction with long-term use.
Fracture	Increased risk with long-term use, especially in elderly patients taking high doses.
Endocrine	Central action via hypothalamic pituitary axis; adrenal insufficiency; sexual dysfunction, infertility can all occur with long-term use.
Immune system	Exact effects are unclear, but may impair immune response with long-term use; limited evidence for effects on cancer cells.
Other	Myoclonic jerks can occur, especially with opioid toxicity. Urinary retention is possible. Pruritus is common after neuraxial administration; low-dose MOP antagonist may help. Muscle rigidity, especially after intravenous bolus administration of potent phenylpiperidines, may cause significant problems with ventilation because of chest wall rigidity and decreased respiratory compliance. May be minimised by coadministration of opioids with intravenous anaesthetic agents and benzodiazepines, reversed by naloxone or prevented by neuromuscular blocking agents. Thermoregulation impaired, similar to volatile agents.

Opioid structure

The structures of opioid analgesics are diverse ( Figs 6.5 and 6.6 ), although for most opioids the active compound is usually the laevorotatory (laevo) stereoisomer. Agents in current use include phenanthrenes (e.g. morphine), phenylpiperidines (e.g. meperidine [pethidine], fentanyl) and diphenylpropylamines (e.g. methadone). Structural modification affects agonist activity and alters physicochemical properties such as lipid solubility. A tertiary nitrogen is necessary for activity, separated from a quaternary carbon by an ethylene chain. Chemical modifications that produce a quaternary nitrogen significantly reduce potency as a result of decreased CNS penetration. If the methyl group on the nitrogen is changed, antagonism of analgesia may be produced.

Fig. 6.5, The structures of morphine and the phenanthrenes.

Fig. 6.6, The structures of phenylpiperidine opioids.

Other important positions for activity and metabolism include the C-3 phenol group (the distance of this from the nitrogen affects activity) and the C-6 alcohol group. With regard to morphine, potency may be increased by hydroxylation of the C-3 phenol; oxidation of C-6 (e.g. hydromorphone); double acetylation at C-3 and C-6 (e.g. diamorphine); hydroxylation of C-14 and reducing the double bond at C-7/8. Further additions at the C-3 OH group reduce activity. A short-chain alkyl substitution is found in mixed agonist-antagonists, and hydroxylation or bromination of C-14 produces full antagonists, and removal or substitution of the methyl group reduces agonist activity.

Pharmacokinetics and physicochemical properties

Knowledge of the specific physicochemical properties and pharmacokinetics of individual agents is important in determining the optimal route of drug delivery. This is needed to achieve an effective receptor site concentration for an appropriate duration of action. All opioids are weak bases. The relative proportion of free and ionised fractions depends on plasma pH and the p K a of the particular opioid. The amount of opioid diffusing to the site of action (diffusible fraction) is dependent on lipid solubility, concentration gradient and degree of binding (see Chapter 1 ). Plasma concentrations of albumin and α _l -acid glycoprotein as well as tissue binding determine the availability of the unbound, unionised fraction. This diffusible fraction moves into tissue sites in the brain and elsewhere; the amount reaching receptors is dependent not only on lipophilicity but also on the amount of non-specific tissue binding, such as CNS lipids.

The ionised, protonated form is active at the receptor site. This has important implications for speed and duration of activity. For example, morphine is relatively hydrophilic and penetrates the blood–brain barrier slowly. However, a large mass of any given dose eventually reaches the receptor site because of low concentrations of non-specific tissue binding. The offset time may be prolonged, resulting in a longer duration of action than would be expected from the plasma half-life. Most opioids have a very steep dose–response curve. Therefore if the dose is near the minimum effective analgesic concentration (MEAC), very small fluctuations in plasma or effect-site concentrations may lead to large changes in analgesia.

Opioids tend to have a large volume of distribution ( V _D ) because of their high lipid solubility. A consequence of this can be that redistribution, particularly after a bolus dose or short infusion, can have significant effects on plasma concentrations. In addition, first-pass effects in the lungs may remove significant amounts of drug from the circulation, reducing the initial peak plasma concentration. However, the drug re-enters the plasma several minutes later. Plasma concentrations of opioids such as fentanyl, sufentanil and meperidine are affected by this; the effect is negligible for remifentanil. Other lipophilic amines such as lidocaine and propranolol are affected similarly and may reduce pulmonary uptake of coadministered opioids.

After prolonged infusion, significant sequestration in fat stores and other body tissues occurs for highly lipid-soluble opioids. Context-sensitive half-life (see Chapter 1 ) is increased after prolonged infusion for most opioids apart from remifentanil. For example, the elimination t _1/2 for fentanyl after bolus administration is 3–5 h but increases markedly after repeated boluses or prolonged infusion.

Most opioid metabolism occurs in the liver (phase 1 and 2 reactions) with the hydrophilic metabolites predominantly excreted via the kidneys, although a small amount may be excreted in the bile or unchanged in the urine. As a result, hepatic blood flow is one of the major determinants of plasma clearance. Enterohepatic recirculation may occur when water-soluble metabolites excreted in the gut may be metabolised by gut flora to the parent opioid and then reabsorbed. Lipid-soluble opioids may diffuse into the stomach, become ionised because of the low pH and then be reabsorbed in the small intestine; this results in a secondary peak in plasma concentration.

Details of the pharmacological properties of some opioids are shown in Tables 6.7 and 6.8 . Metabolism (including production of active metabolites), distribution between tissues and elimination can all differ between individuals (see Chapter 1 ) to produce clinically important variations in effect.

Table 6.7

Metabolism and excretion of some opioids

Drug	Metabolism	Excretion
Naturally occurring opioids
Morphine	Liver: glucuronidation, sulphation N -dealkylation; also microsomal UDP glucuronyl transferases (UDPGT) in liver, kidney and intestine; some active metabolites	Mainly urine; 90% in 24 h (10% morphine; 70% glucuronides; 10% 3-sulphate; 1% normorphine; 3% normorphine glucuronide)
Codeine	Liver: O -demethylation, glucuronidation; some active metabolites	Mainly urine; 86% in 24 h (5%–10% codeine; 60% codeine glucuronide; 5%–15% morphine (mainly conjugated); trace normorphine)
Semisynthetic
Diamorphine	Liver: O -deacetylation, glucuronidation; some active metabolites	Mainly urine; 80% in 24 h (5%–7% morphine; 90% morphine glucuronides; 1% 6-acetylmorphine; 0.1% diamorphine)
Oxycodone	Liver; CYP3A4, CYP2D6 (phase 1 metabolism); glucuronidation	Mainly urine; noroxycodone is weaker metabolite
Hydromorphone	Liver: no phase 1 metabolism; glucuronidation; active metabolite: hydromorphone-3-glucoronide	Some active metabolites excreted in urine (HM-3-glucuronide), dose adjustment recommended in renal impairment
Buprenorphine	Liver: glucuronidation, N -dealkylation	70% mainly unchanged in faeces; 2%–13% in 7 days; mainly N -dealkylbuprenorphine (and glucuronide); buprenorphine-3-glucuronide
Synthetic opioids
Meperidine (pethidine)	Liver: N -demethylation, hydrolysis	70% in 24 h (10% meperidine; 10% normeperidine; 20% meperidinic acid; 16% meperidinic acid glucuronide; 8% normeperidinic acid; 10% normeperidinic acid glucuronide; plus small amounts of other metabolites)
Fentanyl	Liver: N -dealkylation, hydroxylation; no phase 2 metabolism	9% excreted in faeces; rest in urine: 70% in 4 days (5%–25% fentanyl; 50% 4- N -( N -propionylanilino-piperidine) plus other metabolites); very little excreted unchanged in urine
Alfentanil	Mainly hepatic metabolism (phase 1: CYP3A4), inactive metabolites	Very little excreted unchanged in urine
Sufentanil	Mainly hepatic metabolism phase 1 (including CYP3A4), some active metabolites	Very little excreted unchanged in urine
Remifentanil	Plasma: rapid hydrolysis – plasma and tissue non-specific esterases; non-saturable, clearance greater than hepatic blood flow; not affected by plasma cholinesterase deficiency or hepatic or renal dysfunction	Remifentanil acid – main metabolite, excreted in urine, no clinically significant activity
Methadone	Liver: N -dealkylation, no active metabolites	30% excreted in faeces; 60% in 24 h (33% methadone; 43% EDDP; 10% EMDP plus small amounts of other metabolites)
Tapentadol	Liver: via glucuronidation (main route)	1% unchanged in faeces; majority excreted in urine (3% unchanged, remainder conjugates and other metabolites)
Tramadol	Liver: phase 1(CYP3A4, CYP2D6) to active drug, O-desmethyltramadol, plus inactive metabolite, nortramadol; no phase 2 metabolism	~30% of dose excreted unchanged in urine; metabolites excreted in urine, dose adjustment in renal impairment

EDDP, 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine; EMDP, 2-ethyl-5-methyl-3,3-diphenylpyrroline.

Table 6.8

Pharmacokinetics and physicochemical properties of some opioids

Opioid	p K a	Protein binding (%)	Octanol:water partition coefficient	Terminal half-life (h)	Clearance (ml kg ^–1 min ^–1 )	Volume of distribution (L kg ^–1 )	Duration of action (h)
Morphine	7.9	30	6	1.7–3.0	15–20	3–5	3–5
Oxycodone	8.5	45		3–4	13	2–3	2–4
Codeine	8.2	20	0.6	2–4		2.5–3.5
Meperidine (pethidine)	8.5	70	39	3–5	8–18	3–5	2–4
Fentanyl	8.4	90	813	2–4	10–20	3–5	1–1.5
Alfentanil	6.5	91	128	1–2	4–9	0.4–1	0.25–0.4
Remifentanil	7.3	70	18	0.1–0.2	40–60	0.3–0.4	2–5 min
Sufentanil	8.0	93	1778	2–3.5	10–15	2.5–3	0.8–1.3
Methadone	8.3	90	26–57	15–20	2	5	4–8

Factors affecting pharmacokinetics of opioids include the following:

Age. Dose is often calculated on body weight, although there is little evidence to support this in adult clinical practice. Age is often more important because of both pharmacokinetic and pharmacodynamic factors. Metabolism and volume of distribution are reduced in the elderly, leading to increased free drug concentrations in the plasma. Hepatic blood flow may have declined by 40%–50% by age 75 years, with reduced clearance of opioids. Increased CNS sensitivity to opioid effects also occurs in the elderly.
Hepatic disease has unpredictable effects, although there may be little clinical difference unless there is coexisting encephalopathy. Reductions in plasma protein concentrations increase the plasma concentrations of free unbound drug.
Renal failure may have significant effects for opioids with active metabolites excreted by the kidney, such as morphine, diamorphine and meperidine.
Obesity results in a larger V _D and prolonged elimination t _1/2 . This may be a particular problem if infusions are used.
Hypothermia, hypotension and hypovolaemia may also result in variable absorption, altered distribution and metabolism.

Routes of administration

Peak plasma concentrations may be affected by site of administration and haemodynamic status. Opioids may be given by many routes; variations between specific agents are discussed later. It is unclear how much cross-tolerance exists for different routes of administration, such as intravenous versus epidural.

The choice of route depends on the clinical situation, and several factors should be considered:

If GI transit time is delayed, the biological half-life of agents administered orally may be prolonged. Similarly, if GI transit time is rapid or area for absorption reduced, then drug absorption may decrease, particularly with long-acting agents.
Intrathecal administration is associated with fewer supraspinal effects, although both urinary retention and pruritus may be more common. Highly lipid-soluble opioids (e.g. fentanyl) do not spread readily in CSF. It is claimed that they are less likely than water-soluble opioids (e.g. morphine) to cause late respiratory depression because of rostral spread.
Dural penetration from epidural administration is dependent on molecular size and lipophilicity For example, only 3%–5% of morphine crosses into the CSF, with a peak concentration after 60–240 min; fentanyl peaks at approximately 20 min.

MOP agonists

Morphine is the standard opioid against which other agents are compared. Other MOP agonists have a similar pharmacodynamic profile but differ in relative potency, pharmacokinetics and biotransformation to other active metabolites.

Phenylpiperidine opioids (see Fig. 6.6 ) are potent MOP receptor agonists with moderate (alfentanil) to high (sufentanil) lipid solubility and good diffusion through membranes. Both potency and time to reach the effect site vary considerably. In contrast to morphine, these agents do not cause histamine release. All except remifentanil may cause postoperative respiratory depression as a result of secondary peaks in plasma concentrations. This may be caused by release from body stores if large doses have been infused intraoperatively.

Morphine

Morphine is a relatively hydrophilic phenanthrene derivative. It may be given orally (immediate or modified release), rectally, topically, parenterally and via the neuraxial route. The standard parenteral dose for adults is 10 mg, although many factors affect this and the dose should be titrated to effect. Its oral bioavailability is dependent on first-pass hepatic metabolism and may be unpredictable (35%–75%). Single-dose studies of morphine bioavailability indicate that the relative potency of oral to intramuscular morphine is 1:6, although with repeated regular administration, this ratio becomes approximately 1:3. The dose of short-acting morphine for breakthrough pain should be approximately one-sixth of the total daily dose. Morphine has a plasma half-life of approximately 3 h and duration of analgesia of 4–6 h.

Morphine is metabolised, at least in part, by microsomal UDP glucuronyl transferases (UDPGT) in the liver, kidney and intestines. Several of these metabolites may have clinically significant effects (see later). Although morphine conjugation occurs in the liver, extrahepatic sites may also be important, such as the kidney and GI tract. The site of conjugation on the molecule also varies, leading to a variety of metabolites (see Table 6.7 ). After glucuronidation, metabolites are excreted in urine or bile, dependent on molecular weight and polarity; more than 90% of morphine metabolites are excreted in the urine. The main metabolite in humans is morphine-3-glucuronide (60%–80%), and this may have an excitatory effect via CNS actions not related to opioid receptor activation. Morphine-6-glucuronide (M-6-G) is active at the MOP receptor, producing analgesia and other MOP-related effects. It is significantly more potent than morphine. Therefore M-6-G produces significant clinical effects despite only 10% of morphine being metabolised in this way. As it is excreted via the kidneys, it may accumulate in patients with impaired renal function, causing respiratory depression. Accumulation of morphine metabolites, especially M-6-G, may become significant when creatinine clearance declines to 50 ml min ^–1 or less.

Codeine

Codeine is a constituent of opium. Up to 10% of a dose of codeine is metabolised by the hepatic microsomal enzyme CYP2D6 to morphine, which contributes significantly to its analgesic effect. The rest is metabolised in the liver to norcodeine and then conjugated to produce glucuronide conjugates of codeine, norcodeine and morphine. Codeine is considerably less potent than morphine. Around 8% of Western Europeans are deficient in the CYP2D6 enzyme and may not experience adequate analgesia with codeine. Similarly, with super-metabolisers, there may be problems with opioid toxicity; particular care is needed in the breastfeeding mother as morphine is transferred in milk. Codeine can cause significant histamine release, and intravenous administration should be avoided. It has marked antitussive effects and also causes significant constipation. It is often combined with paracetamol.

Diamorphine

Diamorphine is available for parenteral and oral use. It is more lipid soluble than morphine, affecting distribution and tissue penetration. One advantage over morphine is in settings where high concentrations are required in relatively low volumes, such as palliative care. Furthermore, when lipid solubility is important in regulating site of action (e.g. epidural, intrathecal use), some practitioners believe that diamorphine has specific advantages over morphine.

Diamorphine is a prodrug. It is inactive at opioid receptors but is converted rapidly to the active metabolites 6-monoacetylmorphine (6 MAM), morphine and M-6-G. Presence of 6-MAM in urine or salvia can be used to differentiate between morphine and heroin (diamorphine) consumption. Further metabolism is similar to that of morphine (see Table 6.7 ); similar problems may arise in renal impairment.

Oxycodone

Oxycodone is a potent semisynthetic opioid that has been in use for many years. In addition to actions at the MOP receptor, it may also have analgesic effects mediated via the KOP receptor, resulting in incomplete cross-tolerance with morphine. It has a good oral bioavailability, and its plasma concentrations are more predictable than those of morphine after oral administration. It is available in both long- and short-acting oral preparations and, more recently, in a parenteral formulation. Oral oxycodone is roughly 1.5 times more potent than oral morphine.

Hydromorphone

Hydromorphone, a potent opioid, is used mainly in the palliative care setting or in patients who are not opioid naive. It can be useful if considering opioid rotation. Hydromorphone 1.3 mg is approximately equianalgesic to morphine 10 mg. Both immediate- and sustained-release preparations are available.

Meperidine (pethidine)

Meperidine (pethidine) is available as parenteral and oral preparations. There is no evidence that this opioid provides any advantage over morphine, such as treatment of colicky-type pain. Its analgesic action is fairly short, but the metabolite normeperidine can accumulate ( t _1/2 ~ 15 h) if repeated doses are given and especially if there is renal dysfunction. Normeperidine is a CNS stimulant and can cause seizures. Its clearance is significantly reduced in hepatic disease. Chronic use may result in enzyme induction and an increase in normeperidine plasma concentrations. Its metabolism is decreased by the oral contraceptive pill.

Meperidine has other significant effects related to activity at non-opioid receptors. For example, its atropine-like action may cause a tachycardia, in addition to direct myocardial depression at high doses. It was used originally as a bronchodilator. It can also reduce shivering related to hypothermia or epidural anaesthesia, although the mechanism for this is not fully understood. Meperidine also has a local anaesthetic-like membrane stabilising action.

Fentanyl

Fentanyl is available in a variety of preparations for parenteral, transdermal and transmucosal (including buccal) administration. Because of high first-pass metabolism (~70%) it is not given orally. It is approximately 80–100 times more potent than morphine in the acute setting, although it is approximately 30–40 times as potent when given chronically (e.g. slow-release transdermal patches). With transdermal administration, the patch and underlying dermis act as a reservoir, and plasma concentration does not reach steady state until approximately 15 h after initial application. Plasma concentration also declines slowly after removal ( t _1/2 ~15–20 h).

Fentanyl is very lipophilic, with a relatively short duration of action. There are several new buccal/transmucosal preparations developed for rapid-onset breakthrough pain. These aim to have a very rapid onset in approximately 10 min, although this may not be the case in clinical practice. Fentanyl has a large V _D with rapid peripheral tissue uptake, limiting initial hepatic metabolism. This may result in significant variability in plasma concentrations and secondary plasma peaks. It binds to α _l -acid glycoprotein and albumin; 40% of the protein-bound fraction is taken up by erythrocytes. The lungs may be important in exerting a first-pass effect on fentanyl (up to 75% of the dose), thus buffering the plasma from high peak drug concentrations.

Alfentanil

The low p K a of alfentanil (6.9) results in it being largely unionised at plasma pH, allowing rapid diffusion to the effect site ( t _1.2 k _eo ~1 min) and rapid onset of action despite it being less lipid soluble than other opioids. It does not bind strongly to opioid receptors, and the effect-site concentration also decreases rapidly as plasma concentrations decrease. Alfentanil is metabolised by the hepatic cytochrome P450 isoform CYP3A4. Genetic variability in the activity of this enzyme may result in two- to threefold variations in pharmacokinetic values when given by infusion. Low, medium or high metabolisers have been identified; this has implications for duration of action when prolonged use is contemplated.

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