Pain management and quality in healthcare

Best Practice & Research Clinical Anaesthesiology Vol. 15, No. 4, pp. 633±653, 2001

doi:10.1053/bean.2001.0196, available online at http://www.idealibrary.com on

10 Pain management and quality in healthcare Lesley A. Colvin*

MBChB, FRCA, PhD

Consultant/Senior Lecturer in Anaesthesia and Pain Medicine Dept of Anaesthesia, Critical Care and Pain Medicine, Western General Hospital, Crewe Rd, Edinburgh, EH4 2XU UK

Ian Power

BSc Hons, MBChB, FRCA, MD, FFPMANZCA, FANZCA

Professor Department of Anaesthesia, Critical Care and Pain Medicine, University of Edinburgh, Lauriston Place, Edinburgh, EH3 9YW UK

Management of pain in the acute peri-operative setting still leaves a signi®cant number of patients su€ering from moderate to severe pain. In order to improve this, it is important to understand the underlying mechanisms of pain perception, and be able to apply this to clinical settings. E€ective assessment of pain is needed, with re-assessment to detect treatment ecacy. Meta-analyses and systematic reviews are available for many of the analgesic therapies used, and this can be used as a basis for formulating an e€ective management plan. By optimizing pain management in the peri-operative period, and utilizing this, it should be possible to minimize resultant disability and hospital stay. Key words: pain management; post-operative/drug therapy; analgesics; assessment.

INTRODUCTION The alleviation of pain is central to the role of the anaesthetist, who is uniquely placed to deliver e€ective analgesia using a combination of appropriately directed pharmacological and interventional techniques. Before going on to consider how pain can best be managed in the peri-operative setting, we need to be clear what exactly we are treating and why. The IASP de®nition states `Pain is an unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage'.1 This re¯ects the complex nature of pain perception, with many factors in¯uencing the expression of pain and distress in the individual. The biopsychosocial model (Figure 1) outlines some of the factors involved. Although this review is limited mainly to the management of acute post-operative pain, many of the areas discussed can be applied to other pain settings. A basic assumption is that it is bene®cial to relieve pain. This is not only a humanitarian and ethical right, but also has a sound economic basis. Prompt and *All correspondence to: L.A. Colvin. 1521±6896/01/040633‡21 $35.00/00

c 2001 Harcourt Publishers Ltd. *

634 L. A. Colvin and I. Power

Social environment Illness (pain behaviour)

Affective (suffering)

Cognition (pain)

Sensory (nociception)

Figure 1. The biopsychosocial model. This model indicates the multidimensional nature of pain experience that must be considered in all patients in pain.

e€ective management of pain will allow early re-establishment of function, minimizing any associated disability. This will consequently decrease economic costs. It has been estimated that acute pain costs Australian society up to $10 billion per year.2 Strategies to maximize delivery of e€ective analgesia and to utilize the bene®ts from this can lead to a decrease in hospital stay, with bene®ts for both patients and society.2 CURRENT PAIN MANAGEMENT Pain is one of the commonest symptoms for which a patient consults their general practitioner. Despite this, many studies have found that pain is not well managed by our profession. In one survey, more than 70% of adults believed pain to be inevitable after surgery, with this being a signi®cant cause of fear and anxiety prior to surgery. Unfortunately, Australian, British and American audits of pain management show that these fears may indeed be justi®ed. About a decade ago, a report on pain after surgery highlighted signi®cant de®ciencies in this area.3,4 Some improvements have been made, but many aspects of acute pain management could still be improved (Table 1). An audit of 3000 UK hospital patients found that up to 87% of patients reported severe or moderate pain.5 Another study involving 3000 patients in 15 UK hospitals found that by introducing a programme of education for sta€, formal assessment and use of simple algorithms for pain management, moderate to severe pain could be reduced from 37% to 13%.6 A prospective audit carried out by the Picker Institute found that within a UK hospital setting around 58% of patients had moderate to severe pain.7 In France, an audit of the e€ectiveness of introducing a quality assurance programme over 1 year found that pain control could be improved by education of all sta€ involved, systematic assessment and use of protocol-driven provision of modern analgesic techniques. This was without requiring specially quali®ed personnel in every

Pain management and quality in healthcare 635 Table 1. Challenging areas for acute pain management: Potentially dicult areas for acute pain management are in bold. Possible in¯uences contributing to make management dicult are shown. Dicult patient areas Patient factors

Health care workers

System factors

Neonates and infants

Assessment diculties

Cultural and attitudinal barriers

Inadequate funding and stang

Elderly

Fear of addiction

Low priority on Poor knowledge importance of pain relief base and training

Burns

Expectation of pain and disability

Communication problems

In¯uences of legal prescribing requirements

Trauma

Pharmacokinetic variability

Inadequate assessment

Ine€ective or lack of evidence for treatment available

Cancer

Social and cultural in¯uences

Head injury/impaired Opioid tolerance conscious level Drug abuse

ward area.8 Another European study had similar results, with a signi®cant improvement in acute pain management after surgery by the introduction of a nurse-led, anaesthesia-supervized acute pain service. Education and the provision of regular, simple analgesics were thought to be the main factors contributing to the improvement in analgesia.9 Pain management has been traditionally divided into acute and chronic, often with di€erent strategies used in treatment. As more is understood about nociceptive transmission and rapid plasticity within the peripheral and central nervous system, the rigid division between acute and chronic becomes unhelpful. If pain is viewed as a continuum, dicult pain problems presenting acutely should become easier to diagnose and treat. One important area that is not yet understood is the factors pre-disposing to developing persistent pain. The `dicult patient' that anaesthetists are asked to assess, several days after surgery, could simply be more susceptible to rapid plastic changes resulting in altered nociceptive processing. Alternatively, there may be more complex factors regulating pain perception and the expression of pain in particular individuals (Figure 1). The incidence of persistent pain after surgery is probably under-estimated, with a minority of su€erers attending a chronic pain clinic. One study found that about 20% of patients attending pain clinics did so because of pain related to surgery.10 Studies in this area are of mixed quality, often with a non-standard de®nition of chronic pain and variable assessment measures.11 A recent review concluded that there is a need for research in this area to determine predisposing factors and causes.12 In developing strategies to improve management of acute pain, it is important to base these on the best evidence currently available, with careful assessment of both safety and ecacy for any intervention.13 Regularly updated and high quality web sites can be used, such as the Oxford Pain Website (www.jr2.ox.ac.uk/bandolier/index.html) and the Cochrane database. Use of meta-analysis and systematic reviews should help to provide de®nitive management plans, although these must be ¯exible enough for individual patient variation. It is clear that current management of acute pain is far

636 L. A. Colvin and I. Power

from ideal (Table 1). Principles for optimizing treatment of post-operative pain need to be developed, providing pain relief that allows early mobilization and return to normal function. This review will aim to cover each of these areas: 1. 2. 3. 4.

pain mechanisms; assessment: treatment; approaches to achieving high-quality pain management.

PAIN MECHANISMS A clear understanding of the pathways involved in nociceptive transmission and how these can be a€ected by tissue injury is essential for a logical approach to pain management. The following section will give a brief overview of the scienti®c basis of nociceptive transmission. Nociceptive transmission A basic outline of nociceptive pathways is shown in Figure 2. This provides a framework for understanding the changes occurring in the neuraxis (the peripheral and central nervous system) as a result of tissue injury.20±23 The dorsal root ganglia are where cell bodies of primary sensory neurones are situated. This is where all the neurotransmitters essential for chemical transmission at the synapses are synthesized, before peripheral and central transport to axon terminals.24 The main neurotransmitter involved in fast synaptic transmission is glutamate, acting at the ionotropic receptor, the a-amino-3-hydroxyl-5-methyl-4isoxazole propionic acid (AMPA) receptor. Neuropeptides, such as substance P are also released in response to noxious stimulation.25,26 At the level of the thalamus, multiple areas of the brain can be activated, re¯ecting the complex nature of pain perception. This has been studied in the clinical setting, using brain imaging techniques such as functional magnetic resonance imaging (fMRI) to study the cortical response to nociceptive stimuli.27,28 A recent meta-analysis of brain imaging studies of pain states found that the most consistently activated areas included second somatic and insular regions and the anterior cingulated cortex.29 Response to tissue injury Acute pain has been described as `physiological' pain, whereas `pathological' pain can occur in the absence of ongoing tissue injury (Table 2).30 In the peri-operative period a variety of peripheral and central changes can contribute to an alteration in nociceptive processing. Why these responses can persist in some individuals is as yet poorly understood. The immediate response to a noxious stimulus results in encoding for intensity, duration and location resulting in perception of acute pain in that area. As a result of tissue injury, this direct relationship can alter, with subsequent changes in signs and symptoms (Table 3). The relative importance of di€erent underlying mechanisms may vary between individuals despite similar presentations.31

2

3 4

5

Figure 2. Basic pain pathway. 1. A high intensity stimulus activates polymodal nociceptors in the periphery; 2. These unmodi®ed bare nerve endings initiate action potential generation in small, myelinated A-d(®bres and unmyelinated C ®bres, within a mixed peripheral nerve; 3. Impulses ascend and enter the spinal cord via the dorsal root; synapsing with second order neurones in the super®cial dorsal horn (the substantia gelatinosa) and Rexed's lamina V (mainly A-d(®bres); 4. From the ®rst central synapse, onward transmission includes activation of neurones within the anterolateral spinothalamic tract. Larger myelinated A-d(®bres have also been shown to enter the dorsal horn, synapsing predominantly in laminae III and IV. A low intensity stimulus, such as light touch, would be required to activate these neurones rather than a noxious stimulus92,93; 5. The ascending pathways give o€ branches within the brainstem, then synapse in the thalamus, from where multiple areas within the brain are activated; 6. Descending systems, originating in the periaqueductal grey matter in the midbrain and the nucleus raphe magnus in the pons exert modulatory in¯uences in the spinal cord.

High intensity stimulus

1

6

Brain

Thalamus

Pain management and quality in healthcare 637

638 L. A. Colvin and I. Power Table 2. Physiological vs pathological pain. Physiological

Pathological

. Acute . Initiates withdrawal response: removes from further injury . Protective function . Immobilizes to allow healing

. Can be acute or develop over time . Ongoing tissue damage not necessarily present . Maladaptive . Reduces level of function . Disability and distress

Table 3. Altered symptoms and signs after tissue injury. Symptom/sign

Description

Possible mechanisms

Spontaneous pain

Pain arising without peripheral stimulus

Ectopic discharges Summation of subthreshold electrical activity initiating action potentials

Allodynia

Pain arising from innocuous stimulus

Lower nociceptors threshold (peripheral); rewiring (central)

Primary hyperalgesia

Exaggerated pain response in injured area

Increased neuronal activation; after-discharges of stimulated neurones

Secondary hyperalgesia

Exaggerated pain response outwith injured area

Altered receptive ®eld size; recruitment of previously silent synapses

Peripheral responses As a result of tissue injury, peripheral changes can a€ect both action potential generation and chemical transmission. Peripheral sensitization can occur, with a resultant alteration in response. Speci®c animal models of tissue injury may contribute to our understanding of pain mechanisms and the way in which the neuraxis responds to peripheral injury.32,33 After surgery, the exact changes can depend on the nature of the tissue injury. For example, after thoracotomy, there may be a combination of an acute in¯ammatory response and peripheral nerve injury. In¯ammation As a result of tissue damage a cascade of responses may be initiated that result in an in¯ammatory response with a decrease in activation threshold of peripheral nociceptors.34 Alterations in regional blood ¯ow, recruitment of immune cells, and release of in¯ammatory mediators are all involved in this process (Figure 3). The interaction between in¯ammatory mediators and receptors on sensory neurones is key to this process of peripheral sensitization (Table 4). There are also changes in neuropeptide synthesis within the dorsal root ganglia (Table 5). The mechanisms have been reviewed recently by Kidd and Urban.35 Nerve injury As a result of damage to peripheral nerves, the precise relationship between stimulus and coded input is lost. There are changes in both action potential generation and

Pain management and quality in healthcare 639

action potentials

Sympathetic neurones Thermal Mechanical Chemical

NGF Neurophils

TNF IL-1 PGs

Mast cells

BK Blood vessels

Peptides Adenosine

Figure 3. Peripheral in¯ammatory response. Tissue damage can initiate a series of responses that result in local alterations in blood ¯ow, changes in autonomic activity and recruitment of immune cells into the area. A variety of substances are released into the damaged area including nerve growth factor (NGF), cytokines such as tumour necrosis factor (TNF) and interleukin-1 (IL-1), prostaglandins (PG) and bradykinin (BK) as well as peptides such as substance P and purines such as adenosine. The pH in the area may also decrease. One result of these changes is an increase in responsiveness of sensory neurones, with a resultant increased input into the spinal cord.

Table 4. Peripheral receptors important in nociceptive processing after tissue damage. Receptor

Type

Putative ligands

Vanilloid

Several subtypes, nonselective cation channel

Capsaicin, thermal stimuli, Szallasi et al, 199996 protons, anandamide

Acid-sensing ion channels (ASIC)

Several subtypes throughout CNS; ion channel

Protons (low pH)

Waldmann et al, 199797

Purinergic

Several subtypes; ionotropic

Adenosine and phosphorylated compounds

Burnstock et al, 199698

Proteinases e.g. tryptase, trypsin

Vergnalle et al, 200199

ProteinaseSeveral subtypes; G-proteinactivated receptor coupled

References

neuronal transport (Figure 4).36,37 There are also major alterations in the synthesis of neurotransmitters within the dorsal root ganglia (Table 5).38,39 During nerve regeneration, axonal sprouts generate neuronal activity, and ectopic activity can develop at the site of neuromas or at the dorsal root ganglia.36 The resultant barrage of activity to the spinal cord can contribute to central changes.36

640 L. A. Colvin and I. Power Table 5. Neuropeptide changes in dorsal root ganglia after in¯ammation or peripheral nerve injury. Neuropeptide

Normal

Substance P Calcitonin gene-related peptide Somatostatin Neuropeptide Y Galanin

Small Small Small Little Little

In¯ammation

Nerve injury

" " ! ! !

# # " "

cells cells cells present present

Table 6. Number needed to treat. NNT Codeine 60 mg Paracetamol 1000 mg Morphine 10 mg i.m. Ibuprofen 400 mg Diclofenac 50 mg Paracetamol 1000 mg ‡ codeine 60 mg

16.7 4.6 2.9 2.7 2.3 1.9

From McQuay and Moore, 1998.

Central responses Spinal cord A complex series of responses occur in the spinal cord as a result of peripheral injury. Some of these changes are similar in both in¯ammation and nerve injury, with ampli®cation of sensory transmission. 1. Acutely, the phenomenon known as `wind up' occurs in response to repeated noxious stimulation.40 The key neurotransmitters involved in this include glutamate, acting via the N-methyl-D-aspartate (NMDA) receptor, and substance P, acting via the neurokinin (NK-1) receptor.41 During normal sensory transmission, the NMDA receptor is blocked by magnesium. As a result of repeated high intensity stimulation the voltage-dependent magnesium block is lifted and NMDA receptors are activated by any subsequent release of glutamate.42 2. Changes in gene transcription can occur rapidly, with early alterations in activity of immediate early genes (IEGs) within dorsal horn neurones. Within minutes of intense noxious stimulation, an increase in IEG protein products, such as c-fos and cjun, can be found.43±45 3. There are major changes in neurotransmitter levels both in the dorsal root ganglia and also within the spinal cord itself. The speci®c nature of these changes is dependent on the type and severity of tissue damage.46 4. After nerve injury, there can be sprouting of A-beta ®bres from the deeper dorsal horn into more super®cial areas.47 This may be one of the mechanisms underlying mechanical allodynia.48 In addition to sensory neuronal sprouting, alterations in sympathetic neurones have been found, with sprouts forming around sensory cell bodies in the dorsal root ganglia.49

Pain management and quality in healthcare 641

(a)

Primary afferent drive

Loss of stimulus-encoded input, BUTNew ion channels at: • nerve injury site • along the axon • dorsal root ganglion

Ectopic discharges

(b)

Primary afferent phenotype changes

Retrograde transport blocked

Thermal Mechanical Chemical Peripherally synthesised substances

Figure 4. Peripheral nerve injury changes. (a) Spontaneous ectopic discharges develop at the nerve injury site and within the dorsal root ganglia after nerve injury. There is some evidence that these are related to the generation of spontaneous pain.94 Mechanosensitive areas may also develop around the nerve injury site. (b) Alterations in neuronal transport as a result of nerve injury may contribute to the alterations in the characteristic neurotransmitters synthesized by primary sensory neurones in the dorsal root ganglia. There is some evidence that growth factor substances such as NGF may be important in this process.95

Brain Using brain-imaging techniques such as positron emission tomography scanning and fMRI, it has been possible to study neuronal responses to both acute and chronic pain in humans.28 It is not yet known if these techniques can di€erentiate between excitatory and inhibitory neuronal activity, but they do provide a non-invasive way of assessing neuronal response within the brain.50 Studies of upper limb amputees have revealed a strong positive correlation between cortical remapping and phantom limb pain.51,52 This could be due to alterations in cortical anatomy or unmasking of previously silent synapses.53 There is some evidence from primate studies that cortical and sub-cortical neurones can sprout some distance in response to peripheral nerve injury.54,55

642 L. A. Colvin and I. Power

PAIN ASSESSMENT Firstly we need to consider why it is important to assess pain: . Poor pain assessment is a barrier to good pain control56; . Regular assessment of pain can improve pain management. The use of pain charts has been shown to increase the quality of analgesia. This may be related more to actually having a chart rather than the details of the chart itself.18,57 There is, however, some evidence that pain assessment by both doctors and nurses may underestimate pain severity58; . A reliable technique is needed to compare the ecacy of di€erent treatments59,60; . From a clinical perspective, it is important to know not just how e€ective a treatment or intervention is, but also the level of risk associated with it. This can be assessed by calculating the number-needed-to harm (NNH), as outlined in McQuay and Moore.13

While for research and detailed audit assessment of pain can include complex tools to study all aspects of pain perception, for day-to-day ward-based practice, a quick and simple assessment is required. If it becomes too complex, then the likelihood is that due to stang and time constraints, the assessment will not be carried out, nor will analgesia be delivered appropriately.61 In everyday clinical practice, we need a means of assessment that is simple and practical, yet will reliably predict dicult pain problems to allow early intervention. One example of this is in the CSAG Report on Services for Patients with Back Pain, where early intervention is guided by following detailed protocols that highlight `red ¯ags' (requiring specialist medical assessment) and `yellow ¯ags' (requiring psychological intervention). Assessment tools As pain is a subjective experience, varying between individuals, it could be argued that to attempt to quantify and objectively assess pain is misleading.62 Given that there is no de®nitive physiological variable that changes in a predictable fashion with pain experience, a reliable and sensitive way of interpreting patient reporting of pain must be used. These can be divided into measurements of pain intensity or relief and broader measures of pain experience. Pain intensity measures (Figure 5) These can be: . categorical; . visual analogue; . numerical. Simple rating scales can be used, either verbal or numerical. To be useful, a rating scale must be simple, with minimal re-assessment variability and be sensitive enough to re¯ect response to treatment. A 100 mm visual analogue scale (VAS) is often used, and has been shown to be reliable over time, with little to choose between this and an 11-point numeric rating scale. Both have been shown to be more robust in clinical use than a 4-point verbal rating scale.63,64 The use of di€erent pain measurement techniques can make comparisons between di€erent studies dicult. Comparing results from many randomized controlled trials, it was found that a score of 430 mm

Pain management and quality in healthcare 643

Categorical Rating Scale

Severe Moderate Slight None

Pain intensity 3 2 1 0

Verbal numerical rating 0 = no pain to 10=worst imaginable pain

Visual Analogue Scale (VAS)

No pain

Worst imaginable pain

Global subjective efficacy rating e.g. binary question: ‘is pain half gone?’

Figure 5. Pain measurement: these scales can be used to measure pain intensity or pain relief.

on a VAS for pain intensity was equivalent to moderate or greater pain.65 More recently the use of simple global rating scales has received attention as a means of comparing treatment ecacy.59 Questionnaires Many questionnaires have been designed to measure the overall pain experience; most are used in the research setting. Before using a particular questionnaire, it is important to assess that it has been validated for use in that setting. Factors such as ethnicity must be considered.66 Another example is the widely used McGill Pain Questionnaire, which has been validated extensively, but may be more robust as a total score, rather than individual scores for each component of pain perception.67 A mechanistic approach The use of quantitative sensory testing could be one way to try to link our improved understanding of sensory mechanisms of pain, with diagnosis and directed treatment in the clinic. This technique uses detailed and quanti®able ways in which to test for sensory response to speci®c stimuli, such as graded thermal or mechanical stimuli. Areas of allodynia, hyper-algesia and reduced sensation can be mapped. This technique has been used in the assessment of post-herpetic neuralgia, where it is claimed that it is possible to di€erentiate between peripherally and centrally maintained pains.68±70 Accurate assessment of pain is essential to formulate a cohesive and e€ective management plan. Dicult pain problems can be a mixture of acute tissue injury, neuropathic or radicular pain, exacerbated by anxiety about the underlying disease. An example is outlined in the case history. TREATMENT Paracetamol Systematic reviews have found that paracetamol is e€ective when taken alone or in combination for mild to moderate pain, or as an adjunct to opioids.13,71,72 In one study,

644 L. A. Colvin and I. Power

61 ASA physical status I and II patients were enrolled in a double-blind, randomized, placebo-controlled, parallel study to investigate the e€ect of a combination of paracetamol (acetaminophen) and morphine after open reduction and internal ®xation of acute limb fractures. Patients were given either oral paracetamol (1 g every 4 hours) or placebo as an adjuvant to morphine by patient-controlled analgesia (PCA) postoperatively. The paracetamol group had lower pain scores on day 1 (2.1 vs 3.3; P ˆ 0.03), a shorter average duration of PCA use (35.8 vs 45.5 h; P ˆ 0.03), and greater overall patient satisfaction.72 Non-steroidal anti-in¯ammatory drugs Systematic reviews have found that non-steroidal anti-in¯ammatory drugs (NSAIDs) are e€ective for mild to moderate pain, and are useful adjuncts for severe pain.13,71 However, NSAID use is restricted by side-e€ects: peptic ulceration; antiplatelet actions; aspirin-induced asthma; and renal dysfunction.72 A recent review has indicated that new agents that selectively inhibit the inducible form of cyclo-oxygenase (Cox-2) and spare the constitutive Cox-1 that provides various physiological tissue functions (e.g. prostaglandin protection of the gastroduodenal mucosa, thromboxane-induced platelet aggregation) could represent a signi®cant safety advance and permit their more widespread use for acute pain relief.74 Opioids Opioids are the basis of the management of moderate to severe pain, but they have signi®cant side-e€ects: sedation; respiratory depression; nausea and vomiting; depression of gastrointestinal motility; and disruption of sleep patterns.73 Possibly the most serious limitation of opioid use is inability to control movement-associated pain after surgery. Generally patients given systemic opioids after major surgery achieve adequate analgesia at rest but not during movement, when they may su€er severe discomfort. As a result, the patient minimizes any movement, but modern postoperative rehabilitation regimes following major surgery are dependent upon analgesia that encourages mobilization.75 Local anaesthetic techniques Systematic reviews have found that the use of local anaesthetics for central neural blockade is e€ective for the relief of post-operative pain, is opioid sparing, and therefore facilitates early rehabilitation.73 In addition, neural components of the stress response are blunted by epidural local anaesthesia, and this can be associated with a reduction in peri-operative medical complications.76,77 A cumulative meta-analysis of randomized, controlled trials on the comparative e€ects of post-operative analgesic therapies on pulmonary outcome con®rmed that the use of epidural analgesia is associated with less post-operative respiratory morbidity.76 Multimodal peri-operative management after major urological surgery, employing thoracic epidural analgesia to enable mobilization and oral nutrition, reduces hormonal and metabolic stress and aids convalescence.77 Epidural local anaesthetics are often used in combination with low doses of epidural opioids, which are added to improve the analgesia.73 Unfortunately, even small opioid doses given spinally produce urinary retention, urticaria, nausea and vomiting, and a reduction in gut motility. For example, epidural morphine, but not bupivacaine, inhibits gastric motility on the day after cholecystectomy.78

Pain management and quality in healthcare 645

The use of local anaesthetics for analgesia is not only restricted to the treatment of nociceptive pain by large nerve blockade; lidocaine given systemically is e€ective for the relief of neuropathic pain.73 This anti-neuropathic or `anti-allodynic' e€ect of lidocaine was con®rmed in a rat model of neuropathic pain and the site of action found to be predominantly peripheral.79 Tramadol Tramadol is a synthetic analgesic with both opioid agonist and spinal and central nervous system e€ects through noradrenergic and serotoninergic pathways, with minimal sedation, respiratory depression, gastrointestinal stasis, or abuse potential. The two enantiomers of tramadol may be analgesic by complementary mechanisms.80 In one study of patients having hysterectomy, the subjects were given tramadol 3 mg/ kg or morphine 0.2 mg/kg at wound closure. The authors found that tramadol was as e€ective as morphine in providing post-operative analgesia while permitting more rapid psychomotor recovery.81 Ketamine The use and ecacy of low-dose ketamine in the management of acute post-operative pain was con®rmed in a recent review; ketamine reduces post-operative morphine requirements.82 Unfortunately, even low doses of ketamine can produce side-e€ects such as hallucinations and so alternative NMDA antagonists (e.g. dextromethorphan) are being assessed. In one study, dextromethorphan given by mouth before laparotomy signi®cantly reduced intra-operative opioid requirements.83 Low-dose ketamine therapy is also e€ective for the relief of neuropathic pain.73 Clonidine Clonidine and other a2 agonists can provide e€ective post-operative analgesia84, although side-e€ects of sedation and hypotension limit general use. Traditional use has concentrated on spinal or epidural administration of clonidine to take advantage of the known attenuating e€ect of stimulating spinal a2 receptors on pain perception. Antidepressants and anticonvulsants Systematic reviews con®rm that tricyclic antidepressants and anticonvulsants are e€ective for the relief of neuropathic pain.13,72 The anti-allodynic e€ects and the sites of action (peripheral, spinal or central) of amitriptyline, gabapentin, and lidocaine were investigated using a rat model of neuropathic pain. All were e€ective; gabapentin acted centrally, lidocaine peripherally, whereas amitriptyline appeared to have multiple sites of action.79 Comparing di€erent analgesics McQuay and Moore proposed a method of comparing di€erent drugs: the `numberneeded-to treat' ± the number of patients who must be given active drug for one to achieve at least 50% relief of pain, compared with placebo.13 An NNT of 1 describes an event that occurs in every patient given treatment, but not with placebo. It would be exceptional in clinical studies for the treatment to be 100% e€ective and the placebo

646 L. A. Colvin and I. Power Table 7. Number needed to treat: carbamazepine. Ecacy Trigeminal neuralgia Diabetic neuropathy

2.6 3.0

Adverse events 3.4 2.5

Severe events 24 20

From McQuay and Moore, 1998.

completely ine€ective, and NNTs of 2 or 3 indicate e€ective analgesia (Table 6). NNT for neuropathic pain for ecacy and adverse e€ects (NNH ± see above) are known for the anticonvulsants and tricyclic antidepressants (e.g. carbamazepine)13 (Table 7). APPROACHES TO ACHIEVING HIGH QUALITY PAIN MANAGEMENT Neuropathic pain in the post-operative period and the prevention of chronicity Neuropathic pain is common after some surgical operations, and attempts must be made to prevent chronicity.12,85±88 The problem is dysfunction in the peripheral or central nervous system, as discussed previously; possible causes can include nerve damage by surgical section, compression, stretching, ischaemia, or infection. Changes in the neuraxis can take days and could explain the lack of ecacy of pre-emptive analgesia. Neuropathic pain is more likely in the post-operative period when persistent central changes may be favoured (e.g. inadequate analgesia in the peri-operative period, large operations, pre-existing pain).86±88 It is essential to recognize and treat neuropathic pain after surgery73: . . . . . .

Pain in the absence of ongoing tissue damage; Pain in an area of sensory loss; Paroxysmal, spontaneous pain; Allodynia, hyper-algesia, dysaesthesias; Burning, pulsing, stabbing pain; Poor response (not unresponsiveness) to opioids.

Peri-operative neuropathic pain can be controlled initially with systemic lidocaine (1 mg/kg/hour) or ketamine (5±10 mg/hour), and later with an oral tricyclic antidepressant or anticonvulsant. Pre-emptive analgesia It has been proposed that e€ective analgesia given prior to an insult can act preemptively and reduce central sensitization and post-operative pain.89 Evidence of this from animal experiments is convincing, but clinical studies are less impressive.86 Clinical studies of pre-emptive analgesia can su€er from poor design, containing confounding factors such as the necessity of providing anaesthesia and analgesia to control groups.90 In essence, the clinical signi®cance of pre-emptive analgesia remains uncertain.87 Pre-emptive therapy with a single agent given before surgery is likely to fail, as a€erent neuronal activity into the spinal cord continues for some time afterwards. To have any chance of producing a clinically signi®cant e€ect, pre-emptive

Pain management and quality in healthcare 647

analgesia must include a strategy for modulating the sustained neuronal input into the spinal cord in the post-operative period.86 Multimodal analgesia There is evidence of the bene®ts of employing multimodal analgesia after surgery.91 NSAIDs, paracetamol, local anaesthetics, other non-opioid analgesics and opioids are given in combination to improve analgesia and reduce side-e€ects.73,87 Non-opioid analgesics contribute signi®cantly to multimodal analgesia and recovery of the patient by minimizing opioid side-e€ects (e.g. opioid-induced gastrointestinal stasis). It is possible to eliminate pain after surgery using multimodal analgesia, with a signi®cant reduction in total opioid consumption. Evidence from recent research has suggested that the use of multimodal analgesia after major surgery can hasten recovery and reduce costs.77 Kehlet has proposed that the `pain-free state' should be used to facilitate post-operative mobilization and oral feeding in a process of acute rehabilitation.91 Multimodal analgesia has the particular advantage over unimodal systemic opioid administration of providing excellent pain relief upon movement allowing early mobilization, and is therefore a fundamental component of `fast-track' surgery.2 SUMMARY This review has addressed the question of pain management and quality in healthcare by considering pain mechanisms, assessment, treatment, and approaches to achieving high quality pain relief. The essential point about pain mechanisms is that injury can result in many changes both peripherally and centrally that can in¯uence nociceptive transmission and pain perception. More information is required about these processes in the expectation that preventative strategies might be possible. The accurate assessment of pain is fundamental to the diagnosis of di€erent pain states and also to the appraisal of treatment success or failure. Assessment of pain is particularly important in dicult pain problems that may have mixed nociceptive and neuropathic features. There is a continuing need to develop clinical assessments that may enlighten us about the predisposition of some individuals to develop chronic

Practice points Improve pain management . current pain management is far from ideal3 . education of sta€ and patients is needed6,14 . knowledge of underlying mechanisms of nociception and pain perception is essential15 . adequate and regular patient assessment leads to improved pain control16,17 . e€ective, logically-directed treatment requires multidisciplinary approach9 . stang levels and motivation important - need systems in place to maximize resources18,19 . risk-bene®ts of available treatments need to be considered13 . need to utilize modern analgesic techniques when appropriate2

648 L. A. Colvin and I. Power

Understanding pain mechanisms . peripheral injury can result in many changes both peripherally and centrally that can in¯uence nociceptive transmission and pain perception (Table 3) . peripheral changes include: . in¯ammatory response . altered neuronal ®ring activity . change in retrograde transport of peripherally synthesized substances . neurochemical changes within the dorsal root ganglia . central changes include: . anatomical re-wiring . altered neurotransmitter release in the spinal cord . di€erential response to glutamate . increased neuronal activity . alteration in supraspinal response . improved understanding of these mechanisms should lead to: . more logical use of currently available strategies . development of speci®cally targeted treatment (either peripheral or central) . targeting at-risk surgical patients to decrease the development of persistent pain and improve rapidity of recovery Basic pain assessment . any assessment must take account of all aspects of pain perception . sensory±nociceptive . a€ective±motivational . cognitive±behavioural . history and exam . validated measures to allow assessment of severity and treatment ecacy . rating scales . questionnaires . believe the patient . re-assess . neuropathic pain is diagnosed by clinical features . early treatment is recommended . multimodal analgesia is e€ective and facilitates patient recovery

Research agenda . factors predisposing to developing persistent pain . underlying mechanisms: . models of post-operative pain . clinical models . sensitive and reliable assessment measures . how does the extent of central sensitization relate to the development of postoperative neuropathic pain? . studies of `pre-emptive' strategies modulating pain a€erent and neuronal activity throughout the peri-operative period . outcome studies of strategies maximizing the bene®ts of multimodal analgesia . does multimodal analgesia reduce chronic pain after surgery?

Pain management and quality in healthcare 649

Case History±Management of a dicult case . An 18-year-old boy had thoracic surgery for excision of a recurrent osteosarcoma. He had been treated for 4 years at the local children's hospital, but on this occasion the surgery was carried out in the regional neurosurgical unit. His pain was dicult to deal with post-operatively, with respiratory depression resulting from his use of PCA morphine, but without adequate analgesia. Nursing sta€ found him and his family dicult to deal with. Assessment revealed high levels of parental anxiety, signi®cant pain both at rest and on movement, allodynia in a radicular distribution.

Key points . social issues±parents unhappy about move from familiar environment of children's hospital; lower stang levels with no specialist paediatric training; . emotional±adolescence and patient wish for more independence; fear of underlying cancer and of the future; concern about addiction to morphine; . sensory changes±neuropathic pain, with non-opioid responsive component. As a result of careful assessment several treatment strategies were used: . pharmacological: PCA ketamine, transfer onto oral opioids±MST/sevredol, regular paracetamol/NSAIDs, addition of adjuvant analgesia±amitriptyline and gabapentin (NNT noted) . discussion with nursing sta€±involvement of Macmillan nurse from children's hospital . liaison with inpatient palliative care service, including psychology input. The patient was re-assessed at regular intervals, and discharged home with good pain control and continued support organized in the community setting.

pain after acute injury. The scienti®c evidence for the use of di€erent agents for the treatment of pain is increasing rapidly, and so the concepts of NNT and NNH should be expanded so that clinicians and patients have reliable information on the risk± bene®t ratios of commonly used analgesics. With the rapid expansion in understanding of pain mechanisms, we need to know which analgesics can modify these changes. Pre-emptive analgesia should be reconsidered using strategies for modulating the sustained neuronal input into the spinal cord in the post-operative period. More outcome studies are required to explore the true value of multimodal analgesia, and the question of the prevention of chronic pain after surgery must be addressed. REFERENCES 1. Merskey H. IASP Subcommittee on Taxonomy: Classi®cation of chronic pain. Pain 1986; 3: S216±S222. * 2. Wilmore DW & Kehlet H. Management of patients in fast track surgery. British Medical Journal 2001; 322: 473±476. 3. The Royal College of Surgeons of England, The College of Anaesthetists. Report of the Working Party on Pain after Surgery. London: HMSO, 1990. 4. Justins DM. Postoperative pain: a continuing challenge. [review]. Annals of the Royal College of Surgeons of England 1992; 74: 78±79.

650 L. A. Colvin and I. Power 5. Bruster S, Jarman B, Bosanquet N et al. National survey of hospital patients. British Medical Journal 1994; 309: 1542±1546. * 6. Harmer M & Davies KA. The e€ect of education, assessment and a standardized prescription on postoperative pain management. The value of clinical audit in the establishment of acute pain services. Anaesthesia 1998; 53: 424±430. 7. Straw P, Bruster S, Richards N & Lilley S-J. Situp, take notice. Health Service Journal 2000; 5704: 24±26. 8. Mann C, Beziat C, Pouzeratte Y et al. [Quality assurance program for postoperative pain management: impact of the Consensus Conference of the French Society of Anesthesiology and Intensive Care]. Annales Francaises d'Anesthesie et de Reanimation 2001; 20: 246±254. 9. Bardiau FM, Braeckman MM, Seidel L et al. E€ectiveness of an acute pain service inception in a general hospital. Journal of Clinical Anaesthesia 1999; 11: 583±589. 10. Davies HTO, Crombie IK, Macrae WA & Rogers KM. Pain clinic patients in northern Britain. Pain Clinic 1992; 5: 129±135. 11. Macrae WA & Davies HTO. Chronic postsurgical pain. In Crombie IK (ed.) Epidemiology of Pain, 1st edn, pp 125±142. Seattle: IASP, 1999. *12. Macrae WA. Chronic pain after surgery. British Journal of Anaesthesia 2001; 87: 88±98. *13. McQuay H & Moore A. An Evidence-based Resource for Pain Relief. Oxford: Oxford University Press, 1998. 14. Dalton JA, Blau W, Lindley C et al. Changing acute pain management to improve patient outcomes: an educational approach. Journal of Pain and Symptom Management 1999; 17: 277±287. 15. Woolf CJ. Somatic pain ± pathogenesis and prevention. British Journal of Anaesthesia 1995; 75: 169±176. 16. Chibnall JT & Tait RC. Pain assessment in cognitively impaired and unimpaired older adults: a comparison of four scales. Pain 2001; 92: 173±186. 17. Willson H. Factors a€ecting the administration of analgesia to patients following repair of a fractured hip. Journal of Advanced Nursing 2000; 31: 1145±1154. 18. Rawal N & Berggren L. Organization of acute pain services: a low cost model. Pain 1994; 57: 117±123. 19. Parsons G & Edwards P. Acute pain algorithm. Professional Nursing 1999; 15: 136. 20. Stamford JA. Descending control of pain. British Journal of Anaesthesia 1995; 75: 217±227. 21. Swett JE & Woolf CJ. The somatotopic organization of primary a€erent terminals in the super®cial laminae of the dorsal horn of the rat spinal-cord. Journal of Comparative Neurology 1985; 231: 66±77. 22. Cervero F & Iggo A. The substantia gelatinosa of the spinal cord: a critical review. Brain 1980; 103: 717±772. 23. Bouhassira D, Chitour D, Villaneuva L & Le Bars D. The spinal transmission of nociceptive information: modulation by the caudal medulla. Neuroscience 1995; 69: 931±938. 24. Willis WD & Coggeshall RE. Sensory Mechanisms of the Spinal Cord, 2nd edn. New York, London: Plenum Press, 1991. 25. Duggan AW, Hendry IA, Morton CR et al. Cutaneous stimuli releasing immunoreactive substance P in the dorsal horn of the cat. Brain Research 1988; 451: 261±273. 26. Allen BJ, Rogers SD, Ghilardi JR et al. Noxious cutaneous thermal stimuli induce a graded release of endogenous substance P in the spinal cord: imaging peptide action in vivo. Journal of Neuroscience 1997; 17: 5921±5927. 27. Berman HH, Kim KHS, Talati A & Hirsch J. Representation of nociceptive stimuli in primary sensory cortex. Neuroreport 1998; 9: 4179±4187. *28. Davis KD. The neural circuitry of pain as explored with functional MRI. Neurological Research 2000; 22: 313±317. 29. Peyron R, Laurent B & Garcia-Larrea L. Functional imaging of brain responses to pain. A review and meta-analysis (2000). Neurophysiologie Clinique-Clinical Neurophysiology 2000; 30: 263±288. 30. Woolf CJ. Recent advances in the pathophysiology of acute pain [comment]. British Journal of Anaesthesia 1989; 63: 139±146. *31. Woolf CJ & Mannion RJ. Neuropathic pain: aetiology, symptoms, mechanisms, and management [see comments]. Lancet 1999; 353: 1959±1964. 32. Kim KJ, Yoon YW & Chung JM. Comparison of three rodent neuropathic pain models. Experimental Brain Research 1997; 113: 200±206. 33. Abram SE. Necessity for an animal model of postoperative pain. Anesthesiology 1997; 86: 1015±1017. 34. Schaible H-G & Grubb BD. A€erent and spinal mechanisms of joint pain. Pain 1993; 55: 5±54. 35. Kidd BL & Urban LA. Mechanisms of in¯ammatory pain. British Journal of Anaesthesia 2001; 87: 3±11. 36. Arnarson A, Michaelis M & Janig W. Development of ectopic spontaneous activity, mechano- and thermosensitivity in axotomized sural nerve ®bres in rats. P¯ugers Archiv-European Journal of Physiology 1997; 433: P201. 37. Tal M & Devor M. Ectopic discharge in injured nerves: comparison of trigeminal and somatic a€erents. Brain 1992; 579: 148±151.

Pain management and quality in healthcare 651 38. Nahin RL, Ren K, De LeoÂn M & Ruda M. Primary sensory neurons exhibit altered gene expression in a rat model of neuropathic pain. Pain 1994; 58: 95±108. 39. Hokfelt T, Zhang X & Wiesenfeld-Hallin Z. Messenger plasticity in primary sensory neurons following axotomy and its functional implications. Trends in Neuroscience 1994; 17: 22±29. *40. Davis SN & Lodge D. Evidence for involvement of N-methyl-D-aspartatic acid receptors in `wind up' of class 2 neurons in the dorsal horn of the rat. Brain Research 1987; 424: 402±406. 41. Thompson SW, Dray A & Urban L. Injury-induced plasticity of spinal re¯ex activity: NK1 neurokinin receptor activation and enhanced A- and C-®ber mediated responses in the rat spinal cord in vitro. Journal of Neuroscience 1994; 14: 3672±3687. 42. Woolf CJ & Thompson SWN. The induction and maintenance of central sensitization is dependent on Nmethyl-D-aspartic acid receptor activation; Implications for the treatment of post-injury pain hypersensitivity states. Pain 1991; 44: 293±299. 43. DeLander GE, Schott E, Brodin E & Fredholm BB. Spinal expression of mrna for immediate early genes in a model of chronic pain. Acta Physiologica Scandinavica 1997; 161: 517±525. 44. Leah JD, Sandkuhler J, Herdegen T et al. Potentiated expression of fos protein in the rat spinal cord following bilateral noxious cutaneous stimulation. Neuroscience 1992; 48: 525±532. 45. Munglani R & Hunt SP. Molecular biology of pain. British Journal of Anaesthesia 1995; 75: 186±192. 46. Honore P, Rogers SD, Schwei MJ et al. Murine models of in¯ammatory, neuropathic and cancer pain each generates a unique set of neurochemical changes in the spinal cord and sensory neurons. Neuroscience 2000; 98: 585±598. 47. Woolf CJ, Shortland P & Coggeshall RE. Peripheral nerve injury triggers central sprouting of myelinated a€erents. Nature 1992; 335: 75±78. *48. Cervero F & Laird JMA. Mechanisms of touch-evoked pain (allodynia): a new model. Pain 1996; 68: 13±23. 49. McLachlan EM, Janig W, Devor M & Michaelis M. Peripheral nerve injury triggers noradrenergic sprouting within dorsal root ganglia. Nature 1993; 363: 543±545. 50. Logothetis NK, Guggenberger H, Peled S & Pauls J. Functional imaging of the monkey brain. Nature Neuroscience 1999; 2: 555±562. *51. Flor H, Elbert T, Knecht S et al. Phantom-limb pain as a perceptual correlate of cortical reorganization following arm amputation. Nature 1995; 375: 482±484. 52. Karl A, Birbaumer N, Lutzenberger W et al. Reorganization of motor and somatosensory cortex in upper extremity amputees with phantom limb pain. Journal of Neuroscience 2001; 21: 3609±3618. 53. Birbaumer N, Lutzenberger W, Montoya P et al. E€ects of regional anesthesia on phantom limb pain are mirrored in changes in cortical reorganization. Journal of Neuroscience 1997; 17: 5503±5508. 54. Florence SL, Taub HB & Kaas JH. Large-scale sprouting of cortical connections after peripheral injury in adult macaque monkeys [see comments]. Science 1998; 282: 1117±1121. 55. Florence SL, Hackett TA & Strata F. Thalamic and cortical contributions to neural plasticity after limb amputation. Journal of Neurophysiology 2000; 83: 3154±3159. 56. Von Roenn JH, Cleeland CS, Gonin R et al. Physician attitudes and practice in cancer pain management. Annals of Internal Medicine 1993; 119: 121±126. 57. Gould TH, Crosby DL, Harmer M et al. Policy for controlling pain after surgery: e€ect of sequential changes in management. British Medical Journal 1992; 305: 1187±1193. 58. Krivo S & Reidenberg MM. Assessment of patients' pain. New England Journal of Medicine 1996; 334: 59. 59. Collins SL, Edwards J, Moore RA et al. Seeking a simple measure of analgesia for mega-trials: is a single global assessment good enough? Pain 2001; 91: 189±194. 60. Jenkinson C, Carroll D, Egerton M et al. Comparison of the sensitivity to change of long and short form pain measures. Quality of Life Research 1995; 4: 353±357. 61. McQuay H, Moore A & Justins DM. Treating acute pain in hospital. British Medical Journal 1997; 314: 1531±1535. 62. Cox P. The fallibility of pain scores. Anaesthesia 2001; 56: 499±500. 63. DeLoach LJ, Higgins MS, Caplan AB & Sti€ JL. The Visual Analogue Scale in the immediate postoperative period: intrasubject variability and correlation with a numeric scale. Anesthesia and Analgesia 1998; 86: 102±106. 64. Hartrick CT. A four-category verbal rating scale (VRS-4), an 11-point numeric rating scale (NRS-11), and a 100-mm visual analog scale (VAS) were compared in the assessment of acute pain after oral surgery. Clinical Journal of Pain 2001; 17: 104±105. 65. Collins SL, Moore RA & McQuay HJ. The visual analogue pain intensity scale: what is moderate pain in millimetres? Pain 1997; 72: 95±97. 66. Bergstrom G, Jensen IB, Bodin L et al. Reliability and factor structure of the Multidimensional Pain Inventory±Swedish Language Version (MPI-S). Pain 1998; 75: 101±110. 67. Turk DC, Rudy TE & Salovey P. The McGill Pain Questionnaire reconsidered: con®rming the factor structure and examining appropriate uses. Pain 1985; 21: 385±397.

652 L. A. Colvin and I. Power 68. Attal N, Brasseur L, Parker F et al. E€ects of gabapentin on the di€erent components of peripheral and central neuropathic pain syndromes: A pilot study. European Neurology 1998; 40: 191±200. 69. Attal N & Bouhassira D. Mechanisms of pain in peripheral neuropathy. Acta Neurologica Scandinavica 1999; 100: 12±24. 70. Rowbotham M, Harden N, Stacey B et al. Gabapentin for the treatment of postherpetic neuralgia ± A randomized controlled trial. Journal of the American Medical Association 1998; 280: 1837±1842. 71. McQuay HJ. Acute Pain. In Tramer MJ (ed.) Evidence-based Resource in Anaesthesia and Analgesia, pp 87±103. London: BMJ Books, 2000. 72. Schug SA, Sidebotham DA, Mcguinnety M et al. Acetaminophen as an adjunct to morphine by patientcontrolled analgesia in the management of acute postoperative pain. Anesthesia and Analgesia 1998; 87: 368±372. *73. NHMRC. Acute Pain Management: Scienti®c Evidence. Canberra, Australia: National Health and Medical Research Council, 1999. 74. Kam PCA & Power I. New selective Cox-2 inhibitors. Pain Reviews 2000; 7: 3±13. 75. Kehlet H. Organizing postoperative accelerated recovery programs. Regional Anesthesia 1996; 21: 149±151. 76. Ballantyne JC, Carr DB, Deferranti S et al. The comparative e€ects of postoperative analgesic therapies on pulmonary outcome: cumulative meta-analyses of randomized, controlled trials. Anesthesia and Analgesia 1998; 86: 598±612. 77. Brodner G, Van Aken H, Hertle L et al. Multimodal perioperative management ± combining thoracic epidural analgesia, forced mobilization, and oral nutrition reduces hormonal and metabolic stress and improves convalescence after major urologic surgery. Anesthesia and Analgesia 2001; 92: 1594±1600. 78. Thorn SE, Wattwil M & Naslund I. Postoperative epidural morphine, but not epidural bupivacaine, delays gastric-emptying on the 1st day after cholecystectomy. Regional Anesthesia 1992; 17: 91±94. 79. Abdi S, Lee DH & Chung JM. The anti-allodynic e€ects of amitriptyline, gabapentin, and didocaine in a rat model of neuropathic pain. Anesthesia and Analgesia 1998; 87: 1360±1366. 80. Eggers KA & Power I. Tramadol [editorial]. British Journal of Anaesthesia 1995; 74: 247±249. 81. Coetzee JF & Vanloggerenberg H. Tramadol or morphine administered during operation ± a study of immediate postoperative e€ects after abdominal hysterectomy. British Journal of Anaesthesia 1998; 81: 737±741. 82. Schmid RL, Sandler AN & Katz J. Use and ecacy of low-dose ketamine in the management of acute postoperative pain: a review of current techniques and outcomes [review]. Pain 1999; 82: 111±125. 83. Grace RF, Power I, Zammit A et al. Preoperative dextromethorphan reduces intraoperative but not postoperative morphine requirements after laparatomy. Anesthesia and Analgesia 1998; 87: 1135±1138. 84. Sandler AN. The role of clonidine and alpha(2)-agonists for postoperative analgesia. Canadian Journal of Anaesthesia 1996; 43: 1191±1194. 85. Hayes C & Molloy AR. Neuropathic pain in the perioperative period. In Molloy AR & Power I (eds) Acute and Chronic Pain, Vol. 35 (2), pp 67±81. Philadelphia: Lippincott-Raven, 1997. 86. Cousins MJ, Power I & Smith G. Pain ± a persistent problem. Regional Analgesia and Pain Medicine 2000; 25: 6±21. 87. Cousins MJ & Power I. Acute and postoperative pain. In Wall PD & Melzack R (eds) Textbook of Pain, 4th edn. London: Churchill Livingstone, 1999. 88. Perkins FM & Kehlet H. Chronic pain as an outcome of surgery ± a review of predictive factors. Anesthesiology 2000; 93: 1123±1133. 89. Woolf CJ & Chong MS. Preemptive analgesia-treating postoperative pain by preventing the establishment of central sensitization. [review]. Anesthesia and Analgesia 1993; 77: 362±379. *90. Kissin I. Preemptive analgesia ± why its e€ect is not always obvious. Anesthesiology 1996; 84: 1015±1019. 91. Kehlet H & Dahl JB. The value of `multimodal' or `balanced analgesia' in postoperative pain treatment. [review]. Anesthesia and Analgesia 1993; 77: 1048±1056. 92. Brown AG. The dorsal horn of the spinal-cord. Quarterly Journal Of Experimental Physiology and Cognate Medical Sciences 1982; 67: 193±212. 93. Cesare P & McNaughton P. Peripheral pain mechanisms. Current Opinion in Neurobiology 1997; 7: 493±499. 94. Ossipov MH, Lai J, Malan P & Porreca F. Spinal and supraspinal mechanisms of neuropathic pain. New Medications for Drug Abuse 2000; 909: 12±24. 95. Friedman B, Wong V & Lindsay RM. Axons, schwann cells and neurotrophic factors. The Neuroscientist 1995; 1: 192±198. 96. Szallasi A & Blumberg PM. Vanilloid (capsaicin) receptors and mechanisms. Phamacological Reviews 1999; 51: 159±211. 97. Waldmann R, Champigny G, Bassilana F et al. A proton-gated cation channel involved in acid-sensing Nature 1997; 386: 173±177.

Pain management and quality in healthcare 653 98. Burnstock G & Wood JN. Purinergic receptors: their role in nociception and primary a€erent neurotransmission. Current Opinion in Neurobiology 1996; 6: 526±532. 99. Vergnalle N, Bunnett NW, Sharkey KA et al. Proteinase-activated receptor-2 and hyperalgesia: A novel pain pathway. Nature Medicine 2001; 7: 821±826.