In this chapter and throughout this text, we have adopted the following conventions in terminology.

Opiate is a specific term that is used to describe drugs derived from the juice of the opium poppy. For example, morphine is an opiate but methadone (a completely synthetic drug) is not.(4)

Opioid is a general term that includes naturally occurring, semi-synthetic, and synthetic drugs which produce their effects by combining with opioid receptors and are stereospecifically antagonized by naloxone. In this context we refer to opioid agonists, opioid antagonists, opioid peptides, and opioid receptors.

Narcotic is commonly used to describe morphine-like drugs and other drugs of abuse. The term is derived from the Greek narke, meaning numbness or torpor. Since this is an imprecise and pejorative term that is not useful in a pharmacological context, its use with reference to opioids is discouraged. The term narcotic is not used in this book.

Opioids are agonists at highly specific receptor sites, and there is general agreement on the existence of at least three types of opioid receptor: the morphine receptor µ (mu), the κ (kappa) receptor at which the prototype agonist is ketocyclazocine, and the enkephalin receptor δ (delta). A fourth receptor, σ (sigma), was originally included in this group. However, actions mediated through σ receptors are not reversed by naloxone so it is not a true opioid receptor. The µ receptors have been further sub-classified into two distinct sub-types (µ1 and µ2), as have the δ receptors (δ1 and δ2). Kappa receptors have been divided into κ1, κ2, and κ3 sub-types. Recently, several of these receptors have been successfully cloned.

In animal models, some laboratories have cloned up to 10µ receptor sub-types.(5) However, the functional significance of these ‘spliced variants’ remains unclear at present

Table 1 shows the putative effects mediated by the three main opioid receptors.(6) This classification is based on the original description by Martin et al.(7) The effects presumed to be mediated at µ receptors have been defined as a result of both human and animal studies, while the effects mediated at κ receptors derive predominantly from animal models. κ receptors mediate analgesia that persists in animals made tolerant to δ agonists; κ agonists produce less respiratory depression and miosis than µ agonists. It is assumed that opioid receptors mediate the sedative and mental clouding effects of opioids, in addition to their other pharmacological actions.

Opioid receptors are found in several areas of the brain, particularly in the periaqueductal grey matter, and throughout the spinal cord. Supra-spinal systems have been described for µ1, κ3, and δ2 receptors, whereas µ2, κ1, and δ1 receptors modulate pain at the spinal level.(8) Our understanding of the effect profiles of opioid receptors remains incomplete, as new advances make it clear that their disposition and structure are extremely complex.

Molecular biology techniques have enabled the primary amino acid sequence of the human µ,κ, and δ opioid receptors to be determined. The pharmacological and functional properties of the cloned receptors, the development of ‘knockout’ animals (which are deficient in a receptor or part of a receptor), and the manipulation and substitution of various amino acids in critical domains of the various opioid receptors are providing new information on receptor function and organization that will lead to an increased understanding of opioid neurotransmission at the molecular level and of the factors controlling the development of responses to opioid drugs.

The three opioid receptor genes, encoding mu (MOR), delta (DOR), and kappa (KOR) have been cloned. The binding affinities of a range of opioids to the µ-, κ-, and δ-opioid receptors and also to the cloned µ receptor have been examined in animals. The animal data indicate that while the commonly prescribed opioids (agonists and antagonists) bind preferentially to the µ receptor, they also interact with all three receptor types. Morphine and normorphine (a minor metabolite of morphine) show the greatest relative preference for the µ receptor. Methadone (which also has some NMDA-receptor blocking activity) shows significant binding to δ receptors, while buprenorphine, and to a lesser extent naloxone, avidly bind to all three receptor types. There is evidence (albeit inconsistent) that the D-enantiomer of methadone blocks the NMDA receptor. The binding affinity of buprenorphine to the µ receptor is much greater than that of naloxone, which explains why the latter only partially reverses buprenorphine toxicity.

Animal data also indicate that codeine and diamorphine have very poor binding to opioid receptors, which reinforces the possibility that both are prodrugs where the pharmacologically active species are morphine(9) and 6-monoacetyl morphine,(10) respectively. Oxycodone may also act through an active metabolite, though there are some data which suggest that this is not the case.(11)

Pethidine is considered to be a potent µ receptor agonist, but it does bind weakly to all three opioid receptors. Ketobemidone has a lower affinity for the µ receptor than does morphine, but it shows greater discrimination for this receptor compared to κ receptors. The binding of both of these opioids to the δ receptor is similar.(12)

The binding of morphine, methadone, buprenorphine, and naloxone to the cloned human µ receptor shows excellent congruence with the animal data.(13,14) Fentanyl shows a similar binding affinity, while codeine demonstrates greater binding affinity to the cloned human receptor. Thus, for these commonly administered opioids, there is no great variability in their affinity for the human µ receptor.

The clinical relevance of these data is that different opioids act in different ways. We are aware too from anecdotal clinical experience that there is considerable interindividual variability in response to each opioid and this reinforces our need to assess an individual's response to opioid analgesia carefully. It would be premature to extrapolate from laboratory data, which in many instances have not yet been replicated, to the clinic. However, these data increasingly inform the clinical use of these drugs and will be particularly relevant to new approachs to their use such as ‘opioid switching’.

Based on their interactions with the various receptor sub-types, opioid compounds can be divided into agonist, agonist–antagonist, and antagonist classes (Table 2).

Relative potency is the ratio of the doses of two analgesics required to produce the same analgesic effect. By convention the relative potency of each of the commonly used opioids is based upon a comparison with 10 mg of parenteral morphine. Data from single- and repeated-dose studies in patients with acute or chronic pain have been used to develop an equianalgesic dose table (Table 3) that provides guidelines for dose selection when the drug or route of administration is changed. The information contained in the equianalgesic dose table does not represent standard doses, nor is it intended as an absolute guideline for dose selection. Many variables may influence the appropriate dose for an individual patient, including intensity of pain, prior opioid exposure in terms of drug, duration, and dose (and the degree of cross-tolerance that this confers), age, route of administration, level of consciousness, metabolic abnormalities (see below), and genetic polymorphism in the expression of relevant enzymes or receptors.

As noted above, there is no ceiling to the analgesic effects of full agonist opioids. As the dose is raised, analgesic effects increase as a log linear function. In practice, the appearance of adverse effects, including confusion, sedation, nausea, vomiting, or respiratory depression, imposes a limit on the useful dose of an opioid agonist. Thus the efficacy of any particular drug in an individual patient will be determined by the degree of analgesia produced following dose escalation to intolerable and unmanageable side-effects.

An expert committee convened by the Cancer and Palliative Care Unit of the World Health Organization (WHO) proposed a structured approach to drug selection for cancer pain, which has become known as the ‘WHO analgesic ladder’.(16) When combined with appropriate dosing guidelines, this approach is capable of providing adequate relief to 70–90 per cent of patients.(17,18,19,20,21,22 and 23) Emphasizing that the intensity of pain, rather than its specific aetiology, should be the prime consideration in analgesic selection, the approach advocates three basic steps (Fig. 3):

According to these guidelines, a trial of opioid therapy should be given to all patients with pain of moderate or greater severity.

The evidence of the long-term efficacy of this approach and the evidence base underlying its recommendations has been the subject of criticism.(26) Several other developments have also contributed to a reevaluation of the WHO ladder. The introduction of low-dose formulations of opioid agonists traditionally used for severe pain, and of other agents such as tramadol has widened the repertoire of agents suitable for the management of moderate pain (step 2). Indeed, many authorities now advocate the use of the same opioid for all pains of moderate or greater intensity.(27,28,29 and 30)

Despite these reservations, the guiding principle that analgesic selection should be primarily determined by the severity of the pain remains sound, and continues to be widely endorsed.(1,27,31)

The division of opioid agonists into ‘weak’ or ‘strong’ opioids, which was incorporated into the original analgesic ladder proposed by the WHO, was not based on fundamental differences in their pharmacology, but rather reflected the customary manner in which these drugs were used. In this chapter we will refer to opioids for mild to moderate pain and opioids for moderate to severe pain rather than ‘weak’ or ‘strong’ opioids. This terminology is now incorporated into the current version of the WHO analgesic ladder.

Codeine (methylmorphine) is a naturally occurring opium alkaloid used as an analgesic, antitussive, and antidiarrhoeal agent (Fig. 4). Codeine is much less potent than morphine and produces its analgesic effects in part by binding to µ opioid receptors but with low affinity and, in part through biotransformation to morphine by cytochrome P-450 CYP2D6 (sparteine oxygenase) which exhibits genetic polymorphism. Approximately 7 per cent of Caucasians lack CYP2D6 activity (poor metabolizers) due to inheritance of two non-functional alleles and in these individuals codeine has a diminished analgesic effect.(32,33)

Codeine phosphate is absorbed well from the gastrointestinal tract, but oral bioavailability varies considerably between individuals (from 12 to 84 per cent in one study(34)). The main metabolite is codeine-6-glucuronide, with much smaller amounts of norcodeine, morphine, and morphine 3- and 6-glucuronides also being produced.(35) The usual oral dose of codeine is 30–60 mg and its duration of action is 4–6 h.

Codeine is not generally given as a single agent when used orally as an analgesic, but is usually combined with a non-opioid and recent systematic reviews confirm that the combination of codeine and paracetamol is more effective that paracetamol alone.(36,37) A sustained-release formulation of codeine is available in some countries. When changing from regular administration of a codeine/non-opioid combination to morphine, patients receiving a total daily dose of 240–360 mg codeine are usually started on 60 mg morphine daily.

Dihydrocodeine is a semi-synthetic analogue of codeine that is used as an analgesic, antitussive, and antidiarrhoeal agent. When administered by mouth, dihydrocodeine is equianalgesic to codeine. However, when administed parenterally it is approximately twice as potent as codeine. This may be explained by the consistently poorer bioavailability of dihydrocodeine (20 per cent), which probably results from hepatic presystemic metabolism.(38)

The usual starting dose is 30 mg every 4–6 h (by mouth), and this may be increased to 60 mg. However, dihydrocodeine appears to have a narrower therapeutic index than codeine, with a high incidence of adverse effects at the 60-mg dose. A controlled-release formulation of dihydrocodeine is available in several countries.

There have been a number of reports of severe toxicity associated with dihydrocodeine in patients with impaired renal function.(39,40) The mechanism is not clear because of the limited data available on the pharmacokinetics of this drug, although it seems most likely that the cause is accumulation of active glucuronide metabolites, as occurs with morphine.

There is confusion about the relative analgesic potency of dihydrocodeine. It seems reasonable to assume that oral dihydrocodeine is roughly equipotent to oral codeine, and to use a similar conversion ratio when changing to morphine.

Propoxyphene is a synthetic derivative of methadone, and its dextrorotatory stereoisomer dextropropoxyphene is responsible for its analgesic activity. Dextropropoxyphene is a µ agonist with low receptor affinity similar to that of codeine. It is readily absorbed from the gastrointestinal tract with peak serum levels about 2 h after administration. The mean elimination half-life is about 12 h, with steady state levels being reached after 3–4 days of regular administration every 6–8 h. The half-life may be very long (over 50 h) in elderly patients.(41)

Dextropropoxyphene undergoes extensive first-pass metabolism. Its principal metabolite is norpropoxyphene, which is active but penetrates the brain to a much lesser extent and has much weaker opioid effects. Norpropoxyphene has a longer half-life (about 23 h) than dextropropoxyphene itself and
accumulates in plasma.(42) Norpropoxyphene accumulation is associated with excitatory effects, including tremulousness and seizures.

The analgesic efficacy and relative potency of dextropropoxyphene have been questioned. This is in part because single-dose studies comparing aspirin, paracetamol, and non-steroidal anti-inflammatory drugs (NSAIDs), including ibuprofen 400 mg, mefenamic acid 250 mg, and fenoprofen 50 mg, have shown dextropropoxyphene to be a less effective analgesic.(43) A more recent systematic review found that paracetamol alone is as effective as the combination of paracetamol with dextropropoxyphene,(44) though the studies included were again all single-dose studies. Single-dose studies may be misleading, as is the case with single-dose studies of oral morphine.

The extensive first-pass metabolism of dextropropoxyphene is dose dependent such that the systemic availability of the drug increases with increasing oral doses.(45) Thus, with regular administration, there is enhanced bioavailability and some degree of accumulation because of the long elimination half-lives of the parent drug and its main metabolite. Both dextropropoxyphene and norpropoxyphene reach plasma concentrations in the steady state which are five to seven times greater than those found after the first dose. There is therefore a pharmacokinetic basis for believing that repeated doses of dextropropoxyphene are likely to be more effective than single doses. The usual starting dose of morphine for patients receiving dextropropoxyphene–paracetamol combinations every 4–6 h (representing 260–390 mg of dextropropoxyphene daily) is 60 mg per day.

Oxycodone is a semi-synthetic congener of morphine, which has been on the market for 80 years but until recently was only available in formulations which effectively circumscribed its use. In the United States, it has been prescribed in low-dose combination products with a non-opioid for oral administration (usually 5 mg of oxycodone with either aspirin or paracetamol) and has traditionally been used as a step 2 analgesic. In the United Kingdom and some other countries only a rectal suppository and no oral formulations have been available, so that it has been used only for patients unable to take oral medication.(51) Oxycodone has been more widely used by mouth as a first line step 3 opioid in Scandinavia where it has also been widely used as a post-operative opioid.(52) Recently, oxycodone has been produced as a single agent in new oral formulations, both normal release and sustained release, which has substantially improved the convenience of administration. In many countries sustained release oxycodone is available in 5, 10, 20, 40, and 80 mg formulations with a corresponding range of normal release formulations. Oxycodone is increasingly used as a step 3 opioid,(53,54 and 55) though the low-dose formulations allow its use at step 2 also. Oxycodone probably provides the best example of the overlap in efficacy between opioids at steps 2 and 3.

Tramadol is a centrally acting analgesic which possesses opioid agonist properties and may also activate monoaminergic spinal inhibition of pain.(56) It has modest affinity with µ opioid receptors, with weak affinity to δ and κ receptors, and its analgesic effect is reversed by naloxone. Unlike other opioids, it also inhibits the uptake of noradrenaline and serotonin, and in an animal model systemically administered yohimbine or ritanserin blocks tramadol-induced analgesia,(56) suggesting that this effect contributes significantly to the drug's analgesic action.

Tramadol can be administered orally, rectally, intravenously, subcutaneously, or intramuscularly. In many countries, it is available in both normal- and sustained-release formulations. Parenterally, 50–150 mg of tramadol is equianalgesic to 5–15 mg morphine.(57) There are insufficient data for a reliable assessment of its oral to parenteral relative analgesic potency and estimates range from 1 : 4(58) to 1 : 10.(59)

Recent studies have demonstrated the efficacy of oral tramadol in the management of chronic cancer pain of moderate severity.(58,59 and 60) Few patients with severe pain are adequately managed by tramadol.(59,61) Tramadol has a similar side-effect profile to morphine, but may cause less constipation and respiratory depression at equianalgesic doses.

The morphine-like agonist drugs (Table 2) are widely used to manage cancer pain. Although they may differ from morphine in quantitative characteristics they qualitatively mimic the pharmacological profile of morphine, including both desirable and undesirable effects. Controversy has developed over the choice of an opioid drug, in part because of the dearth of well-controlled studies comparing the efficacy and side-effects of these drugs during chronic administration, and in part because of the large amount of survey data and anecdotal reports supporting one drug over another.

Clinicians in most countries have some choice when selecting which opioid drug(s) to prescribe, but the options can vary from country to country.

Morphine is still considered to be the opioid drug of choice by many practitioners(30) and has occupied this place throughout recorded history. However, some of the other potent µ receptor agonists are gaining popularity for a variety of reasons. While greater choice is very important in analgesic therapy, it should not be forgotten that morphine is an excellent analgesic and maintains a key position and reference point for all opioids in our therapeutic armamentarium. Similarly, while there is theoretical evidence (on the basis of receptor binding profiles) that opioid combinations may give optimum analgesia with a more favourable side-effect profile, there is as yet no good clinical evidence to support such treatment strategies which are likely to be appropriate only in rare situations.

Morphine is a potent µ-agonist drug that was first introduced into clinical use almost 200 years ago. It is the main naturally occurring alkaloid of opium derived from the poppy Papaver somniferum and is available for therapeutic use as the sulphate, hydrochloride, and tartrate. Recent evidence suggests that biosynthetic pathways for morphine exist in animal and human tissues such as liver, blood, and brain.(67) Its chemical structure is shown in Fig. 4. The WHO has placed oral morphine on the Essential Drug List, and preparations are available for oral, rectal, parenteral, and intraspinal administration.

Single-dose studies of morphine in post-operative cancer patients demonstrated an oral-to-intramuscular potency ratio of 1 : 6.(92) However, empirical clinical practice using chronically administered oral morphine in cancer patients has generated a different ratio of 1 : 3 or 1 : 2.(93,94) The reason for the discrepancy between relative potency estimates derived from single-dose versus chronic dosing studies is probably associated with both methodology(95) and the pharmacokinetics and pharmacodynamics of M6G.(93) It is possible that M6G accumulation relative to morphine may be greater with oral than with parenteral administration; this would lead to an increase in the relative potency of the orally administered drug when given on a chronic basis.

The important principle for clinical practice is that there is a difference in relative analgesic potency when the route of administration is changed, and that adjustment of dose is necessary in order to achieve an equivalent effect and to avoid either underdosing or toxicity. The usual practice when converting from oral morphine to subcutaneous morphine (or diamorphine) is to divide the oral dose by two or three.(30)

Diamorphine (diacetylmorphine) is a semi-synthetic analogue of morphine and has a long tradition of use for cancer pain in the United Kingdom. It is only available for legal medicinal use in the United Kingdom and Canada.

Following oral administration of diamorphine, only morphine can be measured in the patient's blood. The use of oral diamorphine is an inefficient way of delivering morphine to the systemic circulation. There is no good basis to believe that there is any difference between these two drugs when given by mouth. Sublingual administration of diamorphine has been advocated by some but, as discussed below, this route is not appropriate for either morphine or diamorphine because of poor absorption.

It has been thought that diamorphine does not itself bind to the µ opioid receptor but must be biotransformed to 6-acetylmorphine and morphine to produce its analgesic effect.(101) However, recent studies with mor-knockout mice seem to indicate that it does not produce its effects through µ receptor binding and may have effects at other receptors.(102) This may explain some of the pharmacodynamic differences between morphine and diamorphine when given parenterally.

Since diamorphine is more soluble and lipophilic than morphine, it does have some advantages for parenteral administration. When administered by subcutaneous or intramuscular injection, diamorphine is approximately twice as potent as morphine. There are also differences between diamorphine and morphine administered by intravenous injection: diamorphine has a marginally quicker onset of action, produces greater sedation, and possibly less vomiting.(103) This may be explained by different receptor binding. The greater solubility of diamorphine (shared also with hydromorphone and morphine tartrate) is of particular advantage for patients who require large doses of subcutaneous opioids.

Methadone is a synthetic opioid with an oral-to-parenteral potency ratio of 1 : 2 and an oral bioavailability greater than 85 per cent. In single-dose studies, methadone is only marginally more potent than morphine; however, with repeated administration it is several times more potent. Methadone has a very long plasma half-life, averaging approximately 24 h (with a range from 12 to over 150 h).(104,105) Whereas most patients can be well controlled on 8–12-h dosing, some patients require dosing at a 4–8-h interval to maintain analgesic effects.(106) Methadone may be a useful alternative to morphine, but its safe administration requires knowledge of its pharmacology and experience of its use.

After treatment is initiated or the dose is increased, plasma concentration rises over a prolonged period, and this may be associated with a delayed onset of side-effects. Consequently, patients must be followed closely until there is reasonable certainty that a steady state plasma concentration has been approached (approximately 1 week). Serious adverse effects can be avoided if the initial period of dosing is accomplished with ‘as needed’ administration.(107) When steady state has been achieved, scheduled dose frequency should be determined by the duration of analgesia following each dose.(108)

Oral and parenteral preparations of methadone are available. Subcutaneous infusion is possible(109) but caution is required since local skin toxicity may be a problem.(110)

The equianalgesic dose ratio of morphine to methadone has been a matter of confusion and controversy. Recent data from crossover studies with morphine and methadone and hydromorphone and methadone indicate that methadone is much more potent than previously described in literature, and that the ratio correlates with the total opioid dose administered before switching to methadone.(111) Among patients receiving low doses of morphine, the ratio is 4 : 1. In contrast, for patients receiving more
than 300 mg of oral morphine (or parenteral equivalent) the ratio is approximately 10 : 1 or 12 : 1.(111)

Pethidine is a synthetic opioid with agonist effects similar to those of morphine but a profile of potential adverse effects that limits its utility as an analgesic for chronic cancer pain. Intramuscular pethidine 75 mg is equivalent to 10 mg of intramuscular morphine. Pethidine has an oral bioavailability of 40–60 per cent, and its oral-to-parenteral potency ratio is 1 : 4. It is more lipophilic than morphine, and produces a faster onset and shorter duration of analgesia of 2–3 h.

Pethidine is N-demethylated to norpethidine, which is an active metabolite that is twice as potent as a convulsant and half as potent as an analgesic compared with its parent compound. Accumulation of norpethidine after repetitive dosing of pethidine can result in central nervous system excitability characterized by subtle mood effects, tremors, multifocal myoclonus, and occasionally, seizures.(112,113) Naloxone does not reverse pethidine-induced seizures, and it is possible that its administration to patients receiving pethidine chronically could precipitate seizures by blocking the depressant action of pethidine and allowing the convulsant activity of norpethidine to become manifest.(114) If naloxone is necessary in this situation, it should be diluted and slowly titrated while appropriate seizure precautions are taken. Selective toxicity of pethidine can also occur following administration to patients receiving monoamine oxidase inhibitors. This combination may produce a syndrome characterized by hyperpyrexia, muscle rigidity, and seizures which may occasionally be fatal.(115) The pathophysiology of this syndrome is related to excess availability of serotonin at the 5HT_1A-receptor in the central nervous system.

Although accumulation of norpethidine is most likely to affect patients with overt renal disease, toxicity is sometimes observed in patients with normal renal function. These potential adverse effects contraindicate pethidine for the management of chronic cancer pain.
Given the availability of alternative drugs that lack these toxicities, its use in acute pain management is also not recommended.(117)

Hydromorphone is another morphine congener. It is five times more potent than morphine and can be administered by the oral, rectal, parenteral, and intraspinal routes. Its oral bioavailability varies from 35 to 80 per cent, and its oral-to-parenteral potency ratio is 1 : 5.(118) Its half-life is 1.5–3 h and it has a short duration of action. Although it is largely excreted unchanged by the kidney, it is partially metabolized in the liver to a 3-glucuronide, which is excreted by the kidneys.(118,119)

Its solubility, the availability of a high-concentration preparation (10 mg/ml), and high bioavailability by the subcutaneous route (78 per cent) make it particularly suitable for subcutaneous infusion.(120) In the United States, it is routinely available in oral, rectal, and injectable formulations, and a sustained-release oral formulation.(121) For patients who require very high opioid doses via the subcutaneous route, hydromorphone can be constituted in concentrations of up to 50 mg/ml from lyophilized powder. It has also been administered via the epidural and intrathecal routes to manage acute and chronic pain. Hydromorphone is hydrophilic and, when administered via the epidural route, its pharmacokinetic profile, including its long half-life and extensive rostral distribution in cerebrospinal fluid, is similar to that of morphine.(122)

The equianalgesic ratio of parenteral morphine to hydromorphone has become a matter of controversy; recent data suggests that for chronic dosing it is less than the traditionally quoted ratio of 1 : 7 and that it is probably closer to 1 : 4.(123,124)

Levorphanol is a morphine congener with a long half-life (12–16 h).(125) It is five times more potent than morphine and has an oral-to-parenteral potency ratio of 1 : 2.(126) Like methadone, the discrepancy between plasma half-life (12–16 h) and duration of analgesia (4–6 h) may predispose to drug accumulation following the initiation of therapy or dose escalation. Although dose titration needs to be done carefully in the opioid-naive patient, problems with drug accumulation appear to be less than those produced by methadone.

In the United States, levorphanol is generally used as a second-line agent in patients with chronic pain who cannot tolerate morphine. The possibility that this drug may be particularly useful in morphine-tolerant patients has been proposed on the basis of its affinity for receptors κ3 and δ that are presumably not involved in morphine analgesia.(127) It is no longer available in the United Kingdom or Canada.

As previously described, oxycodone is a synthetic morphine congener that has a high oral bioavailability (60–90 per cent) and an analgesic potency 30–50 per cent greater than morphine.(128,129) Since the development of sustained release formulations in doses suitable for severe pain, it is now widely used for this indication. The sustained release formulation is available in a wide range of dose formulations (5, 10, 20, 40, and 80 mg)(55) and has a duration of action of 8–12 h. The sustained-release formulation achieves effective therapeutic levels within an hour(130) and appears to be suitable for dose titration.(131) Oxycodone pectinate is available in the United Kingdom as a 30-mg rectal suppository which has a delayed absorption and prolonged duration of effect.(51)

There has been confusion about the relative efficacy of oxycodone. Until recently, it has been viewed primarily as a ‘step 2’ opioid because it has for long been available in low dose in combination products with non-opioid analgesics. It seems clear that the relative potency of oxycodone has been underestimated in early clinical studies in which it appeared to be less potent than morphine. As indicated above more recent studies indicate that it is more potent, in a ratio of about 1.5 : 1.(128)

There remains uncertainty also about the role of its active metabolite oxymorphone in mediating the effects of oxycodone. However, current evidence suggests that the metabolites of oxycodone including oxymorphone do not contribute significantly to its pharmacological effects.(11)

Oxymorphone is a lipophilic congener of morphine. It is currently most widely used in suppository form, infrequently used parenterally on a chronic basis, and is not available orally. The injectable formulation is 10 times more potent than morphine.(132) A rectal formulation that is approximately equipotent with parenteral morphine is also available in the United States. The plasma half-life of oxymorphone is 1.2–2 h, and its duration of action is 3–5 h. It is less likely to produce histamine release than morphine,(133) and may be particularly useful for patients who develop itch in response to other opioids.(134) Oxymorphone is currently not available in the United Kingdom.

Fentanyl is a semisynthetic opioid and is a highly selective µ agonist(135) that is about 80 times as potent as parenteral morphine in the non-tolerant acute pain patient. It is also extremely lipophilic and is extensively taken up into fatty tissue.(136) Its elimination half-life ranges from 3 to 12 h and is influenced by the duration of prior administration and the extent of fat sequestration. Fentanyl has been used mainly as an intravenous anaesthetic agent and continues to be used parenterally as a pre-medication for painful procedures and in continuous infusions. When used intravenously, fentanyl has a very short duration of action of 0.5–1 h. This is related to the rapid redistribution of the drug into body tissues rather than to hepatic and renal elimination.(137) The development of a transdermal system and an oral transmucosal formulation has broadened the clinical utility of fentanyl for the management of cancer pain.

The agonist–antagonists produce analgesia in the opioid-naive patient but may precipitate withdrawal in patients who are physically dependent on morphine-like drugs. Therefore, when used for chronic pain, they should be tried before repeated administration of a morphine-like agonist drug.

Pentazocine, butorphanol, and nalbuphine are µ antagonists and κ agonists or partial agonists. All three drugs are strong analgesics when given by injection: pentazocine is one-sixth to one-third as potent as morphine, nalbuphine is roughly equipotent with morphine, and butorphanol is 3.5–7 times as potent. The duration of analgesia is similar to that of morphine (3–4 h). Oral pentazocine is closer in analgesic efficacy to aspirin and paracetamol than the weak opioid analgesics, such as codeine. Neither nalbuphine nor butorphanol is available as an oral formulation, and butorphanol is no longer available in any form in the United Kingdom.

At usual therapeutic doses, nalbuphine and butorphanol have respiratory depressant effects equivalent to that of morphine (although the duration of such effects may be longer with butorphanol). Unlike morphine, there appears to be a ceiling to both the respiratory depression and the analgesic action.

All three drugs have a lower abuse potential than the agonist opioid analgesics such as morphine. However, all have been subject to abuse and misuse, and pentazocine (but not the others) is subject to controlled drug restrictions. In North America, the oral preparation of pentazocine is marketed in combination with naloxone (but is available without naloxone elsewhere).

Meptazinol is a synthetic hexahydroazepine derivative with opioid agonist and antagonist properties, but is unlike either the nalorphine-type agonist–antagonists or buprenorphine. Meptazinol has central cholinergic properties which may account at least in part for its analgesic effects. Receptor binding studies show it to be a specific µ1 agonist. Meptazinol is one-tenth as potent as morphine by intramuscular injection and has a duration of action of about 4 h. Some studies have shown adverse effects to be more frequent than with morphine, although respiratory depression and constipation appear to be less.

In therapeutic doses, the mixed agonists–antagonists may produce certain self-limiting psychotomimetic effects in some patients; pentazocine is the most common drug associated with these effects. These drugs play a very limited role in the management of chronic cancer pain because the incidence and severity of the psychotomimetic effects increase with dose escalation, and nalbuphine and butorphanol are only available for parenteral use.

A transnasal formulation of butorphanol is now on the market in the United States, but there is no reported experience of its use in the management of chronic cancer pain.

Buprenorphine (Table 2) is a semi-synthetic derivative of thebaine and chemically closely related to the strong agonist etorphine. Buprenorphine is a true partial agonist at the µ receptor and exhibits a ceiling effect in dose response curves in various animal models. In some, a bell-shaped curve is seen, indicating that at doses above a certain level the pharmacological effect actually decreases with increasing dose.(152) Buprenorphine has until recently only been available by injection or for sublingual administration. A dose of 0.4 mg sublingually gives similar analgesia to 0.2–0.3 mg intramuscularly, with an onset of analgesia within 30–60 min of administration and a duration of 6–9 h.(153) In contrast, if taken orally, buprenorphine is a poor analgesic due to extensive presystemic elimination.(154) The long duration of analgesia with buprenorphine may be related to its affinity for the µ-opioid receptor and an unusually slow dissociation constant for the drug–receptor complex.

Buprenorphine has been in clinical use for more than 25 years and has been evaluated in a variety of acute pain models. Direct single dose comparisons with other analgesics such as morphine is complicated by its long duration of action, but results from a number of studies in post-operative pain suggest that single doses of 0.3 mg buprenorphine parenterally or 0.4 mg sublingually give equivalent analgesia to 10–15 mg intramuscular morphine. A ceiling effect for analgesia in humans has not been clearly demonstrated.

Buprenorphine produces typical opioid adverse effects. Overall the available data (which is limited) suggest that the incidence of common adverse effects compared with morphine is similar. Naloxone appears to be relatively ineffective in reversing opioid effects due to buprenorphine.(155) Co-administration of buprenorphine to patients receiving high doses of a morphine-like agonist may precipitate withdrawal symptoms.

Buprenorphine was introduced in high-dose sublingual tablet formulations in 1999 for the management of drug dependence. This potential use of the drug has long been recognized(156) and it has been suggested that there is less overdose risk compared with other opioids.(157)

Buprenorphine has been recently introduced in a patch for transdermal administration. The drug is incorporated in a polymer adhesive matrix (with no liquid reservoir). Three patch sizes are available delivering 35, 52.5, and 70 µg buprenorphine per hour, and each lasts for 3 days. Therapeutic plasma concentrations are achieved within 11–21 h and steady state between the second and third applications of the patch. At usual clinical doses of 3–4 mg per 24 h buprenorphine functions as a pure µ agonist.

Transdermal buprenorphine has been licensed for use in both cancer pain and non-cancer pain but clinical experience with this formulation is limited.

A trial of opioid therapy should be given to all patients with pain of moderate or greater severity, irrespective of the underlying pathophysiological mechanism. As discussed in Chapter 8.2.11, the suggestion that some forms of pain, such as neuropathic pain, are intrinsically refractory to opioid analgesia has been refuted by several studies that demonstrate that pain mechanisms do not accurately predict analgesic outcome from opioid therapy.(158) Given the variability of response, all opioid trials in the clinical setting should include dose titration until adequate analgesia occurs or intolerable adverse effects supervene. This approach will identify those responders who can gain substantial clinical benefit from opioid therapy.

Patients whose pain is not easily controlled with an opioid analgesic because of troublesome adverse effects may benefit from alternative strategies and these are discussed below.

The factors that influence opioid selection include pain intensity, pharmacokinetic considerations and available formulations, previous adverse effects, and the presence of co-existing disease.

Opioids should be administered by the least invasive and safest route capable of providing adequate analgesia. In a survey of patients with advanced cancer, more than half required two or more routes of administration prior to death, and almost a quarter required three or more.(165)

As described above, when changing from the oral to parenteral routes, or vice versa, an adjustment in dose is required to avoid either toxic effects or a reduction in analgesia. The ratios of oral to parenteral relative potency given in Table 3 are estimates and should not be taken as precise figures but used as guidelines to achieve a roughly equianalgesic effect. There is considerable variation between patients, and upward or downward adjustment may then be required for individual patients. The slower onset of analgesia after oral administration often requires some adaptation on the part of a patient who is accustomed to the more rapid onset seen after parenteral opioid. In some patients, the problems associated with switching from the parenteral to the oral route of opioid administration may need to be minimized by slowly reducing the parenteral dose and increasing the oral dose over a 2–3-day period.

Usually, no dose adjustment is required when patients are switched from the subcutaneous to the intravenous route or vice versa.

Adverse symptoms in patients taking opioids are not always caused by the opioid. Drug induced effects must be differentiated from other causes and from drug interactions (Table 2). Indeed, the appearance of a new adverse change in patient well-being that occurs in the setting of stable opioid dosing is rarely caused by the opioid, and an alternative explanation should be vigorously sought.

In general, four different approaches to the management of opioid adverse effects have been described:

Among patients receiving opioid analgesic therapy, there are two key steps in the initial management of adverse effects. First, the clinician must distinguish between morphine adverse effects and co-morbidity or drug interactions, and deal with the latter appropriately. In patients with advanced cancer, side-effects due to drug combinations are common. The potential for additive side-effects and serious toxicity from drug combinations must be recognized. The sedative effect of an opioid may add to that produced by numerous other centrally acting drugs, such as anxiolytics, neuroleptics, and antidepressants.(223) Likewise, drugs with anticholinergic effects probably worsen the constipating effects of opioids.

If it seems that there is a true adverse effect of the opioid, consideration should be given to reducing the opioid dose. If the patient has good pain control, the morphine dose should be reduced by 25 per cent.

The ability to continue driving is very important to maintaining the quality of life of many patients with advanced cancer. Many assume that they must stop driving whilst taking regular potent opioid analgesics, but this is not necessarily so. The usual advice to patients is that they should not drive or engage in other skilled activities such as operating machinery when they first start on morphine or a similar opioid, or when they increase the dose. However, once the initial sedative effects have resolved and both the patient and physician are confident that cognitive and psychomotor performance are no longer impaired, driving and other similar activities may restart.

This advice is based to a large extent on empirical experience and there have been few objective data to substantiate it. However, recent studies confirm, perhaps surprisingly, that morphine produces little measurable impairment of cognitive and psychomotor function,(228) particularly in patients receiving continuous treatment with stable doses.(229) In one study, which used a battery of performance tests designed specifically to assess functions related to driving ability, chronic morphine use was associated with slower reaction times, more mistakes, and a slowing in ability to process visual information and perform motor sequences, but these changes were not statistically significant compared with a control group of cancer patients not taking morphine.(225) These data support the clinical impression that stable doses of morphine are unlikely to cause substantial impairment of the psychomotor skills required for driving, and allow us to continue to advise patients to this effect.

Morphine and other opioids cause histamine release, and this is said to contribute to asthma or urticaria in allergic patients.(133,230,231) There is no published information on the incidence of this phenomenon and, in our experience, it is very rare.

However, it is not uncommon for patients to claim that they are ‘allergic’ to morphine. This usually means that they have had a bad experience with the drug but, on investigation, what they describe are its common side-effects. There is no doubt that most patients experience some adverse effects when they first start regular morphine treatment. Most commonly this is sedation, nausea, and, less often, vomiting. All patients must be warned about this and appropriate measures must be taken, as described above. If patients are not warned and experience unpleasant adverse effects they will be discouraged from continuing with the drug, and if they do not understand what is going on they may assume they that are ‘allergic’ to it.

Addiction and substance abuse are social and medical problems of pandemic proportions which are associated with major social and human costs. Commonly, opioid drugs are the preferred substances of abuse. This association, combined with the principle of non-maleficence is the basis for concern regarding risk of addiction caused by the medical use of opioids. In recent years, the relationship between the medical use of opioids and the risk of addiction has been the focus of policy makers, medical sociologists, and pain clinicians. Overall, this body of research has demonstrated: (i) the risk of developing addictive behaviours or substance abuse as a consequence of the medical use of opioids is low; (ii) patient, family members, members of the health care professions, and regulators commonly overestimate the risk of addiction; (iii) patient, family members, members of the health care professions, and regulators often confuse physical dependence and addiction and; (iv) together, these concerns contribute substantially to physician reluctance to prescribe opioids and patient reluctance to use them.(232,233 and 234)

To understand these phenomena as they relate to opioid treatment of cancer pain, it is useful first to present a concept that might be called ‘therapeutic dependence’. Patients who require a specific drug therapy to control a symptom or disease process are clearly dependent on the therapeutic efficacy of the drugs in question. Examples of this ‘therapeutic dependence’ include the requirements of patients with congestive cardiac failure for cardiotonic and diuretic medication or the reliance of insulin-dependent diabetics on insulin therapy. In these patients, undermedication or withdrawal of treatment would result in serious untoward consequences. Patients with chronic cancer pain have an analogous relationship to their analgesic therapy. This relationship may or may not be associated with the development of physical dependence, but is virtually never associated with addiction.