Analgesic Drugs

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Analgesic Drugs

The ideal analgesic should relieve pain with a minimum of side-effects. When formulating a management plan, it is worth considering what contributes to pain perception and associated distress. 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, while analgesic drugs can be effective in relieving both acute and chronic pain, other factors may also need to be addressed.

There is considerable evidence that patients continue to suffer pain, despite a wide range of available analgesic drugs. When devising a management plan for both acute and chronic settings, using ‘balanced’ or ‘multimodal analgesia’ may be helpful. 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 be additive or synergistic in their mode of action, with resultant dose-sparing effects and a reduction in side-effects. Effective and repeated assessment of patients is essential in determining optimal analgesic management.

OPIOIDS

Opioids are the most frequently used analgesics for the treatment of moderate to severe pain. Despite this, there are still major gaps in our knowledge of their clinical pharmacology, with the choice of drug and dose being largely empirical. Although they may be highly effective, control of dynamic (pain on movement) or incident (breakthrough) pain may be poor and side-effects may be 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. The most widely used opioid is morphine, although a variety of different opioids are available. Incomplete cross-tolerance occurs between them, so an alternative should be tried if morphine is poorly tolerated. There is increasing evidence that in any one individual both analgesic response and side effect profile will be, at least partly, due to that person’s 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 beta-arrestin (intracellular protein involved in receptor internalization).

Dose conversion between different opioids is an inexact science, with equi-analgesic doses being based on relative potencies, often derived from studies that are not designed for dose equivalence calculation. Table 5.1 shows suggested equi-analgesic doses for some opioids.

TABLE 5.1

Equi-Analgesic Doses of Opioids

Mechanism of Action

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

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. Another opioid-like receptor has been identified recently; it is termed the nociceptin orphanin FQ peptide receptor. Receptor nomenclature has changed several times in the last few years; the current International Union of Pharmacology (IUPHAR) classification is MOP (mu), KOP (kappa), DOP (delta) and NOP for the nociceptin orphanin FQ peptide receptor (Table 5.2).

TABLE 5.2

Classification of Opioid Receptors as Defined by the International Union of Pharmacology

Opioid receptors are distributed widely in both central and peripheral nervous systems. The different effects of currently available opioids are dependent on complex interactions at various receptors. There is a range of endogenous neuropeptide ligands active at these receptors (Table 5.2); they function as neurotransmitters, neuromodulators and neurohormones. The endogenous tetrapeptide 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 activity at this receptor. At a cellular level, MOP receptor activation has an overall inhibitory effect via: (i) inhibition of adenylate cyclase; (ii) increased opening of potassium channels (hyperpolarization of postsynaptic neurones, reduced synaptic transmission); and (iii) inhibition of calcium channels (decreases presynaptic neurotransmitter release).

The structures of opioid analgesics are diverse, although for most opioids it is usually the laevorotatory (laevo) stereoisomer that is the active compound. The structures of some of the common agents are shown in Figures 5.1 and 5.2. Agents in current use include phenanthrenes (e.g. morphine – Fig. 5.1), phenylpiperidines (e.g. meperidine (pethidine), fentanyl – Fig. 5.2) and diphenylpropylamines (e.g. methadone, dextropropoxyphene). 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.

FIGURE 5.1 The structure of morphine and the phenanthrenes.

FIGURE 5.2 The structures of phenylpiperidine opioids.

Other important positions for activity and metabolism, as seen on the morphine molecule (Fig. 5.1), include the C-3 phenol group (the distance of this from the nitrogen affects activity) and the C-6 alcohol group. 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, 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 in order to achieve an effective receptor site concentration for an appropriate duration of action. All opioids are weak bases. The relative proportion of free and ionized fractions is dependent on plasma pH and the pK_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. Plasma concentrations of albumin and α_l-acid glycoprotein as well as tissue binding determine the availability of the unbound, unionized 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, e.g. CNS lipids.

The ionized, 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 levels of nonspecific tissue binding. This effect-site equilibration time (t_½k_eo) is measured by assessing the effect of opioids on the EEG. The offset time may also 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 the level of 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 lung 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 (pethidine) 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 co-administered opioids.

After prolonged infusion, significant sequestration in fat stores and other body tissues occurs for highly lipid-soluble opioids. This is reflected in the ‘context-sensitive t_½’ i.e. the time taken for the plasma concentration to reduce by 50% after an infusion designed to maintain constant plasma concentrations has been stopped (see Chapter 1). The context-sensitive t_½ is increased after prolonged infusion for most opioids apart from remifentanil. For example, the elimination t_½ for fentanyl after bolus administration is 3–5 h, but increases to 7–12 h after prolonged infusion.

Most opioid metabolism occurs in the liver (phase I and II reactions) with the hydrophilic metabolites predominantly excreted renally, 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. Metabolism of individual drugs is shown in Table 5.3. Enterohepatic recirculation may occur when water-soluble metabolites excreted in the gut may be metabolized by gut flora to the parent opioid and then reabsorbed. Lipid-soluble opioids may diffuse into the stomach, become ionized because of the low pH and then be reabsorbed in the small intestine; this results in a secondary peak in plasma concentration.

TABLE 5.3

Metabolism and Excretion of Some Opioids

EDDP; 2-ethylidine-1,5-dimethyl-3,3-diphenylpyrrolidine

EMDP; 2-ethyl-5-methyl-3,3-diphenylpyraline

A summary of physicochemical and pharmacokinetic properties of some opioids is shown in Table 5.4. Metabolism (including production of active metabolites), distribution between different tissues and elimination all interact within individual subjects to produce clinically important actions at receptor sites.

TABLE 5.4

Pharmacokinetic and Physicochemical Properties of Some Opioids

Factors affecting pharmacokinetics include:

Age. Systemic 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 often 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 is also found 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 also have effects on plasma concentrations of free unbound drug.

Renal failure may have significant effects for opioids with renally excreted active metabolites such as morphine, diamorphine and meperidine.

Obesity will result in a larger V_D and prolonged elimination t_½. This may be a particular problem if infusions are being used.

Hypothermia, hypotension and hypovolaemia may also result in variable absorption and altered distribution and metabolism.

Routes of Administration

Opioids given parenterally have 100% bioavailability (see Chapter 1), although 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 below. It is unclear how much cross-tolerance exists for different routes of administration, e.g. intravenous versus epidural.

The choice of route is dependent on the clinical situation and several factors may need to be considered:

If there is delayed gastrointestinal transit time, the biological half-life may be prolonged with orally administered agents. Similarly, if there is rapid GI transit time or reduced area for absorption, then there may be reduced absorption, particularly of 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 cerebrospinal fluid (CSF). It is claimed that they are less likely than water-soluble opioids (e.g. morphine) to cause late respiratory depression due to 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 (Fig. 5.2) 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 intra-operatively. Fentanyl, alfentanil and sufentanil are metabolized mainly in the liver to inactive metabolites. Very little is excreted unchanged in the urine (Table 5.3).

Morphine

Morphine is a relatively hydrophilic phenanthrene derivative. It may be given orally, 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%). Oral morphine is available either as immediate-release liquid, simple tablet or as a modified-release preparation. Single-dose studies of morphine bioavailability indicate that the relative potency of oral: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 a duration of analgesia of 4–6 h.

Morphine is metabolized, at least in part, by microsomal UDP glucuronyl transferases (UDPGT) found in the liver, kidney and intestines. Several of these metabolites may have clinically significant effects (see below). Although morphine conjugation occurs in the liver, there is evidence that extrahepatic sites may also be important, e.g. kidney, gastrointestinal tract. The site of conjugation on the molecule also varies, leading to a variety of metabolites (Table 5.3). 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 metabolized in this way. As it is renally excreted, it may accumulate in patients with impaired renal function, causing respiratory depression. Current evidence indicates that accumulation of morphine metabolites, especially M-6-G, becomes significant when creatinine clearance declines to 50 mL min^–1 or less.

Diamorphine

Diamorphine is a prodrug; it is inactive at opioid receptors. However, it is converted rapidly to the active metabolites 6-monoacetylmorphine, morphine and M-6-G. Further metabolism is similar to that of morphine (Table 5.3) and similar problems may arise if there is renal impairment.

It is available for parenteral and oral use. Diamorphine 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. Additionally, 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.

Papaveretum

This naturally occurring opioid is rarely used now. It is a mixture of morphine hydrochloride (253 parts), codeine hydrochloride (20 parts) and papaverine hydrochloride (23 parts). There is no oral preparation. A dose of 15.4 mg is approximately equivalent to 10 mg of anhydrous morphine.

Hydromorphone

This 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 ~ equi-analgesic 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, e.g. treatment of colic-type pain. It is fairly short acting in terms of analgesia, and if repeated doses are given, the metabolite normeperidine can accumulate (t_½ ~ 15 h). This is a CNS stimulant and can cause seizures, especially if there is renal dysfunction. 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 epidurals, although the mechanism for this is not fully understood. Meperidine also has a local anaesthetic-like membrane stabilizing action.

Fentanyl

Fentanyl is available in a variety of preparations for parenteral, transdermal and transmucosal (including buccal) administration. Due to high first-pass metabolism (~ 70%) it is not given orally. It is approx. 80–100 times more potent than morphine in the acute setting, although it is approx. 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 approx 15 h after initial application. Plasma concentration also declines slowly after removal (t_½ ~ 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 ~ 10 minutes, 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 lung 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 pK_a of alfentanil (6.9) results in it being largely unionized at plasma pH, allowing rapid diffusion to the effect site (t_½k_eo ~ 1 min) and rapid onset of action. Although less lipid-soluble than some opioids, it has the most rapid onset time. It does not bind strongly to opioid receptors and the effect-site concentration also decreases rapidly as plasma concentrations decrease. It is metabolized by one of the most abundantly expressed isoforms of hepatic P450 (CYP3 A3/4). Genetic variability in the activity of this enzyme may result in two- to three-fold variations in pharmacokinetic values when given by infusion. Low, medium or high metabolizers have been identified; this has implications for duration of action when prolonged use is contemplated.

Sufentanil

Sufentanil is one of the most potent opioids; it has a rapid onset of action after intravenous administration and peak analgesic effect is at approximately 8 min. It is 625 times more potent than morphine and 12 times more potent than fentanyl. However, diffusion to tissues is slower than alfentanil because, although sufentanil is highly lipid soluble, it is also highly protein bound, resulting in low unbound plasma fractions at body pH. It has very low levels of non-specific binding that may increase potential effect-site concentrations. The speed of onset of a large dose is caused by saturation of receptors and non-specific sites, with potential for overdose. One of its metabolites (desmethylsufentanil) is active at the MOP receptor (10% of sufentanil’s potency).

Remifentanil

Remifentanil is available for parenteral use as a lyophilized white crystalline powder containing glycine. It should not be administered epidurally or spinally. After being made up in solution, it is stable for 24 h. This MOP receptor agonist has a similar potency to fentanyl and is ~ 20 times more potent than alfentanil. It differs from other opioids in that it has an ester linkage, resulting in degradation by tissue and non-specific plasma esterases. This process is non-saturable and clearance is significantly greater than hepatic blood flow. Plasma cholinesterase deficiency does not affect clearance. Hepatic and renal dysfunction have no effect on clearance also, although increased opioid sensitivity in hepatic disease may result in a lower dosage requirement. Other situations requiring a reduction in dose include haemorrhage or shock. Hydrolysis produces a carboxylic acid metabolite with limited action at the MOP receptor (~ 1000 times < remifentanil). It is not thought to be clinically significant, even in renal dysfunction.

Remifentanil has a rapid blood–brain equilibration time of just over 1 min, with a short context-sensitive half-time of 3–5 min which is unaffected by duration of infusion. This makes it ideally suited for infusion during anaesthesia and in the critical care setting. It may be titrated rapidly to achieve the desired effect. The high clearance and low V_D imply that the offset of effect is caused by metabolism rather then redistribution. Hypothermia, such as may occur in cardiac surgery, may reduce clearance by up to 20%.

There is some evidence to suggest that acute opioid tolerance and hyperalgesia may occur after remifentanil infusions. If high doses are used without neuromuscular blockade, muscle rigidity may be a problem. It is unlikely to be a problem when using a concentration of 100 μg mL ^–1 or less and an infusion rate of 0.2–0.5 μg kg^–1 min^–1. Bradycardia has also been reported.

Oxycodone

This potent semi-synthetic opioid 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.

Methadone

Methadone is a diphenylpropylamine. It has very good oral bioavailability (~ 85%) with an oral to parenteral ratio of 1:2. Its plasma half-life can be very variable (3–50 h, average 24 h) but its duration of action is relatively short. With repeated dosing, problems with accumulation can occur because of this discrepancy between half-life and analgesic effect. Careful monitoring is therefore required when converting patients to long-term methadone. Also, there is incomplete cross-tolerance with morphine. The racemic mixture in common use has agonist actions at the MOP receptor (mainly the laevo-isomer) as well as antagonist activity at the NMDA receptor (dextro-isomer). Given the importance of this receptor in central sensitization in a variety of pain states, there may be cases where methadone offers particular advantages over and above other opioids, e.g. neuropathic pain.

Plasma concentrations of methadone can be reduced by carbamazepine and its metabolism is accelerated by phenytoin.

Codeine

Codeine is a constituent of opium. Up to 10% of a dose of codeine is metabolized by the hepatic microsomal enzyme CYP2D6 to morphine, which contributes significantly to its analgesic effect. The rest is metabolized 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 due to genetic polymorphism and such individuals may not experience adequate analgesia with codeine. Similarly, with “super-metabolizers”, there may be problems with opioid toxicity. It can cause significant histamine release and its intravenous administration should be avoided. It has marked antitussive effects and also causes significant constipation. It is often combined with paracetamol.

Dihydrocodeine

Dihydrocodeine is a synthetic opioid developed in the early 1900s. Its structure and pharmacokinetics are similar to codeine and it is used for the treatment of postoperative and chronic pain. Both immediate- and sustained-release preparations are available. Despite its common use, there are very few clinical trials demonstrating efficacy. It has significant abuse potential.

Tramadol

Tramadol is thought to produce analgesia by two distinct actions. Firstly, it has agonist activity at the MOP and KOP receptors. Most of its analgesia is mediated by a metabolite – O-desmethyltramadol – that has a 200 fold higher affinity for the MOP receptor. Secondly, it enhances the descending inhibitory systems in the spinal cord by inhibiting noradrenaline (norepinephrine) reuptake and releasing serotonin from nerve endings. It is available in immediate- and sustained-release oral preparations and for parenteral administration. Its use is contraindicated in patients receiving monoamine oxidase inhibitors (MAOIs). Caution must also be exercised in hepatic impairment as its clearance is reduced to a much greater extent than morphine and related agents.

Mixed Agonist–Antagonist Opioids

These agents have a ceiling effect for analgesia and possibly respiratory depression. They have agonist effects at the KOP receptor and weak antagonist effects at the MOP receptor. Dysphoria and hallucinations are relatively common and withdrawal effects may occur if given to patients taking MOP agonists. Pentazocine may be given orally or parenterally but is now rarely used. It may increase pulmonary and aortic blood pressure and myocardial oxygen demand. Hallucinations and dysphoria occur less commonly with nalbuphine.

Partial Agonists

These agents have high affinity for the MOP receptor but limited efficacy (see Chapter 1). A ceiling effect is seen in the dose-response curve at less than the maximal analgesic effect of full MOP agonists. If given with a full MOP agonist, there may be a reduction in the maximal analgesic effect.

Buprenorphine

This is the only partial agonist in common use. It binds to the MOP receptor and dissociates very slowly from it. Consequently, although significant respiratory depression is less likely compared with morphine, it may be more difficult to reverse. It has poor oral bioavailability and parenteral, sublingual or transdermal formulations are used. In addition to it having a partial agonist effect at the MOP receptor, it is also a partial agonist at the NOP receptor, as well as being an antagonist at the KOP receptor. This may contribute to some of its analgesic effects. Increasingly it is also used (usually in relatively large does up to 24 mg day^− 1) for the management of opioid use, instead of methadone.

Opioid Antagonists

Naloxone is a short-acting opioid antagonist that is relatively selective for the MOP receptor. It is structurally similar to morphine, with some modifications resulting in antagonist activity including an OH group at C-14. It can reverse opioid-induced respiratory depression but repeated administration may be required because of its short duration of action; it can be given by continuous infusion. However, sudden and complete reversal of the analgesic effects of opioids may be accompanied by major cardiovascular and sympathetic responses. Naloxone has a very low oral bioavailability (~ 3%), allowing its use in combination with oxycodone (see below) to reduce gastrointestinal effects.

Naltrexone is a long-acting opioid antagonist used in the management of opioid dependence. It is available only in oral formulation.

New Developments in Opioid Pharmacology

There is considerable interest in developing opioid analgesics with an improved side effect profile, and there are some promising recent developments in this area. It has been recognized that by using agents which act on more than one type of opioid receptor there may be beneficial effects (see Fig. 5.3) Some recently developed agents include:

FIGURE 5.3 Schemtic representation of the potential clinical advantages of using bivalent ligands, with the various combinations of pharmacophores (antagonists and agonists). (Adapted from Dietis N, et al. British Journal of Anaesthesia 2009;103:38-49.)

Oxycodone/Naloxone (Targinact®). This drug combination utilizes a fixed ratio of oxycodone and naloxone (2:1). The oral naloxone has a greater affinity for opioid receptors in the gut than oxycodone and therefore preferentially binds to these receptors. As a result, gastrointestinal side effects may be reduced, without any effect on the central analgesic effect of oxycodone.

Tapentadol. The analgesic effect of this agent is due to actions at several receptors, including the MOP receptor. It is much more potent at the MOP receptor than tramadol and also has a strong action in inhibiting noradrenaline reuptake. Preliminary evidence is that it is equianalgesic to oxycodone, but has reduced gastrointestinal side effects.

MoxDuo® is a novel opioid combination of morphine and oxycodone in a 3:2 ratio, with promising evidence of at least 50% decrease in clinically significant side effects such as nausea, vomiting, and dizziness when compared to either opioid alone. This seems to be achieved by the need to use lower doses of both morphine and oxycodone to reach an equivalent analgesic effect.

PARACETAMOL

Paracetamol (acetaminophen) was first used in 1893 and is the only remaining p-aminophenol available in clinical practice. It is the active metabolite of the earlier, more toxic drugs acetanilide and phenacetin. Its structure is shown in Figure 5.4. Paracetamol is an effective analgesic and antipyretic but has no anti-inflammatory activity. In recommended doses, it is safe and has remarkably few side-effects.

FIGURE 5.4 The structures of paracetamol and aspirin.

Mechanism of Action

The mechanism of action of paracetamol is not well understood but it may act by inhibiting prostaglandin synthesis in the central nervous system with limited effect on the peripheral nervous system. Unlike opioids, paracetamol has no well-defined endogenous binding sites. There is however some recent evidence that paracetamol has an inhibitory action on peripheral prostaglandin synthesizing cyclo-oxygenase enzymes, inhibiting both isoforms in certain tissues. In some circumstances it may exhibit a preferential effect on cyclo-oxygenase 2 (COX-2) inhibition. There is growing evidence of a central antinociceptive effect of paracetamol. It has also been shown to prevent prostaglandin production at cellular transcriptional level, independent of COX activity.

Pharmacokinetics

Paracetamol is absorbed rapidly from the small intestine after oral administration; peak plasma concentrations are reached after 30–60 min. It may also be given rectally and intravenously (either as paracetamol or the prodrug proparacetamol). It has good oral bioavailability (70–90%); rectal absorption is more variable (bioavailability ~ 50–80%) with a longer time to reach peak plasma concentration. The plasma half-life is approx. 2–3 h.

Paracetamol is metabolized by hepatic microsomal enzymes mainly to the glucuronide, sulphate and cysteine conjugates. None of these metabolites is pharmacologically active. A minimal amount of the metabolite N-acetyl-p-amino-benzoquinone imine is normally produced by cytochrome P450-mediated hydroxylation. This reactive toxic metabolite is rendered harmless by conjugation with liver glutathione, then excreted renally as mercapturic derivatives. With larger doses of paracetamol, the rate of formation of the reactive metabolite exceeds that of glutathione conjugation, and the reactive metabolite combines with hepatocellular macromolecules, resulting in cell death and potentially fatal hepatic failure. The formation of this metabolite is increased by drugs inducing cytochrome P450 enzymes, such as barbiturates or carbamazepine.

Pharmacodynamics

Paracetamol has been shown to be effective in both acute and chronic settings and is available for oral or intravenous use. It is an effective postoperative analgesic but probably less effective than NSAIDs in many situations. It may reduce postoperative opioid requirements by up to 30%. The combination of paracetamol with an NSAID also improves efficacy. Paracetamol is also a very effective antipyretic. This is a centrally mediated effect.

Overdose and Hepatic Toxicity

In overdose, there is the potential for the toxic metabolite described above to cause centrilobular hepatocellular necrosis, occasionally with acute renal tubular necrosis. The threshold dose in adults is ~ 10–15 g. Accidental overdosage can occur if combined preparations such as co-codamol are used together with paracetamol. Doses of more than 150 mg kg^–1 taken within 24 h may result in severe liver damage, hypoglycaemia and acute tubular necrosis. Individuals taking enzyme-inducing agents are more likely to develop hepatotoxicity.

Early signs include nausea and vomiting, followed by right subcostal pain and tenderness. Hepatic damage is maximal 3–4 days after ingestion, and may lead to liver failure and death. Treatment consists of gastric emptying and the specific antidotes methionine and acetylcysteine. The former offers effective protection up to 10–12 h after ingestion. Acetylcysteine is effective within 24 h and perhaps beyond. The plasma paracetamol concentration related to time from ingestion indicates the risk of liver damage. Acetylcysteine is given if the plasma paracetamol concentration is > 200 mg L^–1 at 4 h and 6.25 mg L^–1 at 24 h after ingestion.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS

The analgesic, anti-inflammatory and antipyretic effects of salicylates, derived from the bark of the willow tree, were described as early as 1763. Acetylsalicylic acid (aspirin) was first produced in 1853 (Fig. 5.4). More recently, many other NSAIDs have been developed with actions similar to aspirin. Perioperative analgesia using NSAIDs is free from many of the adverse effects of opioids, such as respiratory depression, sedation, nausea and vomiting and gastrointestinal stasis. NSAIDs have been shown to be effective analgesics in acute and chronic conditions, although significant contraindications and adverse effects limit their use.

Mechanism of Action

The mechanism of action of aspirin was discovered in the 1970s. It was shown to irreversibly inhibit the production of prostanoids (i.e. prostaglandins and thromboxanes) from arachidonic acid released from phospholipids in cell membranes (Fig. 5.5). The basal rate of prostaglandin production is low and regulated by tissue stimuli or trauma that activate phospholipases to release arachidonic acid. Prostaglandins are then produced by the enzyme prostaglandin endoperoxide synthase which has both cyclo-oxygenase and hydroperoxidase sites. At least two subtypes of cyclo-oxygenase enzyme have been identified in humans: COX-1 and COX-2. The prostanoids produced by COX-1 are functionally active in many areas, including the gastrointestinal tract, kidney, lung and cardiovascular systems. By contrast, the functional COX-2 enzyme is normally found less widely, e.g. brain, spinal cord, renal cortex, tracheal epithelium and vascular endothelium. However, COX-2 mRNA is widely distributed. In response to specific stimuli, especially those associated with inflammation, the expression of COX-2 isoenzyme is induced or upregulated, leading to increased local production of prostaglandins. A range of specific prostanoid receptors (e.g. EP1-4) are involved in peripheral sensitization associated with inflammation.

FIGURE 5.5 Arachidonic acid metabolism. AA = arachidonic acid, COX = cyclo-oxygenase, PG = prostaglandin, TXs = thromboxanes.

NSAIDs also have central effects as cyclo-oxygenases are widely distributed in both the peripheral and central nervous systems. NSAIDs may also have other mechanisms of action independent of any effect on prostaglandins, including effects on basic cellular and neuronal processes. NSAIDs are ‘non-selective’; they inhibit both COX-1 and COX-2.

Pharmacokinetics

All NSAIDs are rapidly absorbed. They are weak acids and are therefore mainly unionized in the stomach where absorption can occur. When given orally, most absorption occurs in the small intestine because the absorptive area of the microvilli of the small intestine is much more extensive. Most have pK_a values lower than 5 and are therefore 99% ionized at a pH value greater than 7. Most are almost insoluble in water at body pH, although the sodium salt (diclofenac sodium, naproxen sodium) is more soluble. Ketorolac trometamol is the most soluble and can be given intravenously as a bolus and intramuscularly with less chance of significant irritation.

Most NSAIDs are highly protein bound (90–99%), with low volumes of distribution (approx. 0.1– 0.2 L kg^–1). The unbound fraction is active. NSAIDs may potentiate the effects of other highly protein-bound drugs by displacing them from protein-binding sites (e.g. oral anticoagulants, oral hypoglycaemics, sulphonamides, anticonvulsants).

NSAIDs are mostly oxidized or hydroxylated and then conjugated and excreted in the urine. A few have active metabolites. For example, nabumetone is metabolized to 6-methoxy-2-naphthyl acetic acid, which is more active than the parent drug.

The interaction between NSAID and cyclo-oxygenase enzyme is often complex and plasma half-life may not reflect pharmacodynamic half-life. Diclofenac has a terminal half-life of 1–2 h. It is conjugated to glucuronides and sulphates, with 65% being excreted in the urine and 35% in the bile. The metabolites are less active than the parent compound. Ketorolac trometamol has a terminal half-life of 5 h and more than 90% is excreted renally. Naproxen has a terminal half-life of 12–15 h and is excreted almost entirely through the kidney as the conjugate. Tenoxicam is cleared mainly through the urine as the inactive hydroxypyridyl metabolite, although approximately 30% is via biliary excretion as the glucuronide.

Pharmacodynamics

NSAIDs are very effective analgesics, although their use is limited by adverse effects due to their general effect on prostanoid synthesis and the ubiquitous nature of prostanoids. Generally, the risk and severity of NSAID-associated side-effects is increased in the elderly population or those with other significant co-morbidity.

Analgesia

NSAIDs have well-demonstrated efficacy both as postoperative analgesics and in chronic conditions such as rheumatoid and osteoarthritis. They can have significant opioid-sparing effects. NSAIDs are insufficient alone for severe pain after major surgery but are valuable as part of a multimodal analgesic regimen.

Gastrointestinal System

The gastric and duodenal epithelia have various protective mechanisms against acid and enzyme attack, and many of these involve prostaglandin production via a COX-1 pathway. Acute and particularly chronic NSAID administration can result in gastroduodenal ulceration and bleeding; the latter is exacerbated by the antiplatelet effect.

Platelet Function

Platelet COX-1 is essential for the production of the cyclic endoperoxides and thromboxane A₂ that mediate the primary haemostatic response to vessel injury by producing vasoconstriction and platelet aggregation. Aspirin acetylates COX-1 irreversibly, whereas other NSAIDs do so in a reversible fashion. This can result in prolonged bleeding times and increased perioperative blood loss has been reported in some studies. The presence of a bleeding diathesis or co-administration of anticoagulants may increase the risk of significant surgical blood loss.

Renal Function

Renal prostaglandins have many physiological roles, including the maintenance of renal blood flow and glomerular filtration rate in the presence of circulating vasoconstrictors, regulation of tubular electrolyte handling and modulation of the actions of renal hormones. NSAIDs can adversely affect renal function. High circulating concentrations of the vasoconstrictors renin, angiotensin, noradrenaline (norepinephrine) and vasopressin increase production of intrarenal vasodilators including prostacyclin, and renal function may be particularly sensitive to NSAIDs in these situations. Co-administration of other potential nephrotoxins, such as gentamicin, may increase the likelihood of renal toxicity.

Aspirin-Induced Asthma

Aspirin-induced asthma may affect up to 20% of asthmatics; it may be severe and there is often cross-sensitivity with other NSAIDs. Patients with coexisting chronic rhinitis and nasal polyps appear to be at most risk. A history of aspirin-induced asthma is a contraindication to NSAID use after surgery. There is no reason to avoid NSAIDs in other asthmatics if previous exposure has not been associated with bronchospasm. However, patients should be warned of potential problems and advised to stop taking them if their asthma worsens. The mechanism of this problem is unclear; it may be that cyclo-oxygenase inhibition increases arachidonic acid availability for production of inflammatory leukotrienes by lipo-oxygenase pathways.

Contraindications

Specific contraindications to NSAID administration include a history of a bleeding diathesis, peptic ulceration, significant renal impairment or aspirin-induced asthma. Care should be taken in high-risk groups, such as the elderly, those with cardiovascular disease and the dehydrated.

COX-2-SPECIFIC INHIBITORS

These drugs are anti-inflammatory analgesics that reduce prostaglandin synthesis by specifically inhibiting COX-2 with little or no effect on COX-1 (relative specificity varies between drugs). They were developed as an alternative to traditional NSAIDs with the aim of avoiding COX-1-mediated side-effects, primarily gastric ulceration and platelet effects.

Mechanism of Action

The mechanism of action is similar to that of NSAIDs (Fig. 5.4). Both COX-1 and COX-2 enzymes have very similar active sites and catalytic properties, although COX-2 has a larger potential binding site because of a secondary internal pocket. This has allowed design of drugs to target predominantly COX-2. COX-2 is induced at sites of inflammation and trauma, producing prostaglandins, and these drugs, inhibit this process. However, COX-2 is an important constitutive enzyme in the CNS, including the spinal cord, and inhibition at this site is thought to be an important mechanism also.