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.

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).

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).

Pharmacodynamic Effects of Opioids

The ubiquitous nature of opioid receptors implies that agents acting at them have wide-ranging effects, some of which may be problematic. Some opioids or their metabolites also have activity at other receptors, e.g. methadone acts at the N-methyl-D-aspartate (NMDA) receptor. These particular actions are discussed for individual agents below. The more general effects of opioids are described in this section.

Analgesic Action

Opioids with agonist activity mainly at the MOP receptor, and to a lesser extent at the KOP receptor, have analgesic effects. Analgesic effects have also been demonstrated for the spinal DOP receptor 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, then care must be taken with dose titration and a detailed reassessment of analgesic response is essential. Opioids exert their analgesic effect by:

Central Nervous System

In addition to analgesia there are several potential central nervous system (CNS) effects of opioids:

Sedation and sleep. Opioids interfere with rapid-eye-movement sleep with changes in the EEG including a progressive decrease in EEG frequency and production of delta waves. However, burst suppression is not seen, even with large doses. Opioid-related ventilatory depression is more common during sleep. Opioid-induced sedation may be used therapeutically, e.g. critical care setting. 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.

Mood. Significant euphoria is uncommon when opioids are used to treat pain but it occurs frequently when they are used inappropriately. Dysphoria (possibly via a KOP receptor action) and hallucinations can occur. Commonly, the hallucinations are visual in nature and may only affect part of the visual field.

Miosis. This is mediated via a KOP receptor effect on the Edinger-Westphal nucleus of the oculomotor nerve.

Tolerance (i.e. requirement of increasing doses to achieve the same effect) is important clinically because a significant number of patients are receiving long-term opioid therapy for malignant and chronic non-malignant pain; it is also relevant in illicit drug use. Additionally, tolerance may develop much more acutely, e.g. when opioids are used for pain control before surgery or when given intrathecally. However, after initial dose titration, the majority of patients on long-term opioids are usually maintained on a stable dose.

At a cellular level, tolerance is caused by a progressive loss of active receptor sites combined with uncoupling of the receptor from the guanosine triphosphate (GTP)-binding subunit. There is also some evidence that the NMDA receptor may play a role in acute tolerance, via protein kinase C activity lifting the magnesium block at the NMDA site. There may therefore be a rationale for using ketamine in situations of acute tolerance, for example in the postoperative period. Interactions with the NOP receptor may also be important.

The incomplete cross-tolerance between different types of opioids may result from differential activity at opioid receptor subtypes. Withdrawal may occur if there is abrupt cessation of opioids or if an antagonist is given.

Opioid-induced hyperalgesia. This is a paradoxical response where an increase in opioid dose results in hyperalgesia. There is good basic science evidence of underlying mechanisms, but its importance in clinical practice is unclear. It may be part of the spectrum of opioid toxicity, or can occur in isolation. It has been shown to occur after systemic administration of potent short acting opioids such as remifentanil.

Addiction. This is defined as the compulsive use of opioids to the detriment of the patient in terms of physical, psychological or social function. Drug-seeking behaviour is not usually a problem if opioids are used appropriately for pain relief in both acute and chronic situations.

Respiratory

Opioids may cause respiratory depression, particularly in the elderly, neonates and when given without titrating effect to analgesic response. Tolerance does develop to this phenomenon, so it is less of a problem in chronic use. However, care must be taken if nociceptive input is reduced or removed, e.g. after a nerve block. Sensitivity to CO2 is reduced, even with small doses of MOP agonists. This is caused by depression of sensitivity of neurones on the ventral surface of the medulla.

Opioids, given at sufficient dose, are effective at suppressing the stress response to laryngoscopy and airway manipulation. They may reduce the plasma concentrations of catecholamines, cortisol and other stress hormones by inhibiting the pituitary-adrenal axis, reducing central sympathetic outflow and influencing central neuroendocrine responses. Opioids also suppress cough activity and mucociliary function. This may cause inadequate clearing of secretions and hypostatic pneumonia, especially if there is associated sedation and respiratory depression. This antitussive activity is, at least in part, mediated peripherally.

Cardiovascular

In normovolaemic patients, the majority of opioids have no significant cardiovascular depressant effect. However, if histamine is released, then there may be tachycardia, decrease in systemic vascular resistance and a reduction in arterial pressure. Bradycardia may occur in response to some opioids. There is no direct action on baroreceptors but a minimal reduction in preload and afterload may occur. There is no effect on cerebral autoregulation. However, if respiratory depression is present, then the resultant increase in PaCO2 may increase cerebral blood flow.

Opioids decrease central sympathetic outflow. Therefore, in patients who are relying on increased sympathetic tone to maintain cardiovascular stability, opioids may lead to haemodynamic compromise. This may be severe, particularly if potent opioids are given by rapid intravenous bolus.

Other Effects

Myoclonic jerks may occur if there is opioid toxicity and may be associated with sedation and hallucinations. Urinary retention and urgency may occur, probably related to a centrally mediated mechanism as these problems are much more common when neuraxial opioids are used. Pruritus is relatively common after neuraxial administration. The nose, face and torso are particularly affected and this may be reversed by a low dose of a MOP antagonist. Muscle rigidity is a recognized complication, particularly after intravenous bolus administration of potent phenylpiperidines. This may cause significant problems with ventilation because of chest wall rigidity and decreased respiratory compliance. It may be minimized by co-administration of opioids with intravenous anaesthetic agents and benzodiazepines, reversed by naloxone or prevented by neuromuscular blocking agents. Thermoregulation is impaired to a similar extent as that seen with volatile agents. With long-term use, depression of the immune system may occur. Endocrine problems include impaired adrenal and sexual function, and infertility.

Opioid Structure

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.

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 pKa 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 αl-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 (t½keo) 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 (VD) 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 t½’ 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 t½ is increased after prolonged infusion for most opioids apart from remifentanil. For example, the elimination t½ 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.

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.

Factors affecting pharmacokinetics include:

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