PRACTICAL THERAPEUTICS

Drugs 46 (3): 394-408, 1993 0012-6667/93/0009-0394/$07.50/0 © Adis International Limited. All rights reserved. DRUl299

Choosing the Right Analgesic A Guide to Selection

Timothy G. Bushnell and Douglas M. Justins Pain Management Centre, St Thomas' Hospital, London, England

Contents 395 395 395 395 396 396 396 396 396 398 399 400 400 401 402 403 403 403 404 404 404 404 404 405 405 405 405 405 405 406 408 408

Summary I. Types of Pain 1.1 Acute Pain 1.2 Chronic Pain 1.3 Cancer Pain 2. Nonsteroidal Anti-Inflammatory Drugs 2.1 Pharmacology 2.2 Tolerability 2.3 Comparative Features and Clinical Use 3. Opioid Analgesics 3.1 Opioid Receptors 3.2 Opioid Pharmacology 3.3 Tolerability 3.4 Comparative Features and Clinical Use 3.5 Specific Agents 3.6 Opioid Nonresponsive Pain 4. Other Analgesics 4.1 Paracetamol 4.2 Ketamine 4.3 Nefopam 4.4 Nitrous Oxide 5. Secondary Analgesics 5.1 Antidepressants 5.2 Anticonvulsants 5.3 Muscle Relaxants 5.4 Corticosteroids 5.5 Other Drugs 6. Modes of Analgesic Administration 6.1 Pharmacokinetic Differences 6.2 Routes of Administration 7. Other Factors which Influence the Choice of Analgesic 8. Conclusions

Choosing the Right Analgesic

Summary

395

Pain is an unpleasant sensory and emotional experience, unique to each individual patient. In the dynamic processes of nociceptive stimulation, signal transmission, central decoding and interpretation there are many potential sites for pharmacological intervention, and there are many drugs which will produce analgesia. An analgesic 'ladder' has been proposed for rational pain relief in cancer and a similar concept should be used in all forms of acute and chronic pain. Continuing research and drug development undoubtedly extends our understanding, but con- sistent improvement in our clinical ability to relieve pain depends more on our willingness to consider the need of each patient individually, to tailor the drug, route and mode of administration to that patient's requirements, and then to monitor on the basis of the response of the patient to the treatment.

1. Types of Pain The International Association for the Study of Pain defines pain as an unpleasant sensory or emotional experience associated with actual or potential tissue damage, or described in terms of such damage. A simpler version is 'Pain is whatever the patient says it is, and exists wherever he says it does' (Sternbach, personal communication). This has the great value of underlining the subjective nature of pain, and emphasises that all pains are not the same, so that prescriptions for analgesic medication must be tailored to suit each individual patient. There are certain broad categories of pain, which should be discussed to allow better understanding of rational analgesic choice. 1.1 Acute Pain

Acute pain is characterised by the combination of tissue damage, pain and anxiety. It is usually transient, occurring in the period between injury and recovery, and it usually signals actual or potential tissue damage. Acute pain generates psychological and behavioural responses so that an appreciation of factors other than just analgesic pharmacology is important. Acute pain is usually associated with ail obvious cause of ongoing nociceptor stimulatiori, and is usually expected to be of a brief duration .ending in complete resolution. The treatment of acute pain is often less than optimal, although it is a very common symptom (Justins & Richardson 1991). Most surgical procedures result in pain, but acute pain is not purely

a postoperative phenomenon. Pain is a feature of medical conditions (such as myocardial infarction, sickle cell crisis, acute pancreatitis and ureteric colic), orthopaedic conditions (such as gout and prolapsed intervertebral disc), trauma and bums, as well as obstetrics and intensive care. While the pain in some of these conditions may have a specific treatment (e.g. organic nitrates in angina), more general analgesic medication will be prescribed in most cases.

1.2 Chronic Pain Whereas acute pain is a symptom of another condition, chronic pain may become a syndrome in its own right. In general terms, pain becomes chronic when it persists after healing has been completed. Such pain serves no useful function and generally it is no longer a symptom of ongoing injury or disease. The psychological accompaniment to acute pain is anxiety. The accompaniment of chronic pain is more likely to be depression, often with associated feelings of helplessness, hopelessness and meaninglessness (Melzack & Wall 1982). The mechanisms that perpetuate the chronic pain problem may be unclear. Sometimes the peripheral nociceptors respond in a 'normal' way to chronic nociceptive stimulation, as in psteoarthritis. Neuropathic pain results from abnormalities within the peripheral or central nervous system (CNS) in the absence of any clearly defined ongoing peripheral stimulation.

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1.3 Cancer Pain Pain in cancer may be both acute and chronic in nature, with a wide range of aetiologies. Visceral, soft tissue and bone pain are common, but also colic, nerve compression, infection, pleural pain, gastric discomfort and headache may cause the patient significant suffering. The psychological implications of pain in the patient with cancer are also of major importance.

2. Nonsteroidal Anti-Inflammatory Drugs This large group of drugs has been used for many years in conditions such as arthritis, but is now playing an ever increasing role in acute, postoperative and cancer pain. 2.1 Pharmacology When tissues are damaged, a number of substances (e.g. histamine and bradykinin) are released, some of which excite peripheral nociceptors and send signals to the CNS which are processed as pain. Other substances sensitise the primary afferent nociceptors without actually initiating neuronal discharge. One group of these sensitising substances result from the action of cyclo-oxygenase on arachidonic acid, which in turn is a product of the action of phospholipase on the phospholipids released from damaged cell walls. Prostaglandin E2 is one of these so-called prostanoids and is widely found in inflamed tissue. Nonsteroidal anti-inflammatory drugs (NSAIDs) act by blocking the action of cyclo-oxygenase and thus halting the production of the prostanoids responsible for peripheral sensitisation. Some NSAIDs (e.g. ketorolac) seem to produce enhanced analgesia by blocking in addition lipoxygenase, the enzyme responsible for the other metabolic pathway of arachidonic acid, and hence the production of the leukotrienes, another important group of substances involved in allergy, inflammation and peripheral nociceptor sensitisation.

2.2 Tolerability Most ofthe adverse effects of the NSAIDs seem to be a direct result of the inhibition of cyclo-oxygenase. The most significant of these is gastric irritation, which may result in peptic ulceration due to the reduced production of the gastric-protective prostaglandins. While this may be minimised by avoiding the oral route of administration (thus reducing direct irritation), it is still a problem, since it is a result of the intrinsic mode of action of these drugs. A number of gastroprotective medications (e.g. misoprostol) are now licensed for coadministration with NSAIDs, but should only be used to treat gastric irritation when there is no alternative to continuing NSAID therapy, and are only indicated prophylactically when there is a history of proven peptic ulceration. Another serious, though fortunately rare, side effect of prolonged NSAID therapy is renal failure, which may be a consequence of the decreased production of vasodilating prostaglandins in the lenal medulla. It is probably wise to avoid these drugs in anyone whose renal blood supply is liable to be prostaglandin-dependent. This includes hypovolaemic patients, those receiving loop diuretics, and those who already have a degree of renal impairment. Worsening of intrinsic asthma and allergy during NSAID treatment is probably a result of increased production of leukotrienes, although true allergy may occur. Other important adverse effects include decreased platelet aggregation, fluid retention and skin rashes. In general, all the unwanted effects are significantly more prevalent in the elderly age group. 2.3 Comparative Features and Clinical Use The profiles of some available NSAIDs are given in table I. Very broadly, two broad potencies are evident, the lower (drugs such as ibuprofen) having fewer adverse effects than the more potent (drugs such as ketorolac, diclofenac and naproxen). While the side effects of these drugs remain a

Erratum Vol. 46, No.3, 1993, page 396: in the second sentence of the second paragraph of section 2.1, the drug ketorolac should be deleted. It is not an example of a nonsteroidal anti-inflammatory drug which may produce its enhanced analgesia through inhibition of lipoxygenase.

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Table I. Some currently available nonsteroidal anti-inflammatory drugs (NSAIDs) Drug

Route of admin.

Acemetacin

PO

Aspirin

PO

300-600

q4h

Azapropazone

PO

300-600

q6-12h

Dose (mg) 60

Dose interval

Comments

q8-12h

Glycolic acid ester of indomethacin Associated with Reye's syndrome; contraindicated in children High risk of photosensitive rashes; enhancement of effect of warfarin

Diclofenac

PO; PR; 1M, IV; topical

50; 100; 75; 2000-4000

qSh; q1Sh; q6-Sh; q6h

Painful injection; risk of abscess formation with 1M preparation; IV not iicensed in UK; oral oncedaily slow release preparation available Skin rashes, tinnitus can occur Maximum 600 mg/d Maximum 900 mg/d; skin rashes can occur

Diflunisal Etodolac Fenbufen

PO PO PO

250-300 200-600 300-600

q12h q12-24h q12h

Fenoprofen Flurbiprofen

PO PO; PR

600 50; 100

q6-Sh q6-Sh; q12h

Ibuprofen

PO

200-400

q6-Sh

Low incidence of gastrointestinal problems

Indomethacin

PO; PR PO; PR;

25-50; 100 25-50; 100;

Headache, tinnitus and dizziness common Maximum 200 mg/d by any route

50-100 10; 10-30 500 500-1000 250;

Tenoxicam

1M PO; 1M, IV PO PO PO; PR PO; PR PO PO

20 200 20

q6-12h; q12h q6-Sh; q12h; q4h q6h; q4-6h q8h q12-24h q12h; q12h q12-24h; q24h q12h q24h

Tiaprofenic acid Tolmetin

PO PO

200 200

qSh q6-12h

Ketoprofen

Ketorolac Mefenamic acid Nabumetone Naproxen Piroxicam Sulindac

500 10-20;

Fluid retention can occur; oral once-daily slow release preparation available

Maximum 120 mg/d Diarrhoea can occur High tissue penetration Once-daily dosage possible

Prodrug, low incidence gastrointestinal problems Maximum 30 mg/kg/d, up to 1.S g/d

Abbreviations: d = day; 1M = intramuscular; IV = intravenous; PO = oral; PR = rectal; qxh = every x hours.

problem, the NSAIDs are undoubtedly effective in many types of pain, and are particularly useful when used in conjunction with analgesics of other groups. NSAIDs may be chosen as the first analgesic for mild to moderate pain. For more severe pain,

NSAIDs are often used in combination with opioids. There is some evidence to suggest that giving NSAIDs preoperatively may contribute to a preemptive analgesic effect. The whole concept of preemptive analgesia, while based on sound physio-

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logical principles, still requires more intensive clinical investigation (Dahl & Kehlet 1993). For pain in patients with malignant disease, NSAIDs are still the first choice, and aspirin is the first rung ofthe World Health Organization (WHO) analgesia ladder (World Health Organization 1992). NSAIDs remain in common usage for chronic rheumatological-type pains. Patients with many other chronic pain conditions consume NSAIDs in large quantities without any apparent benefit and there is very little evidence to support the contin-

ued prescription of these agents for pains which are, for example, neuropathic in nature.

3. Opioid Analgesics The opioids remain the mainstay of medical practice in the treatment of moderate or more severe pain. The immature poppy head contains a number of substances which are potent analgesics and which have been extracted by many cultures

Table II. Comparative features of potent opioid drugs. Estimates of sedative and emetic potential are given with respect to intramuscular morphine Drug

Morphine

Alfentanil Buprenorphine

Route

PO; IM,IV; Epidural IV 1M; SL

(mg)

Dose

Onset (min)

(h)

Duration

Nausea and vomiting

20; 10; 5 0.75-1 0.3;

45-60; 30-60; 20 2 10-20;

4' 3-4; 4-8 0.33 6-8

tt

0.4

30-90

Butorphanol

1M

2

30-45

1.5-2

Dextromoramide

PO

5-10

20-40

2

Diamorphine

1M;

5-10;

60-90

3-4

PO PO IV 1M; PO 1M; PO 1M; PO 1M; PO 1M; PO

50 5 0.07 1.5; 4 2' 4 10; 20 12;

45-60 5-10 15-30; 30-45 30-60; 60-90 30-45; 20-60 30-45; 30-60 15-30; 15-30

3-4 0.5 4; 4 4-5; 4-5 4-5; 4-5

Dipipanone Fentanyl Hydromorphone Levorphanol Methadone Nalbuphine Oxycodone Oxymorphone Papaveretum Pentazocine Pethidine (meperidine) Phenazocine

SC 1M 1M; PO 1M; PO PO; SL

60 15; 30 1-1.5 15 60; 180 75; 300 5' 5

30-60 30-45; 30-60 30-45; 60-90 20-60

Sedation

tt tt

H H

tt

4' 4 4' 4 4-5 4 3-4; 3-4 3; 4-5 4-8

H

tt

tt

~ ~

H H

Abbreviations and symbols: 1M = intramuscular; IV = intravenous; PO = oral; SC. = subcutaneous; SL = sublingual; - indicates similar to morphine; t indicates slightly greater than with morphine; indicates significantly greater than with morphine; ~ indicates slightly less than with morphine; H indicates significantly less than with morphine.

tt

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Choosing the Right Analgesic

Table III. Comparison of analgesic potency of opioids, with examples of useful equianalgesic doses by various routes

Common ratios

Relative potencya

Example

1 :12 1 : 10 1 : 10

30mg oral codeine -= 2.5mg oral morphine 30mg oral dihydrocodeine -= 3.0mg oral morphine 2 tablets qid (dextropropoxyphene 260mg + paracetamol 4g) -= 15mg morphine sulphate slow release tablets bid

3: 1

30mg oral morphine -= 10mg SC diamorphine 10mg elixir q4h -= 30mg morphine sulphate slow release tablets bid 30mg oral morphine -= 30mg oral diamorphine 30mg oral morphine -= 15mg SC morphine 30mg oral morphine -= 15mg IV morphine 30mg oral morphine -= 10mg IV diamorphine 3mg epidural morphine -= 15mg oral morphine 30mg oral morphine -= 3mg epidural morphine 30mg oral morphine q4h (180 mg/d) -= 45mg rectal oxycodone q6h or 60mg rectal q8h (180 mg/d) 30mg oral morphine -= 250mg oral pethidine 300mg oral pethidine -= 75mg 1M pethidine 50mg 1M pethidine -= 8mg SC diamorphine

Low Potency Opioids

Oral codeine to oral morphine b Oral dihydrocodeine to oral morphine Oral dextropropoxyphene plus paracetamol (acetaminophen) to morphine sulphate slow release tablets Potent Opioids

SC diamorphine to oral morphine Morphine sulphate slow release tablets to oral morphine elixir or tablets Oral diamorphine to oral morphine SC morphine to oral morphine IV morphine to oral morphine IV diamorphine to oral morphine Epidural morphine to oral morphine Oral morphine to epidural morphine Rectal oxycodone to oral morphine Oral pethidine (meperidine) to oral morphine Oral pethidine to 1M pethidine 1M pethidine to SC diamorphine

1:1 1:1 2: 1 2: 1 3: 1 5: 1 1 : 10 1:1

1:8 1: 4 1:6

a b

For example oral morphine is 12 times more potent than oral codeine. Oral morphine refers to morphine elixir or soluble morphine sulphate tablets. Abbreviations: bid = twice daily; d = day; 1M = intramuscular; IV = intravenous; qid qxh = every x hours.

over the centuries. There are now also large numbers of synthetic opioids. 3.1 Opioid Receptors At least three different endogenous opioid receptors (/-t, 0 and K) are found widely in the body, but are most important for nociception in the spinal cord, the brainstem and the midbrain. Opioid receptors are also found on peripheral nerves. In the spinal cord, the most dense concentration of opioid receptors is found in the C-fibre receptor zone of lamina I and in the substantia gelatinosa; 70% are of the /-t type. Distribution within the supraspinal area is less clearly related to nociception alone, but may explain some opioid side effects such as cough inhibition, nausea and vomiting, and respiratory depression. Activation of all three types of opioid receptor

four times daily; SC subcutaneous;

results in inhibition of nociceptor transmission. In the case of the /-t- and o-receptors, this is caused by opening potassium channels and causing hyperpolarisation which may be pre- or postsynaptic. KReceptors close calcium channels, demonstrating an electrophysiological difference from the other receptors (Dickenson 1991). The results of specific receptor activation are not completely clear, not least because endogenous opioids act on more than one receptor subtype. /-t-Receptor agonism is associated with analgesia, depression of respiration, physical dependence, euphoria and decreased heart rate. The separation of analgesia from the other effects has not been achieved. K-Receptor activation causes analgesia associated with less respiratory depression and dependence than /-t-receptor agonism, but unfortunately the clinical usefulness of current K-agonists is limited by other unwanted effects.

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3.2 Opioid Pharmacology Morphine is the standard drug against which other opioids are measured. Morphine produces analgesia and sedation when given to patients suffering from opioid-responsive pain. Relief tends to be best for dull continuous pain, and least for sharp intermittent pain. Vis~eral and somatic pains from joints and integumental structures are usually relieved, although some categories of pain seem to be particularly poorly relieved (see section 3.6). A feeling of relief, decreased apprehension and even euphoria may be evident, and the gait may become ataxic. Morphine is given by a wide variety of routes, with different pharmacokinetics and with large variations in the analgesia produced. Alterations in route and of preparation may have significant effects on the analgesia produced (tables II and III). As activity correlates poorly with plasma concentrations, it is assumed that it is the drug concentration in the CNS that is significant. This may be surprisingly low after intravenous administration due to the poor lipid solubility of morphine, its high ionisation and rapid metabolism in the intravenous phase to morphine-3-g1ucuronide and morphine-6-glucuronide (Chapman et al. 1990). Morphine is conjugated with glucuronic acid in both hepatic and extrahepatic sites (notably the kidney) as its principal means of metabolism. Morphine6-g1ucuronide is active, and significantly more potent than morphine. The presence of active metabolites of morphine and other drugs in this group results in an effective duration of action and elimination half-life which may· appear incompatible with each other: The effective onset times and durations of action as well as some of the properties of the commonly used opioids are given in table II. 3.3 Tolerability

3.3.1 Cardiovascular System In general, morphine and other opioids have few effects upon the cardiovascular system. Provided

the patient is not hypovolaemic there is no change in supine blood pressure, although a certain amount of orthostatic hypotension may be seen. Morphine may cause the release of histamine which can result in a decrease in systemic blood pressure, and possibly brief bradycardia. When opioids are administered with benzodiazepines or volatile anaesthetic agents, some degree of myocardial depression may be seen which is absent when they are given alone.

3.3.2 Respiratory System All opioids when given to pain-free volunteers cause dose-dependent depression of ventilation. There is a diminished responsiveness to arterial pC02, and an effect in the pontine centres results in prolonged pauses between breaths. Clinically, this results in a decreased rate of breathing but with initially at least an increase in tidal volume. With massive overdose apnoea may occur, although if conscious, the patient will take a breath if requested to do so. Most severe episodes of respiratory impairment take place during sleep, and almost all deaths attributed to opioids are due to respiratory depression. In all probability it is the fear of this complication that results in so many patients obtaining inadequate analgesia. Respiratory deprellsion is much less significant when the drugs are given in the presence of pain. Opioids. also depress the cough reflex and reduce bronchial ciliary action, which may result in sputum retention. Shallow breathing, reluctance to cough and sputum retention follow unrelieved pain, and this can be effectively countered by appropriate opioid analgesia.

3.3.3 Gastrointestinal Tract Essentially all opioids cause constipation to a greater or lesser extent, and this is one of the biggest problems in pain relief for patients with cancer. Another major problem is nausea and vomiting which is due to a direct effect on the chemoreceptor trigger zone.

Choosing the RightAnalgesic

3.3.4 Tolerance and Physical Dependence Tolerance is the development of the need to increase the dose of a drug to achieve the same effect. Tolerance should not be confused with increased pain which is far more likely to be the cause of increased analgesic need. The patient may also develop tolerance to side effects such as respiratory depression and sedation, but not to constipation. Physical dependence will develop in patients who take opioids long term but psychological dependence is extremely rare (Portenoy & Foley 1986).

3.3.5 Central Nervous System Sedation and psychotropic effects are a major problem with some opioids, particularly when used in large doses for cancer pain. While tolerance may develop to sedation, psychotropic effects may require changing the drug, and fortunately this is an area where there are significant differences between opioids. 3.4 Comparative Features and Clinical Use The analgesic effect of the opioids is not routedependent so long as appropriate dosages are given by the different routes. Studies in healthy volunteers do not always give an accurate picture of analgesic performance in a clinical setting, especially for side effects such as respiratory depression and dependence potential. Morphine is the standard drug within this group against which others must be compared (table II). While other drugs may act more quickly, have a longer duration of action, or have a different spectrum of adverse effects, few offer significant advantages to the patient when compared with morphine (McQuay 1991). Rapid onset of analgesia may be of importance in acute pain but is of little significance in chronic pain, particularly if it is being given regularly 'by the clock'. When given intramuscularly, highly lipophilic drugs tend to act more quickly. The differences of speed of onset between all the opioids when given intravenously are very small, and probably insignificant in anything but perioperative anaesthetic use. Many lipophilic drugs have

401

their effect terminated not by metabolism (as reflected by their elimination half-life) but by redistribution to inactive sites. Thus fentanyl has a halflife similar to that of morphine, but an effect that is far shorter. The duration of action of some drugs has been prolonged by the availability of sustained release formulations, although this may be at the cost of a slower onset time. Variable patterns of adverse effects are shown . by the opioids. The likelihood of causing sedation or nausea is shown in table II. Other potential problems include the possibility of causing dysphoria (more likely with pentazocine, butorphanol and nalbuphine), the presence of toxic metabolites [norpethidine is a metabolite of pethidine (meperidine) and is a CNS irritant], or the likelihood of altered pharmacokinetics in certain disease states (morphine, codeine and dihydrocodeine in renal failure). . Having decided upon the appropriate opioid, the mode and route of administration are very important. These are discussed later (section 6), but certain points are of particular relevance to the opioids. In cancer pain, it is possible to establish the opioid requirements using intravenous titration and self-administration, using a patient-controlled analgesia system for instance, and then when an adequate dosage has been determined, convert to a 'by the clock' oral regimen. This approach has also been shown to be useful in patients with chronic pain where the degree of opioid responsiveness can be demonstrated (Jadad et al. 1992). A conversion chart of approximately equianalgesic dosages is given in table III. Many routes are available for opioid administration and generally the advantages and disadvantages are the same as for any other drugs. First-pass liver metabolism may be high for some of these drugs, and thus reduced bioavailability make the oral route less reliable for short term administration. Sublingual administration may have advantages by ensuring reliable and reproducible plasma concentrations in this instance. The spinal and epidural routes offer a high quality and longer duration of analgesia from small dosages. Nevertheless, the quality of analgesia in a

402

number of studies was not superior to that after intravenous administration, and adverse effects such as pruritus, nausea and sedation remain a major problem. The specific indications for the spinal route in both acute and chronic pain remain uncertain and await clearer definition (Morgan 1989). 3.5 Specific Agents 3.5.1 Low Potency Opioids Codeine, Dihydrocodeine and Dextropropoxyphene These agents are weak opioid analgesics and, although they are available separately, they are commonly administered in fixed-dose combinations with paracetamol (acetaminophen). As such, they form a convenient 'step up' from simple analgesics such as paracetamol alone. While usually safe, problems can occur when patients take additional paracetamo1. Dextropropoxyphene-induced respiratory depression is only poorly reversed by the opioid antagonist naloxone. These agents represent the second rung of the WHO analgesic ladder for cancer pain and in this context can be extremely effective. They are widely used for mild to moderate postoperative pain once the oral route becomes acceptable and may be usefully given with NSAIDs. They are frequently prescribed to patients with chronic pain with little apparent benefit, and their use should be carefully assessed in this field.

Tramadol This is an interesting drug which has been available in Europe for some years (Lee et a1. 1993). It is a weak agonist at all opioid receptors, but in addition inhibits noradrenaline (norepinephrine) reuptake and causes serotonin release, and thus may affect other neurotransmitter systems in the nociceptive pathways (Vickers et a1. 1992). It is a fairly strong analgesic, with a potency similar to that of pethidine, but seems to cause less respiratory depression than other comparable opioids. It has been successfully used in the second rung of the WHO ladder (Ashburn & Lipman 1993).

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3.5.2 Potent Opioids There are few occasions where morphine is not the strong opioid of choice. For oral administration, there is a range of soluble and sustained release preparations which allow flexibility of administration. The rectal preparation is effective, although oxycodone is a widely used alternative. Intramuscular morphine can be effective in postoperative pain, but papaveretum is a 'possibly better tolerated alternative. There is extensive experience of using morphine in patient-controlled analgesia and by intravenous infusion. Alfentanil is less likely to accumulate when given by intravenous infusion. By the epidural route, diamorphine or fentanyl are probably preferable as they are associated with less respiratory depression. Potent opioids form the third rung of the WHO analgesic ladder in cancer pain management. They also have a major part to play in the initial treatment of acute pain, and if given pre-emptively may reduce overall postoperative pain (Kiss & Mathias 1992). The role of the potent opioids in patients with chronic pain is less certain because these pains are of very variable aetiology and are more often opioid-resistant. The possible development of dependence in a patiet;tt with anon-terminal condition is also a major concern. It would seem illogical to withhold strong opioids from patients with opioid-sensitive pain when other treatments are ineffective, and experience isnow being gained in chronic pain with all routes, inc;luding the spinal and epidural (Plummer et a1. 1~91).

Pai>averetum This is an extract of opium that contains morphine and a 'number of other alkaloids which are claimed to make the preparation better tolerated than morphine alone. The traditional preparation contained no~capine which may have a teratogenic potential in animals, but this has been removed from the cUrlent formulation. Diamorphine Diamorphine (heroin) is a diethyl derivative of morphine, the reputation of which has suffered from its abuse. It is more potent than morphine

403

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and is still widely prescribed in the UK, particularly for subcutaneous and epidural infusions. The concentration of the solution can be varied so that small volumes can be used for subcutaneous infusion. Diamorphine penetrates the eNS very efficiently. It is a prodrug, inactive in itself, but with active metabolites, 6-acetylmorphine and morphine. There is debate as to the advantages of diamorphine over morphine. Diamorphine has been shown to be associated with less respiratory depression than morphine when both drugs are given by the epidural route. Buprenorphine This is a partial agonist at wreceptors, but is highly potent and can produce significant analgesia. It is available in intravenous and sublingual formulations. The sublingual route produces a rapid onset of action but the drug commonly produces nausea and psychotropic effects, and is only poorly reversed by naloxone. Meptazinol This relatively new drug is probably a ~-recep­ tor agonist, but is associated with little respiratory depression (Editorial 1983). It can also be metabolised by neonates making it theoretically preferable to pethidine in labour. Unfortunately, it is quite emetic and causes atropine-like adverse effects. K-Agonists A number of K-agonists are currently being evaluated and it is hoped that analgesia produced by these agents will be associated with less constipation, respiratory depression and abuse potential than wagonists. Sedation and other adverse effects may nonetheless limit the use of these drugs.

inhibitory neurotransmitters. The endogenous opioid system represents just one part of the neuromodulatory mechanism, so that not every form of nociceptive activation and transmission will be inhibited by opioid analgesics. There is a group of patients whose pain appears to respond poorly or not at all to opioids. Neuropathic pain is a common example of opioid nonresponsive pain. Such pains may respond best to the secondary analgesics (anticonvulsants and antidepressant medications; section 5), local anaesthetics, or to nonpharmacological measures such as transcutaneous electrical nerve stimulation. Incident pain is another pain which may be opioid nonresponsive, and 'breakthrough' pain can result from movement or weight-bearing (Hanks 1991). Opioids with rapid onset, patient-controlled analgesia, or spinally administered opioid/local anaesthetic combinations may provide partial relief, but problems such as vertebral collapse may prove very intractable.> Non-opioid drugs, such as the NSAIDs, and other secondary analgesics may also help, but nerve blocks or major surgical procedures may be indicated for these patients. Nociceptive pain produced by ongoing peripheral nociceptor stimulation is usually described as being opioid-sensitive, but it is now recognised that in certain nonmalignant conditions, such as chronic. rheumatoid disease, a state of opioid resistance may develop. One possible explanation is the concept of 'paradoxical pain' claimed to be due to abnormal ratios of morphine metabolites (Bowsher 1993). Opioid insensitivity may be diagnosed in terminal care and in patients with pain caused by cancer where in fact the problem is the complex multifactorial syndrome of 'total pain' resulting from the interaction of physical, pharmacological and psychological factors.

4. Other Analgesics 3.6 Opioid Nonresponsive Pain The transduction of a peripheral nociceptive stimulus into the centrally perceived experience of pain involves a complex, dynamic system which uses a large number of excitatory, facilitatory and

4.1 Paracetamol Paracetamol is a centrally acting cyclo-oxygenase inhibitor which is an effective and widely used analgesic in mild and moderate pain, but the peripheral anti-inflammatory properties of the drug are

404

minimal. Paracetamol is generally safe with an absence of gastric and haematological adverse effects, and it is suitable for all age groups ~3 months. Major problems arise with overdosage, when metabolic pathways are easily saturated, resulting in the formation of hepatotoxic metabolites. The early administration of acetylcysteine may· substantially reduce the incidence of fatal centrilobuc lar hepatic necrosis (see review by James & Routledge 1992), and there is pressure to include this in paracetamol formulations. Paracetamol may be administered orally or rectally and can be surprisingly effective if given regularly postoperatively. It is an effective antipyretic and because of the association of aspirin with Reye's disease in children, paracetamol is the simple analgesic of choice in this group. Other centrally acting cyclo-oxygenase inhibitors are being developed.

4.2 Ketamine Ketamine has been used as an anaesthetic agent for many years but also produces analgesia at lower doses. Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist and this may explain some of its analgesic properties. Commercially available ketamine is a racemic mixture, but it is the (+) stereoisomer that has most of the analgesic properties, and the (-) isomer that produces anaesthetic problems such as emergence hallucinations. Activation of the NMDA receptor, which is found at second and subsequent synapses in the dorsal horn, is associated with increased and extended responsiveness to nociceptive input, a responsiveness that is not readily suppressed by opioids. The profound analgesia produced by ketamine is free of respiratory or cardiovascular depression, but may be associated with hallucinations and unpleasant vivid dreams. Being extremely lipid soluble as well as fairly water soluble, ketamine can be given orally, intramuscularly (with rapid onset of action), intravenously or into the epidural space, and it has a duration of action measured in hours. It can be useful as an infusion with or without opioids in any situation where respiratory or cardiac depression

Drugs 46 (3) 1993

could be a major problem. This combination of properties has secured the drug a place in emergency anaesthesia, but it may also have a new role in analgesia. Ketamine has joined the ranks of the so-called 'designer drugs' and is now a drug of abuse. 4.3 Nefopam Nefopam is structurally and functionally unique among analgesics. Its actions appear to be central, non-opioid, and dependent upon excitation of descending inhibitory pathways by increasing the release and decreasing the reuptake of monoamines. As an analgesic its role is not clear, and it produces many side effects such as dry mouth, blurred vision, anxiety, restlessness and nausea. 4.4 Nitrous Oxide The gas nitrous oxide has been used as an analgesic for many decades. Its actions seem to be dependent upon releasing endogenous opioids within the brain, and the character of the analgesia produced is certainly opioid-like. When administered by inhalation with oxygen, nitrous oxide is a useful analgesic of rapid onset and short duration, but this requires specialised equipment for delivery and can result in nausea, sedation and an unpleasant feeling of disassociation. It is suitable for short painful procedures such as wound dressing, but continuous use is precluded by the development of bone marrow depression after 24 hours.

. 5. Secondary Analgesics A number of drugs have the ability to relieve pain even though they are used principally for some other indication. With the exception of corticosteroids, the usefulness of secondary analgesics in acute pain is small, but these drugs can playa very significant part in chronic pain management. 5.1 Antidepressants Many patients with chronic severe pain become depressed in response to theunremittirig pain. In some patients pain may actually be a symptom of

405

Choosing the Right Analgesic

depression but this is unusual. Even in the absence of clinical depression, some of the antidepressants act as analgesics. The analgesic effect is separate from the antidepressive effect since the analgesia occurs much sooner than any change in mood and often after a much smaller dose than is needed to produce mood changes. This effect is probably due to increased CNS levels of noradrenaline (norepinephrine), the reuptake of which is inhibited by these drugs. Newer specific serotonin reuptake inhibitor antidepressants do not seem to have the same degree of intrinsic analgesic action possessed by the older tricyclic drugs. Amitriptyline is the most widely used drug, commencing at 25mg at night, with the dosage then increased gradually dependent upon effect. Tricyclic antidepressants are particularly indicated for burning pain such as in post-herpetic neuralgia and central post-stroke pain syndromes (McQuay et al. 1992). 5.2 Anticonvulsants Anticonvulsant drugs have found a useful role in the treatment of conditions where neural damage is associated with epileptiform-like bursts of spontaneous 'lightning' or 'shooting' pain. Carbamazepine is widely used for trigeminal neuralgia, and is often effective, but produces significant sedation in high doses. Phenytoin, clonazepam and valproic acid can also be used. 5.3 Muscle Relaxants Many chronic pain states are accompanied by increased muscle tone, which if controlled may lead to a reduction of pain. Orphenadrine and methocarbamol (amethopterin) act at the interneuronal level of the spinal cord and may be successful if used in conjunction with simple analgesics. Severe spasm and contractures, as found in some neurological conditions such as spinal cord injury, can be treated with baclofen or with dantrolene which acts peripherally.

5.4 Corticosteroids Corticosteroids have a significant role in analgesia, having powerful anti-inflammatory properties; these agents block leukotriene synthesis in addition to prostaglandin synthesis. In cancer-induced neuropathic pain, corticosteroids can be extremely effective by reducing nerve compression and by a direct action on ectopic neuronal activity (Hanks & Justins 1992). These pains are often poorly opioid-responsive. Corticosteroids have also been shown to be useful for reducing postoperative pain following faciomaxillary surgery. 5.5 Other Drugs Clonidine is a centrally acting £X2-adrenergic agonist which acts upon potassium channels, similar to those opened by opioid ~-agonists, and this may be the mechanism by which it produces analgesia. Clonidine potentiates the activity of opioids and it has been used by a number of routes, including epidurally. Its major side effects are sedation and cardiovascular instability. Psychostimulants, including the amphetamine derivatives, may have a role to play in the management of pain in malignant disease (Bruera et al. 1992). Finally, membrane-stabilising drugs such as flecainide may be useful in refractory neuropathic pain (Hanks I 991 ).

6. Modes

0/ Analgesic Administration

Many surveys suggest that patients still suffer unrelieved pain despite the availability of appropriate drugs (Royal College of Surgeons of England and the College of Anaesthetists 1990). This failure is frequently the result of rigid, traditional prescriptions which ignore the widespread, unpredictable variation in analgesic requirements between individual patients. 6.1 Pharmacokinetic Differences Many patient factors can alter the degree to which a drug is absorbed, distributed (increased age is associated with decreased volume of distribu-

406

tion), ionised (for instance the acid/base status of the patient), and metabolised (intercurrent hepatic or renal disease). Variation in any of these factors can result in either inadequate plasma concentrations of the drug and thus continued pain, or unwanted adverse effects. There are many other influences on analgesic pharmacokinetics, such as intercurrent drug administration, endocrine conditions and hypothermia, which could be equally important and must be taken into account when prescriptions are being formulated. Pharmacodynamic differences are of particular significance in the field of analgesia where patients can show wide variation in response to analgesics despite similar plasma concentrations. Concepts such as 'Minimal Effective Analgesic Concentration' are of limited value (Owen et al. 1990). 6.2 Routes of Administration

The advantages and disadvantages of the various routes when used in pain relief are given in table IV. In addition to the route by which a drug is given, the mode of administration can be just as important as the choice of drug. 6.2.1 Intermittent Bolus on Demand - Staff Administration This is a simple and cheap mode of delivery which allows some flexibility for pain of variable intensity. Analgesia is only given in response to patient demand when pain is present. However, procedures for the administration of controlled drugs and pharmacokinetic factors may impose further delay before the patient obtains relief of pain. The patient may actually have unrelieved pain for a considerable proportion of any period. This mode of delivery is often very unsatisfactory for postoperative pain, but it can be successful following changes in nursing practice involving regular patient assessment and prescribed responses for unrelieved pain (Gould et al. 1992).

Drugs 46 (3) 1993

6.2.2 Intermittent Bolus on Demand Patient-Controlled Patient-controlled analgesia (PCA) gives the responsibility for drug administration to the patient, so that analgesia can be titrated by the patient against the pain, rather than being controlled by the staff. The patient administers the drug intravenously, subcutaneously or epidurally by the press of a button which activates the microprocessor-controlled pump which prevents overdosage. The technique allows for the wide variation in analgesic requirement between different patients, and over a period within an individual patient. The feeling of autonomy is often important to the patient. The technique requires patient cooperation and comprehension and obviously administers no analgesia during sleep. Nausea and vomiting are significant problems. PCA is still an intermittent mode of administration and is reactive rather than proactive or preventative. A continuous background infusion can be administered concurrently, but this may increase side effects. It has been extensively used in postoperative pain, and also in medical conditions such as sickle crisis and during labour. It has been used successfully in children as young as 5 years (Lowrie et al. 1990). 6.2.3 Regular Intermittent Bolus This is a simple form of administration which can result in extremely effective pain relief since further analgesia is given before pain intensity increases too much. The certainty of obtaining regular, reliable analgesia can considerably reduce patient anxiety. Unfortunately there exists the possibility of drug accumulation and toxic effects, and the technique is unable to respond to rapid changes in analgesic requirements. Its simplicity, convenience and proacti~e treatment of breakthrough pain make it ideal for terminal care. 6.2.4 Continuous Infusion In this technique the peaks and troughs of intermittent bolus administration can be smoothed

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Choosing the Right Analgesic

Table IV. Advantages and disadvantages of the various routes of administration available for analgesics Route

Advantages

Disadvantages

Oral

Painless; easy - no medical supervision required; suitable for longer term use, or later stages of acute pain; pharmaceutically advantageous

Intravenous

Rapid onset; predictable effects; complete availability; continuous infusion techniques possible; rapid titration Standard practice; cheap; simple training only required; fairly rapid onset; regular administration may improve analgesia

Slow onset; fasting patients unsuitable; nausea and vomiting reduce availability; unpredictable absorption of some drugs; gastrointestinal motility frequently reduced postoperatively; some drugs unstable in gastrointestinal tract; high first-pass metabolism may result in low bioavailability; requires cooperative patient or nasogastric tube Intravenous access required; trained staff required to administer and monitor; high peak plasma concentrations potential for toxicity and side effects

Intramuscular

Subcutaneous

Sublingual/buccal

Rectal

Transdermal/topical

Epidural/subarachnoid

Inhalational

Easy access; can be relatively painfree with fine needles, local anaesthetic creams, etc.; often suitable for continuous infusions Bypasses first-pass elimination; independent of gastric stasis, nausea, etc.; high patient acceptability Reduced first-pass elimination; many preparations are slow release - long duration of relief from simple preparation; independent of gastric state; no expertise to administer; some side effects reduced; cheap Slow release - useful for background analgesia; formulation can be varied to vary rate of release; simple to apply High quality of analgesia with small doses; suitable for continuous infusion; long term administration with implanted delivery systems Rapid onset and recovery; often very potent; highly suitable for episodic pains

out, giving optimum control with plasma drug concentrations above analgesic minima yet below toxic concentrations. The pharmacokinetics are complex and change with time. An initial bolus is required to establish analgesia. A high degree of vigilance is

Intermittent technique; painful injections; risk of nerve/ vascular/muscular damage; risk of inadvertent intravenous injection; variable, unpredictable absorption, particularly when cold, shocked, etc. may result in poor control and sudden changes in plasma concentrations as haemodynamic state varies Complex pharmacokinetics; variable absorption, particularly in haemodynamic instability; may be irritant and painful; depot can build up - continued effect after infusions discontinued Patient cooperation required; absorption variable if saliva production variable - unsuitable in end-stage terminal care; taste important for acceptability Patient acceptance variable; slow absorption - not helpful in acute pain; bioavailability variable and unpredictable

Few drugs suitable or available; often produce skin irritation; slow absorption, difficult to titrate; depot may remain in skin once preparation removed Extremely high level of expertise and equipment required to establish; risk of introducing central infection; few drugs as yet suitable; pharmaceutically complicated - preservative-free preparations required Few agents suitable; complicated apparatus required for administration; patient acceptance variable

required to monitor drug dosage and to watch foor unwanted effects. Tolerance can occur rapidly, but the technique provides analgesia in severe pain even when patient cooperation is impaired (Pounder & Steward 1992).

Drugs 46 (3) 1993

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7. Other Factors which Influence the Choice of Analgesic The severity and likely duration of the pain must be weighed against the patient's wishes and the likelihood of adverse effects. Selection from the therapeutic options will be determined by the expertise and experience of the staff, the availability of adequate supervision and surveillance, and the availability of drugs and equipment. The general condition of the patient and concllrrent drug prescription must also be taken into account. It is unwise to embark upon high technology techniques of analgesic administration when there is no adequate backup for the staff or for the patient and family at home. Psychological factors also play a great part in the response to both pain and treatment. These factors may only become clear once treatment has been started. There can be no place for inflexible regimens. Analgesia must be continuously assessed and tailored to suit each patient so that pain relief is balanced against side effects.

8. Conclusions Choosing the right analgesic requires the matching of the pharmacological properties of a drug to the pain intensity and psychosocial situation of the patient at any particular time. Treatment must be individualised to each individual's requirement, and the prescription must be kept under constant review so that adjustments can be made to cope with alterations in pain intensity or the advent of side effects. Where possible, treatment should be pre-emptive or proactive, rather than reactive. Prevention is better than cure! When used properly the currently available drugs and techniques can provide satisfactory analgesia for most pain encountered in clinical practice. Problems are still nevertheless encountered with certain categories of pain such as tbat of neuropathic origin, and with incident bone pain.

Bruera E, Miller MJ, Macmillan K, Kuehn N. Neuropsychological effects of methylphenidate in patients receiving a continuous infusion of narcotics for cancer pain. Pain 48: 163-166, 1992 Chapman CR, Hill HF, Saeger L, Gavin J. Profiles of opioid analgesia in humans after intravenous bolus administration. Pain 43: 47-55, 1990 Dahl ]B, Kehlet ~., The value of pre-emptive analgesia in the treatmentof postoperative pain. British Journal of Anaesthesia 70: 434439, 1993 Dickenson AH. Mechanisms of the analgesic actions of opiates and opioids. British Medical Bulletin 47: 690-702, 1991 Editorial. Meptazinol, review of actions and uses. Lancet 2: 384, 1983 Gould TH, Crosby DL, Hamer M, Lloyd SM, Lunn ]N, et al. Policy for controlling pain after surgery: effect of sequential changes. British Medical Journal 305: 1187-1193, 1992 Hanks GW. Opioid responsive and opioid non-responsive pain in cancer. British Medical Bulletin 47: 718-731, 1991 Hanks GW, Justins DM. Cancer pain: management. Lancet 339: 10311036, 1992 Jadad AR, Carroll D, Glynn CJ, Moore RA, McQuay HJ. Morphine responsiveness in chronic pain: double blind randomised cross over study with PCA. Lancet 339: 1367-1371, 1992 James J, Routledge PA. Recent developments in the management of paracetamol (acetaminophen) poisoning. Drug Safety 7: 170-177, 1992 Justins DM, Richardson PH. Oinical management of acute pain. British Medical Bulletin 47: 561-583, 1991 Kiss IE, Mathias K. Does opiate premedication influence post operative analgesia? Pain 48: 157-158, 1992 Lee CR, McTavish D, Sorkin EM. Tramado1: a preliminary review of the pharmacodynamic and pharmacokinetic properties, and therapeutic potential in acute and chronic pain states. Drugs 46: 313340,1993 Lowrie SC, Forbes DW, Akhtar TM, Morton NS. Patient controlled analgesia in children. Anaesthesia 46: 1074-1076, 1990 McQuay HJ. Opioid clinical pharmacology and routes of administration. British Medical Bulletin 47: 703-717,1991 McQuay HJ, Carroll D, Glynn CJ. Low dose amitriptyline in the treatment of chronic pain. Anaesthesia 47: 646-652, 1992 Melzack R, Wall P. The challenge of pain, 2nd ed., Penguin books, Harmondsworth, 1982 Morgan M. The rational use of intrathecal and extradural opioids. British Journal of Anaesthesia 63: 165-188, 1989 Owen H, Kluger MT, Plummer JL. Variables of PCA 4: The relevance of bolus dose size to supplement a background infusion. Anaesthesia 45: 619-622, 1990 Plummer JL, Cherry DA, Cousins MJ, Gourlay GK, Only MM, et al. Long term spinal administration of morphine in cancer and noncancer pain. Pain 44: 215-220, 1991 Pounder DR, Steward DJ. Post operative analgesia: opioid infusions in infants and children. Canadian Journal of Anaesthesia 39: 969974, 1992 Portenoy RK, Foley KM.Chronic use of opioid analgesics in nonmalignant pain: Report of 38 cases. Pain 25: 171-186, 1986 Royal College of Surgeons of England and the College of Anaesthetists. Pain after surgery. Report of the Working Party of the Commission on the Provision of Surgical Services, London, 1990 Vickers MD, O'F1aherty D, Szekely SM, Read M, Yoshizumi J. Tramdol: pain relief by an opioid without depression of respiration. Anaesthesia 47: 291-296, 1992. World Health Organization Expert Committee. Cancer pain relief and palliative care. World Health Organization, Geneva, Switzerland, 1992

References Ashburn MA, Lipman AG. Management of pain in the cancer patient. Anesthesia and Analgesia 76: 402-416, 1993 Bowsher D. Paradoxical pain. British Medical Journal 306: 473, 1993

Correspondence and reprints: Dr

Douglas Justins, Director, Pain

Management Centre, St Thomas' Hospital, Lambeth Palace ROad, London SEI 7EH, England.