Pain and analgesics

Published on 02/03/2015 by admin

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Michael C. Lee, Mark Abrahams

Synopsis

Pain and analgesics

‘The work which you are accomplishing is immensely important for the good of humanity, as you seek the ever more effective control of physical pain and of the oppression of mind and spirit that physical pain so often brings with it.’

Pope John Paul II (26 July 1987)¹

Definition of pain

The International Association for the Study of Pain defines pain as ‘an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage’. This implies that the degree of pain experienced by the patient may be unrelated to the extent of underlying tissue damage, and that emotional or spiritual distress can add to the patient’s experience of pain (Fig. 18.1).

Fig. 18.1 A model of pain perception. Carr D B, Loese J L, Morris D B (eds) 2005 Narrative, Pain, and Suffering. The Challenge of Narrative to Pain. Progress in Pain Research and Management, vol. 34. IASP Press, Seattle.

This chapter focuses on the use of drugs for pain relief and illustrates the use of many analgesics that may be encountered in clinical practice. However, clinicians should recognise that the experience of pain is influenced by physical, emotional and psychological factors. While drug therapy is an expedient (and familiar) form of treatment, successful management of pain requires a more holistic approach that addresses all the components of pain.²

Nociception

Pain alerts us to ongoing or potential tissue damage and the ability to sense pain is vital to our survival. The physiological process by which pain is perceived is known as nociception. While the neurobiology of nociception is complex, its appreciation provides a useful framework for understanding the way analgesics work (Fig. 18.2).

Fig. 18.2 Schematic representation of nociceptive pathways. Noxious stimuli such as protons (H +), temperature (temp) etc. applied to end-organs activate nociceptors. Injury leads to the release of prostaglandins such as prostaglandin E2 (PGE2), serotonin (5-HT), nerve growth factor (NGF) etc. from damaged cells, bradykinin (BK) from blood vessels and substance P (sP) from nociceptors. These agents either activate nociceptors directly or sensitise them to subsequent stimuli by parallel activation of intracellular kinases by G-protein-coupled receptors and tyrosine kinase receptors. Primary nociceptive afferents (C-fibres, Ad-fibres) of dorsal root ganglion (DRG) neurones synapse on second order neurones (S) in the spinal dorsal horn (magnified in inset). Here, glutamate (Glu) and sP released from primary afferent terminals (A) activate glutamate receptors (NMDA R, AMPA R, mGluRs) and neurokinin-1 (NK-1) receptors, respectively, located postsynaptically on spinal neurones. These synapses are negatively modulated by spinal inhibitory interneurones (I), which employ enkephalins (Enk) or γ-aminobutyric acid (GABA) as neurotransmitters. Spinal neurones convey nociceptive information to the brain and brainstem. Activation of descending noradrenergic/norepinergic and/or serotonergic systems, which originate in the brain and brainstem, leads to the activation of spinal inhibitory interneurones (I) thereby resulting in antinociception (http://encref.springer.de/mp/0002.htm).

Our nervous system is alerted to actual or potential tissue injury by the activation of the peripheral terminals of highly specialised primary sensory neurones called nociceptors. Nociceptors have unmyelinated (C-fibre) or thinly myelinated (Aδ-fibre) axons. Their cell bodies lie in the dorsal root ganglia of the spinal cord or in the trigeminal ganglia. Different nociceptors encode discrete intensities and modalities of pain, depending upon their expression of ion-channel receptors. These receptors are transducers. They convert noxious stimuli into action potentials. Some of these transducers have been identified, including those that respond to heat (> 46°C), cold (< 10°C) and direct chemical irritants such as capsaicin.

Action potentials that result from the transduction of noxious stimuli are conducted along the axon of the sensory neurone into the spinal cord. Conduction of the action potentials in sensory neurones depends on voltage-gated sodium channels, including two that are predominately expressed in nociceptors; Na_v1.7 and Na_v1.8.

The central terminal of the nociceptor makes synaptic contact with dorsal horn neurones within the spinal cord. Glutamate, an amino acid, is the main excitatory neurotransmitter released at these synapses. Its release can be inhibited by ligands that act to activate receptors found on the central terminal of the nociceptors (pre-synaptic inhibition). These include the opioids, cannabinoids, γ-aminobutyric acid (GABA)-receptor ligands and the anticonvulsants, gabapentin and pregabalin. Opioids and GABA also influence the action of glutamate on the dorsal horn neurones. They act on post-synaptic receptors to open potassium or chloride channels. This results in hyperpolarisation of the neurone, which inhibits its activity.

Other neurotransmitters may also be released by the central terminal of the nociceptors. For example, substance P is released during high-intensity and repetitive noxious stimulation. It mediates slow excitatory post-synaptic potentials and results in a localised depolarisation that facilitates the activation of N-methyl-D-aspartate (NMDA) receptors by glutamate. The end-result is a progressive increase in the output from dorsal horn neurones. This amplified output is thought to be responsible for the escalation of pain when the skin is repeatedly stimulated by noxious heat – a phenomenon known as wind-up.

Nociceptive output from the spinal cord is further modulated by descending inhibitory neurones that originate from supraspinal sites such as the periaqueductal gray or the rostral ventromedial medulla and terminate on nociceptive neurones in the spinal cord as well as on spinal inhibitory interneurones that store and release opioids. Stimulation of these brain regions, either electrically or chemically (e.g. opioids), produces analgesia in humans. Transmission through these inhibitory pathways is facilitated by monoamine neurotransmitters such as noradrenaline/norepinephrine and serotonin.

Finally, dorsal horn neurones send projections to supraspinal areas in the brainstem, hypothalamus, and thalamus and then, through relay neurones, to the cortex where the sensation of pain is perceived. The mechanism by which the cortex produces the conscious appreciation of pain is the focus of much research.

Classification of clinical pain

Rational pharmacological treatment of clinical pain depends on a number of factors, including the underlying cause and duration of pain, the patient’s general medical condition and prognosis. Clinical pain is generally divided into three broad categories; acute, chronic, and cancer-related.

Evaluation of pain

Achieving optimal pharmacological management of the patient’s pain will depend on the type and cause of pain, as well as the psychological and physical condition of the patient. A comprehensive evaluation of the pain is, therefore, essential if we are to treat the patient successfully and safely. Underlying organic pathology must be excluded unless an obvious cause of pain is apparent (e.g. after recent surgery or trauma). The presence of organic pathology should also be suspected if the patient’s pain presents in an unusual way, or is of a much greater magnitude than would normally be expected from the assumed pathology.

Once an organic explanation has been eliminated, additional tests are unhelpful. The illusory sense of progress such tests provide for both physician and patient may perpetuate maladaptive behaviour and impede the return to more normal function.

The evaluation of persistent pain should include pain location, quality, severity, duration, course, timing (including frequency of remissions and degree of fluctuation), exacerbating and relieving factors, and co-morbidities associated with the pain (with emphasis on psychological issues, depression, and anxiety). The efficacy and adverse effects of currently or previously used drugs and other treatments should also be determined.

If appropriate, the patient should be asked if litigation is ongoing or whether financial compensation for injury will be sought. A personal or family history of chronic pain can often give insight into the current problem. The patient’s level of function should be assessed in detail, focusing on family relationships (including sexual), social network, and employment or vocation. The interviewer should elicit how the patient’s pain affects the activities of normal living.

It is also important to determine what the pain means to the patient. In some patients, reporting pain may be more socially acceptable than reporting feelings of depression or anxiety. Pain and suffering should also be distinguished. In cancer patients, in particular, suffering may be due as much to loss of function and fear of impending death as to pain. The patient’s expression of pain represents more than the pathology intrinsic to the disease.

Thorough physical examination is essential, and can often help to identify underlying causes and to evaluate, further, the degree of functional impairment. A basic neurological examination may identify features associated with neuropathic pain including:

• Allodynia – pain due to a stimulus which does not normally provoke pain.

• Hyperalgesia – an increased response to a stimulus which is normally painful.

• Paraesthesia – abnormal sensation, e.g. ‘pins and needles’.

• Dyaesthesia – a painful paraesthesia, e.g. burning foot pain in diabetic neuropathy.

Pharmacotherapy

An analgesic is defined as a drug that relieves pain. Analgesics are classified as opioids and non-opioids (e.g. NSAIDs). Co-analgesics or adjuvants are drugs that have a primary indication other than pain but are analgesic in some conditions. For example, antidepressants and anticonvulsants also act to reduce nociceptive transmission in neuropathic pain.

The efficacy and effectiveness of any given analgesic varies widely between individuals. Analgesics also have a relatively narrow therapeutic window, and drug dosages are often limited by the onset of adverse side-effects. For these reasons, an analgesic should be titrated for an individual patient until an acceptable balance is achieved between subjective pain relief and adverse drug effects.

Non-opioid analgesics

NSAIDs (non-steroidal anti-inflammatory drugs)

Mechanism of analgesia

Endothelial damage produces an inflammatory response in tissues. Damaged cells release intracellular contents, such as adenosine triphosphate, hydrogen and potassium ions. Inflammatory cells recruited to the site of damage produce cytokines, chemokines and growth factors. A profound change to the chemical environment of the peripheral terminal of nociceptors occurs. Some factors act directly on the nociceptor terminal to activate it and produce pain, and others sensitise the terminal so that it becomes hypersensitive to subsequent stimuli. This process is known as peripheral sensitisation.

Prostanoid is a major sensitiser that is produced at the site of tissue injury. NSAIDs act by inhibiting cyclo-oxygenase, an enzyme involved in the production of prostanoid, as well as other prostaglandins. This enzyme has a number of isoforms, the most studied being cyclo-oxgenase-1 (COX-1) and cyclo-oxygenase-2 (COX-2). Their actions are inhibited by NSAIDs (see Ch. 16). Increased COX-2 production is induced by tissue injury and accounts for the efficacy of COX-2-specific inhibitor drugs (COXIBs). The inhibitory effect of NSAIDs on the production of other prostaglandins is responsible for the common side-effects of these drugs. Among other functions, the prostaglandins produced by cyclo-oxygenase act to protect the gastric mucosa, maintain normal blood flow in the kidney and preserve normal platelet function. Inhibition of prostaglandin production, therefore, can cause gastric irritation, damage to the kidney and an increased risk of bleeding.

Clinical use

NSAIDs are among the most commonly prescribed analgesics and, unless contraindicated, are effective and appropriate analgesics for use in acute inflammatory pain. There is much evidence to suggest that NSAIDs are effective in cancer-related pain. The benefit of NSAIDs in chronic non-cancer-related pain is less certain, with efficacy only proven in chronic inflammatory musculoskeletal pain, mainly from studies in rheumatoid arthritis. NSAIDs are generally ineffective in neuropathic pain conditions, and a careful risk–benefit assessment should be made prior to use in view of the side-effects associated with long-term use.

Choice of NSAID and route of administration

There is little difference in the clinical benefit conferred by any particular NSAID. However, NSAIDs differ in their pharmacokinetic properties and side-effects. This should be taken into account when choosing a non-steroidal agent for long-term use. For example, the oxicams (e.g. piroxicam, tenoxicam) are metabolised slowly and have a high degree of enteropathic circulation. These NSAIDs have long elimination half-lives (but also higher incidences of gastrointestinal and renal side-effects).

NSAIDs should be given orally when possible. The same dose of NSAID is equally effective whether injected or taken orally. Topical application of NSAIDs for musculoskeletal pain is an exception as it is effective and is associated with a lower incidence of side-effects.

Side-effects

All NSAIDs are associated with dose-dependent side-effects. In particular, there is a risk of gastrointestinal bleed, renal toxicity and a possibility of cardiac-related complications. The morbidity related to gastrointestinal adverse effects is considerable (~ 5 per 1000 patients per year of treatment) and catastrophic bleeding can occur without any preceding warning symptoms. For this reason, it is recommended that, when used in the longer term, NSAIDs should be prescribed along with an appropriate gastro-protective agent (see p. 531).

COX-2-specific NSAIDs provide analgesia with a reduced risk of GI bleed (but have a similar risk of renal toxicity). Trials have shown a slightly increased risk of cardiac complications in at-risk patients. Subsequent trials, however, have indicated that increased cardiac risk may also be associated with the use of non-selective NSAIDs (possibly as a result of hypertension secondary to fluid retention). Current guidelines suggest that all cyclo-oxygenase-inhibiting drugs should be used with caution in patients with known cardiovascular or cerebrovascular disease, i.e. at the lowest effective dose, and for the shortest possible time.

Paracetamol (acetaminophen)

The major advantage of paracetamol over the NSAIDs is its relative lack of adverse effects; this justifies its use as a first-line analgesic. It can be used on its own, or synergistically with non-steroidal drugs or opioids. Paracetamol is also an antipyretic with very weak anti-inflammatory properties. There is increasing evidence that its analgesic effect is central and results from the activation of descending serotonergic pain-inhibiting pathways, but its primary site of action may still be inhibition of prostaglandin synthesis (via COX-3 inhibition). Its major drawback is the liver toxicity seen in acute overdose due to the accumulation in the liver of benzoquinones.

Nefopam

Nefopam is chemically distinct and pharmacologically unrelated to any presently known analgesic and has been used in Europe for intravenous and oral administration since 1976. It is a racemic mixture of its two enantiomers. Although its mechanism of action remains largely unknown, nefopam is thought to increase the inhibiting tone of serotonergic and noradrenergic/norepinephrinergic descending pathways by inhibiting the synaptic uptake of dopamine, noradrenaline/norepinephrine and serotonin. Compared to NSAIDs and opioids, nefopam has the advantages of minimal effects on platelet aggregation and not depressing the central nervous system.There have been rare fatal overdoses with the oral form of the drug, characterised by convulsions and arrhythmia. Its sympathomimetic action precludes its use in patients with limited coronary reserve, prostatitis and glaucoma. Minor side-effects (nausea, dizziness and sweating) are observed in 15–30% of treated patients. Nefopam has been abused primarily for its psychostimulant effects, which are probably linked to its dopamine-reuptake inhibition properties.

Opioid analgesics

Opium (the dried juice of the seed head of the opium poppy) was used in prehistoric times. Modern medical practice still benefits from the use of its alkaloids, employing them as analgesics, tranquillisers, antitussives and in the treatment of diarrhoea.

The principal active ingredient in crude opium was isolated in 1806 by Friedrich Sertürner, who tested pure morphine on himself and three young men. He observed that the drug caused cerebral depression and relieved toothache, and named it after Morpheus, the Greek god of dreams. Opium contains many alkaloids, but the only important opiates (drugs derived from opium) are morphine (10%) and codeine. Papaverine is occasionally used as a vasodilator.

Opioid is a generic term for natural or synthetic substances that bind to specific opioid receptors in the CNS, producing an agonist action.

Mechanism of action of opioids

Opioids produce their effects by activating specific G protein-coupled receptors in the brain, spinal cord and peripheral nervous system. There are three major classes of opioid receptor: δ-opioid (OP1,DOR), κ-opioid (OP2,KOR) and μ-opioid (OP3,MOR), that correspond respectively to their endogenous ligands, enkephalin, dynorphin and β-endorphin. Although studies suggest the existence of subtypes of all three major opioid receptor classes, the evidence is controversial and the sub-classification is of little practical value except, perhaps, to explain the change in side-effect profile sometimes seen during opioid rotation in long-term opioid use or cancer-related pain.

Agonist activity at opioid receptors acts to open potassium channels and prevent the opening of voltage-gated calcium channels. This reduces neuronal excitability and inhibits the release of pain neurotransmitters.

Classification of opioid drugs

Opioids have been traditionally classified as strong, intermediate and weak, according to their perceived analgesic properties and propensity for addiction. This approach can be misleading, as it implies that weak opioids such as codeine are less effective but safe. Codeine may be less potent than morphine but can cause respiratory depression if given in sufficient quantities. Codeine-like drugs are also frequently abused. Opioids may also be classified according to their structure. As described later, the properties of opioids may be predicted on the basis of activity on opioid and other receptor systems. The functional classification is probably of most clinical use (Table 18.1).

Table 18.1 Classification of opioids

Opioid pharmacodynamics

Opioids act to reduce the intensity and unpleasantness of pain. The common side-effects are due to their action on different opioid receptors. They include sedation, euphoria, dysphoria, respiratory depression, constipation, pruritis, and nausea and vomiting. It is important to note, however, that many of these side-effects tend to diminish with time as tolerance to the opioid develops. Constipation and dry mouth (leading to increased risk of dental caries) are more resistant to the development of tolerance and remain problems with long-term use. Impairment of hypothalamic function also occurs with long-term opioid use and may result in loss of libido, impotence and infertility.

Adverse effects associated with the use of opioids in acute pain (and occasionally in chronic non-malignant pain) can often be managed simply by reducing the opioid dose or switching to a different opioid. In palliative medicine, unwanted effects related to long-term opioid use are often treated proactively, laxatives for constipation, excessive sedation by methylphenidate or dextroamphetamine. Rotating to another opioid, or using more frequent but smaller doses of opioids may also help.

Systemic effects of opioid analgesics

Central nervous system

Opioids reduce the intensity and unpleasantness of pain. Patients taking opioid analgesics often report less distress, even when they can still perceive pain. Sedation occurs frequently, particularly in the early stages of treatment, but often resolves although it can remain a problem, especially at higher doses, and is a common cause of drug discontinuation in the chronic pain population.

The sensitivity of the respiratory centre to hypercarbia and hypoxaemia is reduced by opioids. Hypoventilation, due to a reduction in respiratory rate and tidal volume, ensues. Cough is inhibited by a central action. Prolonged apnoea and respiratory obstruction can occur during sleep. These effects are more pronounced when the respiratory drive is impaired by disease, for example in chronic obstructive pulmonary disease, obstructive sleep apnoea and raised intracranial pressure.

Nausea and vomiting commonly accompany opioids used for acute pain. The mechanism may be activation of opioid receptors within the chemoreceptor trigger zone within the medulla, although opioid effects on the gastrointestinal tract and vestibular function probably play a role. Antiemetics are effective.

Miosis occurs due to an excitatory effect on the parasympathetic nerve innervating the pupil. Pin-point pupils are characteristic of acute poisoning; at therapeutic doses the pupils are merely smaller than normal.

Cardiovascular system

Opioids cause peripheral vasodilatation and impair sympathetic vascular reflexes. Postural hypotension may occur, but this is seldom troublesome in the reasonably fit patient and is rare with long-term use. Intravenous administration of opioids to patients who are hypovolaemic or have poor cardiac reserve can result in marked hypotension. Intravenous morphine titrated carefully may benefit patients with acute myocardial infarct and left ventricular failure as morphine reduces sympathetic drive (from pain and anxiety) and preload (by venodilatation), thereby reducing the work of the heart.

Gastrointestinal tract

Opioids cause a tonic increase of smooth muscle tone along the gastrointestinal tract. Reduced peristalsis and delayed gastric emptying results in constipation, greater absorption of water and increased viscosity of faeces, and exacerbation of the constipation (but the effect is useful in diarrhoea). Opioid-induced constipation in palliative care can be managed by increasing the fibre content of the diet to > 10 g/day (unless bowel obstruction exists) and prescribing a stool softener (e.g. docusate sodium 100 mg twice or three times daily), usually with a stimulant laxative (e.g. senna or bisacodyl). Stimulant laxatives should be started at a low dose (e.g. Senna 15 mg daily) and increased as necessary. Persistent constipation can be managed with an osmotic laxative (e.g., magnesium citrate) given for 2 or 3 days or with lactulose daily (e.g. 15 mL twice daily).

Pressure within the biliary tree due to spasm of the sphincter of Oddi is increased after opioid administration and gives rise to colicky pain with morphine which can be both diagnosed and relieved by a small dose of the opioid antagonist naloxone. Pethidine (meperidine) is held to produce less spasm in the sphincter of Oddi than other opioids due to its atropine-like effects and is preferred for biliary tree and pancreatic pain. At higher equi-analgesic doses, the effect of pethidine on the sphincter is similar to other opioids, and confers no advantage.

Urogenital tract

Increased tone in the detrusor muscle and contraction of the external sphincter, together with inhibition of the voiding reflexes may aggravate urinary retention.

Others

Opioid administration is often associated with cutaneous vasodilatation that results in the flushing of the face, neck and thorax. This may, in part, be due to histamine release. Pruritus is common with epidural or intrathecal administration of opioids and appears to be mediated by opioid receptor activation, as it is reversed by naloxone.

Pharmacokinetics

Bio-availability varies between opioids after oral administration but is generally poor. Methadone is an exception (80%) (Table 18.2).

Table 18.2 Approximate oral bio-availability of opioids

Opioid	Approximate oral bio-availability %
Hydromorphone	20
Morphine	30
Diamorphine	30
Meperidine	30
Codeine	60
Oxycodone	60
Levorphanol	70
Tramadol	80
Methadone	80

Most opioids have a large volume of distribution (i.e exceeding total body water) and most have an elimination half-life in the range (3–10 h). Notable exceptions are alfentanil (t_½1.6 h) and remifentanil (t_½ 0.06 h) and methadone (t_½ 20–45 h; see section on methadone). Controlled-release opioids typically require days to approach steady-state plasma levels.

Duration of analgesia usually correlates with half-life unless the parent drug has active metabolites (morphine) or if the drug has a high affinity for opioid receptors (buprenorphine). Opioid sensitivity is increased in the neonate and in the elderly. Variation in response and the narrow therapeutic index of opioids make it essential to titrate effects for individual patients. For opioid-naïve patients with acute pain, frequent monitoring of pain relief, sedation, respiratory rate and blood pressure is necessary to guide dosage adjustment.

Route of administration

The oral route is preferred as it is simple, non-invasive and relatively affordable. It requires little in the form of direct medical supervision or complex delivery equipment. The slower onset of action renders this route less convenient for use in acute pain. The oral route is also unsuitable when patients suffer from emesis, dysphagia, gastrointestinal obstruction or malabsorption or in acute trauma where the patient may have delayed gastric emptying.

If parenteral administration is necessary, the intravenous route is preferable to intramuscular injection for repeated boluses because it is less painful. Also, intramuscular or subcutaneous routes of administration should not be used if the patient is peripherally vasoconstricted (e.g. in the acute trauma patient), as the establishment of normal peripheral blood flow, as the patient is resuscitated, may result in a sudden redistribution of the drug to the central circulation. Continuous intravenous or subcutaneous infusion should be considered if repeated parenteral doses produce a prominent bolus effect (i.e. toxicity) at peak levels early in the dosing interval or breakthrough pain at trough levels. Patient-controlled analgesia (PCA) systems (in which the patient can trigger additional drug delivery) can be added to an infusion to provide supplementary doses. These systems are safe for both home and hospitalised patients, but are contraindicated for sedated and confused patients.

Epidural and intrathecal administration of opioids requires special expertise. The dorsal horn of the spinal cord is rich in opioid receptors, and equivalent analgesia can be provided using a lower dose of opioid, resulting in fewer systemic side-effects. However, rostral spread of the drug can result in delayed toxicity (e.g. respiratory depression) during acute administration, and the cost of infusion systems, staffing and monitoring must also be taken into account. The use of intraventricular morphine appears to be beneficial in treating recalcitrant pain due to head and neck malignancies and tumours (e.g., superior sulcus tumours, breast carcinoma) that affect the brachial plexus.

Pharmacology of individual opioids

Opioid agonist drugs

Morphine

Morphine remains the most widely used opioid analgesic for the treatment of severe pain. It is the gold standard against which other opioids are compared. Commonly given intramuscularly, intravenously, or orally, it can also be administered per rectum and into the epidural space or cerebrospinal fluid. Unlike most opioids, it is relatively water soluble. Metabolism is by hepatic conjugation and its half life is about 2–4 h. The duration of useful analgesia provided by morphine is about 3–6 h, but varies greatly with different drug preparations and routes of administrations.

Morphine 6-glucuronide (M6G), one of its major metabolites, is an agonist at the μ receptor and also at the distinct M6G receptor. It is more potent than morphine. As it is excreted in the urine, it accumulates if renal function is impaired. With repeated use of morphine, morphine 6-glucuronide is responsible for a significant amount of pharmacological activity.

Diamorphine

Diamorphine (3,6 diacetyl morphine), or heroin, is a semi-synthetic drug that was first made from morphine at St Mary’s Hospital, London, in 1874. In almost every country, except the UK, the manufacture of diamorphine, even for use in medicine, is now illegal.

Diamorphine has no direct activity at the μ receptor. It is rapidly converted within minutes to morphine and 6-monoacetylmorphine, a metabolite of both drugs. The effects of diamorphine are principally due to the actions of morphine and 6-monoacetylmorphine on the μ and, to a lesser extent, the κ receptors.

Diamorphine given parenterally has a t_½ of 3 min. When given orally, it is subject to complete presystemic or first-pass metabolism and only morphine (t_½ 3 h) and other metabolites reach the systemic circulation. Thus oral diamorphine is essentially a prodrug. It is likely that there are no significant differences in the pharmacodynamics of diamorphine when compared to morphine when used for acute pain, despite the common belief that diamorphine is associated with more euphoria and less nausea and vomiting. Its greater potency (greater efficacy in relation to weight and, therefore, requiring a smaller volume) and lipid-solubility make diamorphine suitable for delivery by subcutaneous infusion through a syringe driver when continuous pain control is required in palliative care that can no longer be achieved by the enteral route (oral, buccal, rectal).

Codeine

Codeine is obtained naturally or by methylation of morphine. It has a low affinity for opioid receptors and most of its analgesic effect results from its metabolism (about 10%) to morphine. The polymorphic CYP2D6 enzyme is responsible for this transformation and it is absent in some individuals (e.g. 7% of the Caucasian population), suggesting that these patients will derive little benefit from codeine.

Codeine alone is a relatively poor analgesic but can be effective for mild to moderate pain, especially when combined with paracetamol. It can also be useful for the short-term symptomatic control of persistent cough or mild diarrhoea. Prolonged use is often associated with chronic constipation, especially at higher doses (more than 30 mg four times daily)

Dihydrocodeine

Dihydrocodeine (DF118) is a low-efficacy opioid with an analgesic potency similar to that of codeine. It is used to relieve moderate acute and chronic pain on its own or as a compound tablet (co-dydramol; dihydrocodeine 10 mg plus paracetamol 500 mg). Although active metabolites (dihydromorphine and dihydromorphine-6-O-glucuronide) account for some of its pharmacological effects, dihydrocodeine itself has analgesic activity and may be a more reliable analgesic when compared to codeine.

Oxycodone

Oxycodone is a semi-synthetic opioid that has been in clinical use since 1917. Its potency is approximately twice that of morphine. Oxycodone is currently used as a controlled-release preparation for cancer and chronic non-malignant pain. The immediate-release solution and tablets are available for acute or breakthrough pain. Parental oxycodone is an alternative when opioids cannot be given orally. Both oxycodone and morphine provide effective analgesia in acute and chronic pain. Oxycodone may have a more favourable pharmacokinetic profile. Its oral bio-availability, at about 80%, is significantly higher. This results in reduced inter-individual variation in plasma concentrations after oral administration. It has a similar adverse-effect profile to morphine, with a slightly reduced incidence of psychotropic effects.

A fixed-dose oral formulation (Targinact) of oxycodone combined with naloxone has been shown to be effective in patients who derive benefit from opioid therapy, but where use of the opioid is limited because of intractable constipation. Naloxone provides competitive antagonism of the opioid-receptor mediated effects of oxycodone in the gut, thus reducing constipation. Since the bio-availability of naloxone after oral administration is less than 3%, systemic effects from the antagonist drug are unlikely. The recommended maximum daily dose of Targinact is 80 mg oxycodone hydrochloride and 40 mg naloxone hydrochloride.

Hydromorphone

Hydromorphone is a semi-synthetic opioid used primarily for the treatment of cancer-related pain. It can be administered intravenously, orally, and rectally. Hydromorphone is five times as potent as morphine when given by the oral route and eight to nine times as potent when given intravenously, with a similar duration of action. The liver is its principal site of metabolism. In contrast to morphine, the 6-glucuronide metabolite is not produced in any significant amount, the main metabolite being hydromorphone-3-glucuronide. Some metabolites are active but they are present in such small amounts that they are unlikely to have a significant effect except perhaps in renal failure.

Methadone

Methadone is a synthetic opioid used commonly as a maintenance drug in opioid addicts and increasingly used in cancer and chronic non-malignant pain. It is rapidly absorbed after oral administration and is extensively metabolised to products that are excreted in the urine. The principal feature of methadone is its long duration of action, due to high protein binding and slow liver metabolism. The elimination half-life of methadone is 20–45 h, making it suitable for use in long-term therapy, but less useful for acute pain. Steady state concentration is only reached after several days with regular administration and dosages must be carefully titrated.

When used in cancer-related pain or chronic non-malignant pain, an opioid of short half-life should be provided for breakthrough pain, rather than an extra dose of methadone. The long duration of action also favours its use for the treatment of opioid withdrawal.

Fentanyl

Fentanyl is one of the first short-acting opioids developed for use in anaesthesia. It is approximately 100 times more potent than morphine but undergoes hepatic metabolism to produce inactive metabolites. At low doses, it has a short duration of action due to redistribution of the drug. Its terminal half-life is relatively long (1.5–6 h) and, at higher doses, when tissue sites are saturated, its duration of action is much higher. The long t_½ and high lipid solubility make fentanyl ideal for use as a transdermal patch. These preparations are used commonly in cancer-related pain and chronic non-malignant pain.

Oral transmucosal fentanyl citrate offers a unique way of treating breakthrough and incident pain. The transmucosal route offers rapid onset of action in 5–15 min, with peak plasma concentrations at 22 min. Absorption takes place at the buccal and sublingual mucosa, first-pass effect is avoided and overall bio-availability is 50%.

Alfentanil

Alfentanil is less potent and has a shorter half-life than fentanyl. Despite its lower lipid solubility, it has a more rapid onset of action. This is because a greater proportion of the unbound drug is un-ionised and able to diffuse freely across the blood–brain barrier. Like fentanyl, it accumulates with prolonged infusion and the plasma t_½ increases with the duration of infusion.

Remifentanil

Remifentanil is a μ-opioid receptor agonist with an analgesic potency similar to fentanyl and a speed of onset similar to alfentanil. It is broken down by blood and tissue esterases and has a short and predictable t_½ (approximately 5 min) which is not affected by renal or hepatic function or plasma cholinesterase deficiency.

Its main metabolite is a carboxylic acid derivative which is excreted by the kidneys. Although this accumulates in renal failure, significant pharmacological effects are unlikely as its potency relative to remifentanil is only 0.1–0.3%.

Remifentanil is unique in that its plasma half-life remains constant even after prolonged infusion. This property favours its use during anaesthesia, when a rapid wake-up time is desirable (e.g. after neurosurgery).

Papaveretum

Papaveretum is a mixture of opium alkaloids, the principal constituents being morphine (50%), codeine, papaverine and noscapine. Noscapine may be teratogenic, and is no longer a component of commercially available papaveretum in the UK.

Partial agonist opioid analgesics

Buprenorphine

Buprenorphine is a partial agonist at the μ receptor. The partial agonist activity, however, is thought to occur at a higher dose than would be normally used therapeutically and is, therefore, rarely clinically significant. It is 30 times more potent than morphine and its receptor affinity (tenacity of binding) is high. This means that it dissociates from the receptor very slowly. Thus, its peak effect may occur up to 3 h after administration, and its duration of action as long as 10 h. In theory, a partial agonist has less potential for respiratory depression and abuse. Respiratory depression can occur with buprenorphine overdose and, because of its affinity with the μ receptor, may only be partially reversed by naloxone. A respiratory stimulant (doxapram) may be needed in overdose or, occasionally, mechanical ventilation.

Because of extensive first-pass metabolism when swallowed, buprenorphine is normally given by the buccal (sublingual) route or by i.m. or slow i.v. injection. It is a useful analgesic in acute pain because administration by injection can be avoided (for children, or for patients with a bleeding disorder or needle phobia). Its low incidence of drug dependency has led to its increased use in withdrawing opioid addicts and in chronic non-malignant pain. Its prolonged half-life and high lipid-solubility make it suitable for use as a transdermal patch preparation.

Meptazinol

Meptazinol is a high-efficacy partial agonist opioid with central cholinergic activity that is thought to add to its analgesic effect. It is used to relieve acute or chronic pain of moderate intensity. It is thought to have a low incidence of confusion and a low potential for abuse. Its poor oral bio-availability and partial agonist activity make it less useful in severe pain.

Mixed agonist–antagonist opioid analgesics

Drugs in this class include pentazocine, butorphanol, and nalbuphine. They act as partial agonists at the κ receptor and weak antagonist at the μ receptor. Consequently, they may cause withdrawal symptoms in patients dependent on other opioids. As analgesics, mixed agonist–antagonist opioids are not as efficacious as pure μ agonists. Compared to morphine, they produce less dependence (but this definitely occurs), more psychotomimetic effects (κ receptor), and less sedation and respiratory depression (naloxone can reverse the respiratory depression in overdose). They are given to relieve moderate to severe pain, but dysphoric adverse effects often limit their usefulness.

Pentazocine is one sixth as potent as morphine, nalbuphine is slightly less potent than morphine and butorphanol is five to nine times as potent. Adverse effects include nausea, vomiting, dizziness, sweating, hypertension, palpitations, tachycardia and central nervous system disturbance (euphoria, dysphoria, psychotomimesis). Pentazocine has effects on the cardiovascular system, raising systolic blood pressure and pulmonary artery pressure, and should be avoided in myocardial infarction.

Opioids with action on other systems

Pethidine (meperidine)

Pethidine (meperidine) was discovered in 1939 during a search for atropine-like compounds. Its use as a treatment for asthma was abandoned when its opioid agonist properties were appreciated.

Pethidine is primarily a μ-receptor agonist. Despite its structural dissimilarity to morphine, pethidine shares many similar properties, including antagonism by naloxone. It is extensively metabolised in the liver and the parent drug and metabolites are excreted in the urine. Normeperidine is a pharmacologically active metabolite. It can cause central excitation and, eventually, convulsions, if it accumulates after prolonged intravenous administration or in renal impairment.

Pethidine has atropine-like effects, including dry mouth and blurred vision (cycloplegia and sometimes mydriasis, though usually miosis). It can produce euphoria and is associated with a high incidence of dependence. Its use as an analgesia in obstetric practice was based on early clinical research which showed that, unlike morphine, pethidine did not appear to delay labour. However, the doses of pethidine used in these early studies were low and it is now established that pethidine confers no added advantage over other opioids at higher equi-analgesic doses.

Pethidine is eight to ten times less potent than morphine, has poor and variable oral absorption, with a short duration of action in the range of 2–3 h. For all these reasons, it is recommended that pethidine should be avoided if alternatives are available.³

Tramadol

Tramadol is presented as a mixture of two stereoisomers. It is a centrally acting analgesic with relatively weak μ-opioid receptor activity. However, it also inhibits neuronal reuptake of noradrenaline/norepinephrine and enhances serotonin release, and this is thought to account for some of its analgesic action.

It is rapidly absorbed from the gastrointestinal tract. Roughly 20% of an oral dose undergoes first-pass metabolism and less than 30% of a dose is excreted unchanged in the urine. Production of the O-desmethyl-tramadol metabolite is dependent on the cytochrome CYP2D6 enzyme. This metabolite is an active μ agonist with a greater receptor affinity than tramadol. Tramadol is approximately as effective as pethidine for postoperative pain.

Tramadol is less likely to depress respiration and has a lower incidence of constipation compared to opioids, but has a high incidence of nausea and dizziness. It can cause seizures (rare) and should be used with caution in susceptible patients.

Opioid antagonists

Naloxone

Naloxone is a competitive antagonist at μ-, δ-, κ-, and σ-opioid receptors and acts to reverse the effects of most opioid analgesics. It acts within minutes when given intravenously and slightly less rapidly when given intramuscularly. However, the duration of antagonism (approximately 20 min) is usually shorter than that of opioid-induced respiratory depression. Close monitoring of the patient and repeated doses of naloxone may therefore be necessary.

A common starting dosage in an opioid-naïve patient with acute opioid overdosage is 0.4 mg i.v. every 2–3 min until effect. For patients receiving long-term opioid therapy, it should be used only to reverse respiratory depression and must be administered more cautiously to avoid precipitating withdrawal or severe pain. A reasonable starting dose is 0.04 mg (dilute a 0.4 mg ampoule in 10 mL saline) i.v. every 2–3 min until the respiratory rate improves.

Choice of opioid analgesic

An opioid may be preferred because of favourable experience, lower cost (methadone is least expensive), availability, route of administration or duration of action. Opioids with a short half-life (morphine and diamorphine) should be used as first-line agents for acute pain but may be replaced with longer-acting drugs if pain persists.

Knowledge of equi-analgesic doses of opioids is essential when changing drugs or routes of administration (Tables 18.3 and 18.4). Cross-tolerance between drugs is incomplete, so when one drug is substituted for another, the equi-analgesic dose should be reduced by 50%. The only exception is methadone, which should be reduced by 75–90%. Opioid rotation is commonly used in cancer-related and chronic non-malignant pain as a means of reducing side-effects and limiting the development of tolerance.

Table 18.3 Relative potency of opioids

Drug	Oral:parenteral potency ratio*	Parenteral potency relative to morphine**
Morphine	1:6	1.0
Codeine	2:3	0.1
Hydromorphone	1:5	6.0
Meperidine	1:4	0.15
Oxycodone	1:2	1.0
Methadone	1:2	1.0

* Oral–parenteral ratio: for example, morphine is six times more potent parenterally than orally.

** Potency relative to morphine: for example, hydromorphone is six times more potent than an equal dose of morphine when given parenterally.

(Mitchell J P 1989 General care of the patient. In: Claiborne D, Ridner M (eds) Manual of Medical Therapeutics, 26th edn. Little, Brown, p. 5.)

Table 18.4 Opioid oral analgesic equivalents

Analgesic	Single dose	Equi-analgesic dose Oral morphine
Codeine	60 mg	5 mg
Dihydrocodeine	60 mg	8 mg
Tramadol	50 mg	10 mg
Meptazinol	200 mg	8 mg
Buprenorphine sublingual	200 micrograms	10 mg
Hydromorphone	1.3 mg	10 mg
Methadone	1 mg	10 mg
Oxycodone	5 mg	10 mg

Tolerance, dependence and addiction

Although the use of strong opioid analgesics in cancer-related pain is well established, physicians are often reluctant to prescribe opioids in acute, and especially in chronic, non-malignant pain. Patients (and their families, friends and employers) are, likewise, wary about the long-term use of opioids. The reasons for this reluctance may stem from previous experiences of the genuine problems associated with long-term opioid use in patients or, more often, due to the perception of opioids as dangerous and addictive drugs. Patients and physicians also frequently confuse tolerance and dependence with drug addiction.

Tolerance

indicates the need to increase the dose of a drug with time to achieve the same analgesic effect. It is due to physiological adaptation to the drug. In practice, tolerance can be managed by increasing the dose of the opioid drug over time. Tolerance to the adverse effects of opioids (e.g. constipation) is often less predictable, and the development of side-effects may prevent further escalation of the drug.

It is important to distinguish a gradual reduction in efficacy of an analgesic that is due to the development of tolerance from the onset of pain due to progression of the underlying disease process or new pathology.

Dependence

is the physical manifestation of tolerance and its effects are observed soon after abrupt withdrawal of a long-term opioid. The severity of withdrawal symptoms varies depending on the patient, the drug and the length of treatment, and includes symptoms such as coryza, tremor, sweating, abdominal cramps, myalgia, vomiting and diarrhoea. Acute withdrawal can usually be avoided by reducing the drug dose gradually at the end of treatment by about 50% every 2 days (but may require a slower rate of withdrawal in some long-term patients). Patients on long-term opioid therapy should not be given mixed agonist/antagonist drugs, as they can precipitate withdrawal.

Addiction

is a behavioural problem characterised by drug-seeking activity in the individual in order to experience its psychotropic effects. This drug-seeking behaviour may persist despite the knowledge that continued use of the drug will result in considerable physical, emotional, social or economic harm. The incidence of addiction in patients taking opioid medications for acute pain is negligible, and is low even in patients on long-term opioids for chronic non-malignant pain (< 10%), provided that the patients are carefully screened for drug misuse potential and adequately monitored.⁴ The risk of iatrogenic addiction in patients prescribed opioids for cancer-related pain is believed to be extremely low.

Pain relief in opioid addicts

Drug addicts can suffer from pain. Physicians, particularly in hospitals, are often guilty of withholding or under-prescribing opioids for drug-addicted patients in acute pain. This stems from unfounded fears of ‘worsening’ the addiction, distrust of the patient’s motives or misguided attempts to ‘cure’ the patient of his addiction.

Before treating opioid addicts with acute pain, physicians should attempt to establish the patient’s daily opioid intake prior to hospital admission. The patient should then be maintained with an equivalent daily dose of opioid medication throughout their admission. Physicians should be aware that the strength of street drugs is highly variable. The addicted patient may also have an acute medical condition that alters opioid pharmacokinetics unpredictably. It is safer, therefore, to first prescribe an appropriate dose of an opioid with a short duration of action on an ‘as required’ basis, in order to assess opioid requirements, before conversion to longer-acting opioids for maintenance.

The opioid-addicted patient with acute pain will require appropriate analgesia in addition to the calculated maintenance dose. Non-opioid analgesics are useful adjuncts, but should not be used as a substitute for opioid analgesia. The use of opioid agonist–antagonist compounds in known or suspected active opioid addicts is absolutely contraindicated as these drugs may precipitate withdrawal.

Co-analgesics

Co-analgesics (adjuvant analgesics) are important for the treatment of cancer-related and chronic non-malignant pain. These agents provide an ‘opioid-sparing’ effect and are effective for the treatment of neuropathic pain associated with many cancers. In chronic non-malignant pain, co-analgesics are frequently used as ‘first-line’ drugs, and form the mainstay of treatment for chronic neuropathic pain. As co-analgesics are generally used in other medical conditions (e.g. as anticonvulsants or antidepressants), their basic pharmacology will be covered in the relevant chapters elsewhere. This chapter highlights the use of co-analgesics in the context of pain management.

Multipurpose adjuvant analgesics

Corticosteroids

Corticosteroids are among the most widely used adjuvant analgesics in palliative care. They improve quality of life in cancer patients by virtue of their analgesic effects and other beneficial effects on appetite, nausea, mood and malaise. Corticosteroids may also reduce oedema around metastases or damaged nerve plexuses. Patients with advanced cancer who experience pain and other symptoms often respond favourably to a relatively small dose of corticosteroid (e.g. dexamethasone 1–2 mg twice daily).

Neuroleptics

Methotrimeprazine has proven very useful in bedridden patients with advanced cancer who experience pain associated with anxiety, restlessness or nausea. In this setting, the sedative, anxiolytic and antiemetic effects of this drug can be useful, and side-effects, such as orthostatic hypotension, are less clinically significant. Treatment can be started at 6–25 mg/day in three divided doses at mealtimes and increased until optimum effect. Alternatively, as a sedative, a single night-time dose of 10–25 mg can be given.

Benzodiazepines

Benzodiazepines have limited analgesic effects but are often used as a short-term treatment for painful muscle spasm. Their use, however, must be balanced by the potential for side-effects, including sedation and confusion. With the important exception of clonazepam, which is widely accepted for use in the management of neuropathic pain, these drugs are generally prescribed only if another indication exists, such as anxiety or insomnia.

Adjuvant analgesics used in neuropathic pain

Antidepressants

At present, the evidence for analgesic efficacy is greatest for the tertiary amine tricyclic drugs, such as amitriptyline, doxepin and imipramine. The secondary amine tricyclic antidepressants (such as desipramine and nortriptyline) have fewer side-effects and are preferred when there are serious concerns about sedation, anticholinergic effects or cardiovascular toxicity. Dual-reuptake inhibitors (venlafaxine, duloxetine) may be beneficial for patients who obtain relief from tricyclics but find the adverse effects a problem. Duloxetine is currently licensed for the treatment of pain from diabetic neuropathy and fibromyalgia and has been shown to be effective in clinical trials. There is little evidence, however, to suggest that duloxetine is more efficacious compared to tricyclic antidepressant drugs for the treatment of neuropathic pain.

The dose of duloxetine required to treat pain is 60–120 mg, which also has clinically relevant antidepressant effects. This is in contrast to other antidepressant drugs used in neuropathic pain where the analgesic effect of the drugs occurs at a smaller dose and within a shorter time from onset (1–2 weeks) than any antidepressant effect. The drugs should be started at a low dose to minimise initial side-effects (e.g. amitriptyline 10 mg daily in the elderly and 10–25 mg daily in younger patients). Education of the patient is essential. They should be informed that the analgesic effect of the antidepressant medication can take days or weeks to develop, and that the drug must be taken on a regular basis for effect. It is common for patients to report taking the medication intermittently as a supplement to simple analgesics ‘when the pain is bad’. Patient compliance is often improved when physicians emphasise that the drugs are being prescribed for their analgesic effects and not for their antidepressant properties.

Abrupt withdrawal of the antidepressant drugs should be avoided as it can cause a variety of unpleasant symptoms, thought to be related to rebound cholinergic activity. These include vivid dreams, restlessness and gastrointestinal hyperactivity. These symptoms can be minimised if the drug dose is reduced gradually at intervals of 5–10 days.

Anticonvulsants

In 1853, Alfred Trousseau, then director of the medical clinic at the Hôtel-Dieu in Paris, suggested that painful paroxysms seen in trigeminal neuralgia were due to discharges in the trigeminal system that were similar to the neuronal discharges seen in epilepsy. Trousseau’s hypothesis was tested by Bergouigan who successfully used phenytoin to treat trigeminal neuralgia. Carbamazepine was studied in the same condition during a placebo-controlled double-blind design that was among the first of its kind in pain medicine. Since then, anticonvulsants have been extensively used in a wide variety of neuropathic pain syndromes, particularly those associated with ‘lancinating’ or ‘shooting’ pain. Animal studies have shown that peripheral nerve fibres in persistent pain syndromes have altered expression of certain ion channels, particularly novel sodium channels, and N-type calcium channels.

Carbamazepine, phenytoin and sodium valproate have been used for many years to treat neuropathic pain. However, carbamazepine remains the only anticonvulsant licensed within the UK for the treatment of trigeminal neuralgia. All anticonvulsants produce side-effects such as dizziness and drowsiness. Carbamazepine, in particular, may suppress bone marrow function and cause hyponatraemia. Its use requires regular blood monitoring.

Gabapentin and pregabalin are newer anticonvulsant agents that show good efficacy in clinical trials of neuropathic pain. These drugs bind to the α₂δ-1 subunit of voltage-dependent calcium channels and may work by preventing the formation of excitatory synapses within the central nervous system.⁵ Gabapentin is generally better tolerated than the older anticonvulsants and has a licence in the UK for the treatment of neuropathic pain. It is not metabolised by the liver and has few clinically significant drug interactions. It should be started at a dose of 300 mg at night (100 mg in the elderly) and titrated upwards as tolerated or to a dose of 600–1200 mg three times daily. A saturable gut transport mechanism limits bio-availability at high oral doses (but also protects against overdosage). Pregabalin shares a similar mode of action to gabapentin, but has the advantage of more linear pharmacokinetics and can be given as a twice daily preparation (normal maintenance dose up to 300 mg twice daily).