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Cardiotocography and fetal biophysical profiling are twotools often used to determine the physiological status of thepotentially compromised fetus. Unfortunately these tools haveno benefit in predicting and preventing poor outcomes in highrisk pregnancies. Some evidence shows, however, thatcomputerised cardiotocography is more accurate in predictingpoor outcome than subjective clinical assessment alone.The biophysical profile takes into account the tone,movement, breathing, heart rate pattern of the fetus, and liquorvolume.

DopplerUmbilical arterial blood flow becomes abnormal when there isplacental insufficiency—for example, secondary topre-eclampsia. Doppler measurement of fetoplacental bloodvelocity may be a more useful test of fetal wellbeing thancardiocotography or biophysical profiling. However, a recentsystematic review of randomised controlled trials did notindicate that Doppler measurement of fetoplacental bloodvelocity is associated with a substantial reduction in perinatalmortality. Additionally, there is uncertainty over the idealfrequency of examination and the optimum threshold forintervention. Umbilical artery Doppler ultrasonography todetect fetal compromise is part of routine obstetric practice forhigh risk pregnancies in many countries, so there may not befurther randomised controlled trials in high risk populations.

Recent studies have investigated the use of middle cerebralartery and ductus venosus Doppler waveforms in evaluatingcardiovascular adaptations to placental insufficiency. Results arepromising, although the effect on important outcomes whenused as part of clinical practice has yet to be evaluated.

Preventing pre-eclampsiaWomen who have had pre-eclampsia can be given low doses ofaspirin in a future pregnancy. In a systematic review ofrandomised trials that involved over 30 000 women,prophylactic antiplatelet treatment that was started in the firsttrimester reduced the risk of recurrent pre-eclampsia andstillbirth and neonatal death by about 15%.

Calcium supplements in the diet can reduce the risk ofhypertension and pre-eclampsia associated with pregnancy forwomen at high risk, and in communities with a low intake ofdietary calcium.

Mode of deliveryVaginal delivery of the preterm infant is associated with lowermaternal morbidity than delivery by caesarean section. It isimportant, however, to consider the following points:x Obstetric historyx Likely interval between induction and delivery in the contextof deterioration of maternal healthx Probability of achieving a vaginal delivery versus risk ofemergency caesarean sectionx Presentation and prelabour condition of the fetus.

Breech deliveryIn developed countries with good antenatal services most termbreech pregnancies are managed by elective caesarean section,as are many multiple pregnancies. The increase in caesareansections has caused a loss of obstetric skill in vaginal delivery ofbreech and multiple pregnancies. Most planned preterm breechand twin pregnancies are delivered by elective caesarean sectioneven though there is no clear evidence of benefit.

Monitoring the fetal heart rate can help determine the physiologicalwellbeing of the fetus. This cardiotocogram shows fetal tachycardia withreduced variability and decelerations

Doppler measurement of umbilical arterial flow is used to test fetalwellbeing. This recording shows reversed end diastolic velocity waveform

Doppler measurement of middle cerebral arterialflow. Abnormal waveforms can show cardiovascularadaptations to placental insufficiency

Induction of labour is most likely to besuccessful in a woman with a favourablecervix (as assessed by the Bishop score)who has had no caesarean sections andhas a history of vaginal delivery

ABC of preterm birth

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IncidenceOver the past 20-30 years the incidence of preterm birth inmost developed countries has been about 5-7% of live births.The incidence in the United States is higher, at about 12%.Some evidence shows that this incidence has increased slightlyin the past few years, but the rate of birth before 32 weeks'gestation is almost unchanged, at 1-2%.

Several factors have contributed to the overall rise in theincidence of preterm birth. These factors include increasingrates of multiple births, greater use of assisted reproductiontechniques, and more obstetric intervention.

Part of the apparent rise in the incidence of preterm birth,however, may reflect changes in clinical practice. Increasingly,ultrasonography rather than the last menstrual period date isused to estimate gestational age. The rise in incidence may alsobe caused by inconsistent classification of fetal loss, still birth,and early neonatal death. In some countries, infants who areborn after very short gestations (less than 24 weeks) are morelikely to be categorised as live births.

With the limited provision of antenatal or perinatal care indeveloping countries, there are difficulties with populationbased data. Registration of births is incomplete and informationis lacking on gestational age, especially outside hospital settings.Data that are collected tend to give only estimates of perinataloutcomes that are specific to birth weight. These data show thatthe incidence of low birth weight is much higher in developingcountries than in developed countries with good care services.

In developing counties, low birth weight is probably causedby intrauterine growth restriction. Maternal undernutrition andchronic infection in pregnancy are the main factors that causeintrauterine growth restriction. Although the technical advancesin the care of preterm infants have improved outcomes indeveloped countries with well resourced care services, they havenot influenced neonatal morbidity and mortality in countriesthat lack basic midwifery and obstetric care. In these developingcountries, the priorities are to reduce infection associated withdelivery, identify and manage pregnancies of women who are atrisk, and provide basic neonatal resuscitation.

Causes of preterm birthSpontaneous preterm labour and rupture of membranesMost preterm births follow spontaneous, unexplained pretermlabour, or spontaneous preterm prelabour rupture of theamniotic membranes. The most important factors thatcontribute to spontaneous preterm delivery are a history ofpreterm birth and poor socioeconomic background of themother.

Interaction of the many factors that contribute to theassociation of preterm birth with socioeconomic status iscomplex. Mothers who smoke cigarettes are twice as likely asnon-smoking mothers to deliver before 32 weeks of gestation,although this effect does not explain all the risk associated withsocial disadvantage.

Evidence from meta-analysis of randomised controlled trialsshows that antenatal smoking cessation programmes can lowerthe incidence of preterm birth. Women from poorersocioeconomic backgrounds, however, are least likely to stopsmoking in pregnancy although they are most at risk ofpreterm delivery.

No studies have shown that other interventions, such asbetter antenatal care, dietary advice, or increased social supportduring pregnancy, improve perinatal outcomes or reduce thesocial inequalities in the incidence of preterm delivery.

Year of birth

Pret

erm

birt

h ra

te (%

)

1980 1985 1990 1995 19990

2

3

4

5

6

7

1

Total

33-36 weeks

29-32 weeks

<28 weeks

Rates of preterm birth, by gestational age, in singleton live births in NewZealand, 1980-99

Percentage of preterm births in United States*

Gestational ageYear <37 weeks <32 weeks1981 9.4 1.811990 10.6 1.922000 11.6 1.93*Adapted from MacDorman MF et al. Pediatrics 2002;110:1037-52

Risk factors for babies with low birth weight in developingcountriesx Infection, especially malariax Poor maternal nutritionx Maternal anaemiax Low maternal body mass index before pregnancyx Short interval between pregnancies

Cervicalincompetence/

uterine malformationAntepartumhaemorrhage

Intrauterinegrowth restriction

Pregnancyassociated

hypertension

Preterm prelabourrupture of membranes

Spontaneouspreterm labour

Multiplepregnancy

Causes of preterm birth

Smoking cessation programmes can lower the incidence of preterm birth

ABC of preterm birth

2

The rate of preterm birth varies between ethnic groups. In theUnited Kingdom, and even more markedly in the United States,the incidence of preterm birth in black women is higherthan that in white women of similar age. The reason for thisvariation is unclear because differences remain after taking intoaccount socioeconomic risk factors.

Multiple pregnancy and assisted reproductionMultifetal pregnancy increases the risk of preterm delivery.About one quarter of preterm births occur in multiplepregnancies. Half of all twins and most triplets are bornpreterm. Multiple pregnancy is more likely than singletonpregnancy to be associated with spontaneous preterm labourand with preterm obstetric interventions, such as induction oflabour or delivery by caesarean section.

The incidence of multiple pregnancies in developedcountries has increased over the past 20-30 years. This rise ismainly because of the increased use of assisted reproductiontechniques, such as drugs that induce ovulation and in vitrofertilisation. For example, the birth rate of twins in the UnitedStates has increased by 55% since 1980. The rate of higherorder multiple births increased fourfold between 1980 and1998, although this rate has decreased slightly over the past fiveyears. In some countries two embryos only are allowed to beplaced in the uterus after in vitro fertilisation to limit theincidence of higher order pregnancy.

Singleton pregnancies that follow assisted reproduction areat a considerable increased risk of preterm delivery, probablybecause of factors such as cervical trauma, the higher incidenceof uterine problems, and possibly because of the increased riskof infection.

Maternal and fetal complicationsAbout 15% to 25% of preterm infants are delivered because ofmaternal or fetal complications of pregnancy. The principalcauses are hypertensive disorders of pregnancy and severeintrauterine growth restriction, which is often associated withhypertensive disorders. The decision to deliver these infants isinformed by balancing the risks of preterm birth for the infantagainst the consequence of continued pregnancy for themother and fetus. Over the past two decades improvedantenatal and perinatal care has increased the rate of iatrogenicpreterm delivery. During that time the incidence of still birth inthe third trimester has fallen.

Outcomes after preterm birthBroadly, outcomes improve with increasing gestational age,although for any given length of gestation survival varies withbirth weight. Other factors, including ethnicity and gender alsoinfluence survival and the risk of neurological impairment.

The outcomes for preterm infants born at or after 32 weeksof gestation are similar to those for term infants. Most seriousproblems associated with preterm birth occur in the 1% to 2%of infants who are born before 32 completed weeks' gestation,and particularly the 0.4% of infants born before 28 weeks'gestation. Modern perinatal care and specific interventions,such as prophylactic antenatal steroids and exogenoussurfactants, have contributed to some improved outcomes forvery preterm infants. The overall prognosis remains poor,however, particularly for infants who are born before 26 weeks'gestation.

The outcome for preterm infants of multiple pregnanciescan be better than that of singleton pregnancies of the samegestation. In term infants the situation is reversed. The

Twin pregnancy increases the risk of preterm birth

Preterm births by ethnic group in UnitedStates 2000*x Black—17.3%x Hispanic—11.2%x Non-Hispanic white—10.4%*Adapted from MacDorman MF et al. Pediatrics2002;110:1037-52

Gestation (weeks)

Prob

abili

ty o

f mor

talit

y

22 23 24 25 26 27 28 29 30 31 320

0.2

0.4

0.6

0.8

1.01988-90

1993-94

1998-99

Mortality in UK neonatal intensive care cohorts of infants born before 32weeks’ gestation. Adapted from Parry G, et al. Lancet 2003;361:1789-91

Outcomes for infants live born before 26 weeks’gestation in British Isles*

Gestation(weeks)

Survival todischarge (%)

Survival withouthandicap at 30

months (%)22 1 0.723 11 524 26 1225 44 23*Adapted from Wood NS et al. New Engl J Med 2000;343:378-84

Epidemiology of preterm birth

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3 Difficult painLesley Colvin, Karen Forbes, Marie Fallon

Pain occurs in up to 70% of patients with advanced cancer, andin about 65% of patients dying from non-malignant disease. Formost of these patients (about 80%) pain can be controlled byusing a simple, stepwise approach and a limited number of oralanalgesics as set out in the WHO’s analgesic ladder (chapter 2).About 10% of patients will require more complex, sometimesinvasive, management to control their pain, leaving another10% with cancer pain that is difficult to control.

This group of patients with “difficult pain” present complexmanagement problems. Their pain often falls into one of threecategories: it responds poorly to opioids, it is episodic andbreaks through despite background opioid analgesia, oropioids are irrelevant in its management.

Opioid irrelevant painPain is not just a physical experience. Patients with pain thatdoes not respond to escalating doses of opioids should bereassessed and other contributors to their pain explored. “Totalpain” is best treated by exploring the underlying issues, ratherthan using opioids. The term “total pain” is used to describe thefinal sensation of pain perceived by a patient, acknowledgingthat this perception can be exaggerated by factors other than aphysically noxious stimulus—for example, psychosocial distress.

Pain that responds poorly to opioidsThe European Association for Palliative Care (EAPC) guidelineson the use of morphine and alternative opioids in cancer painconfirm oral morphine as the opioid of choice for moderate tosevere pain. Dose titration with normal release morphine everyfour hours, with the same dose for breakthrough pain asrequired, is suggested. The patient’s 24 hour morphinerequirement can then be reassessed daily and their regular doseadjusted accordingly. Measures to treat such patients includeexploring psychosocial issues, managing the side effects,reducing the dose of opioid, switching to an alternative opioid,or changing the route of administration. The use of adjuvantdrugs or co-analgesics may be appropriate, depending on thecause of the pain. Many such patients will have neuropathic pain.

Neuropathic painNociceptive pain results from real or potential tissue damage.Neuropathic pain is caused by damage to the peripheral orcentral nervous system. A simple definition is “pain in an area ofabnormal sensation.” Pain may be described as aching, burning,shooting, or stabbing and may be associated with abnormalsensation; normal touch is perceived as painful (allodynia). Itmay be caused by tumour invasion or compression but also bysurgery, radiotherapy, and chemotherapy. Many patients haveneuropathic pain that responds to opioids, and so initialmanagement should include a trial of opioids. Patients whoremain in pain will require additional measures.

The early addition of adjuvant analgesics, such as a tricyclicantidepressant or an anticonvulsant, should be considered. Thenumber needed to treat is 3 for both categories. There is noevidence for a specific adjuvant for specific descriptors ofneuropathic pain.

Computed tomography scan showing advanced pelvic disease fromcolorectal tumour resulting in severe pain

Patients may be overwhelmed by their situation and thecentral nervous system can express this as physical pain,though social, psychological, or spiritual factors may bemajor components

About 10% of patients will have pain that responds poorly toopioids and is uncontrolled even with a dose of morphinesufficient to give them intolerable side effects

Classical changes associated with a brachial plexopathy due to a rightPancoast tumour: oedema, trophic changes, muscle wasting

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In addition, there is no evidence for combining adjuvants.In clinical practice, an adjuvant is chosen for an individualpatient after all symptoms and potential side effects areconsidered. Doses should be titrated to balance analgesia withadverse effects. If titration has reached a limit and pain hasonly partially responded then a second adjuvant may be addedin some cases. This usually means a reduction in the dose ofthe first. A common example of combining adjuvants isgabapentin, which at maximum tolerated dose can sometimesbe reduced to allow the addition of amitriptyline.

Difficult pain

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Adjuvant analgesics*

Drug Dose Indications Side effectsNSAIDs—for example, 50 mg oral every 8 hours (slow Bone metastases, soft tissue Gastric irritation and bleeding, fluiddiclofenac or COX 2 NSAID release 75 mg every 12 hours); infiltration, liver pain, retention, headache; caution in renal(evidence of GI side effects) 100 mg per rectum once a day inflammatory pain impairmentSteroids—for example, 8–16 mg a day; use in morning; Raised intracranial pressure, Gastric irritation if used together withdexamethasone titrate down to lowest dose that nerve compression, soft NSAID, fluid retention, confusion,

controls pain tissue infiltration, Cushingoid appearance, candidiasis,liver pain hyperglycaemia

Gabapentin 100–300 mg nightly (starting dose) Nerve pain of any cause Mild sedation, tremor, confusion(titrate to 600 mg every 8 hours; higher dose may be needed)

Amitriptyline (evidence for 25 mg nightly (starting dose) Nerve pain of any cause Sedation, dizziness, confusion, dryall tricyclics) 10 mg nightly (in elderly mouth, constipation, urinary retention;

patients) avoid in patients with cardiac diseaseCarbamazepine (evidence 100–200 mg nightly Nerve pain of any cause Vertigo, sedation, constipation, rashfor all anticonvulsants) (starting dose)*Drugs with a primary indication other than pain, but analgesic when used as above.

Non-pharmacological techniquesThere are several non-pharmacological techniques for themanagement of neuropathic pain.

Psychological techniquesPsychological techniques, such as cognitive behaviouraltherapies, include simple relaxation, hypnosis, and biofeedback.These methods focus on overt behaviour and underlyingcognitions and train the patient in coping strategies andbehavioural techniques. Though this is clearly of more use inchronic non-malignant pain rather than in patients with cancerpain, simple relaxation techniques should not be forgotten.

Stimulation therapiesAcupuncture has been used successfully in eastern medicine forcenturies. There does seem to be a scientific basis foracupuncture, with release of endogenous analgesics within thespinal cord. Acupuncture is particularly useful for myofascialpain, which is a common secondary phenomenon in manycancer pain syndromes.

Transcutaneous electrical nerve stimulation (TENS) may have asimilar mechanism of action to acupuncture. There is evidenceto support its use in both acute and chronic pain.

Herbal medicine and homoeopathy are widely used for pain, butoften with little evidence for efficacy. Regulations on safety forthese treatments are limited compared with those forconventional drugs, and doctors should be wary ofunrecognised side effects that may result.

Episodic painIn 2002 an EAPC working group suggested the term episodicpain to describe “any acute transient pain that is severe and hasan intensity that flares over baseline.” Episodic pain thusencompasses breakthrough pain and incident pain.

TENS for control of neuropathic pain that responds poorly to opioids

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Breakthrough pain includes pain returning before the nextdose of opioid is due or acute exacerbations of pain occurringon the background of pain usually controlled by an opioidregimen. Incident pain is usually defined as that occurring dueto a voluntary action, such as movement or passing urine orstool. Pain due to bony metastases exacerbated by movement orweight bearing can be particularly problematic.

Incident painPatients with bony metastases in the spine, pelvis, or femoramay have pain that escalates on movement, walking, standing,or even sitting. Opioid analgesics along with non-steroidal anti-inflammatory drugs are the mainstay of treatment, with the aimof making the patient comfortable at rest. Increasing the opioiddose further is often unhelpful as a dose sufficient to makemovement possible is too sedating when the resting patient’sopioid requirement is decreased. Rescue or breakthrough dosesof normal release opioid are usually used in anticipation ofmovement, along with non-drug measures such as radiotherapy,possible surgery, and appropriate aids and appliances.

Bisphosphonates are interesting drugs established in theprevention of skeletal events due to metastases in most solidtumours. In some patients, analgesia can be achieved acutely,and trial evidence is emerging for good analgesia in pain dueto bone metastases.

Interventional techniquesBefore interventional techniques are considered, it is importantto exclude untreated depression, general anxiety, and distress(though untreated pain may also lead to any or all of these).

Chapter 2 discusses the role of trying a different opioid.The fundamental limiting factor in most patients withuncontrolled difficult pain is the inability to give higher dosesbecause of side effects. It is worthwhile remembering all thestrategies to “open the therapeutic window,” including using adifferent drug.

Methadone deserves a special mention in this context. Ithas unusual properties, which we do not fully understand. Ithas a different receptor binding profile from the pure �agonists and can be remarkably potent at small doses.

It is not unusual to achieve markedly superior analgesia anda better side-effect profile with a switch to methadone. Inaddition, difficult elements of a pain—such as neuropathic orincident pain, or both—may become easier to control.

Starting or switching to methadone can be complicated insome patients, and specialist advice should usually be sought.

Invasive analgesic techniquesDespite appropriate use of analgesia and non-drug therapies,chemotherapy, and radiotherapy by multidisciplinary teams, aconsiderable number of patients will still have uncontrolledpain or unacceptable side effects, or both.

Such patients should be considered for some form of invasiveanalgesic technique as part of their overall management. Thismay range from a simple nerve block to more invasivetechniques such as regional or neurodestructive blocks.

The choice of technique is influenced by:

� Patient’s expectations—Adequate assessment of pain is the firststep in management. Involvement of patients and relatives isimportant and aids decisions about treatment

� Prognosis and required duration of analgesia—Although oftendifficult to predict, prognosis will affect how appropriate any

ABC of palliative care

Radiographs showing lystic lesions in femur (left) and internal stabilisationof bone (right)

Computed tomogram of enlarged liver due to metastatic spread of cancer(reproduced with permission from Times Mirror International Publishing)

Methadone equianalgesic conversion—seek specialist adviceNB: the ratio depends on the dose of previous opioid� If morphine 30–90 mg (oral) use ratio of 4:1 (for instance,

morphine 30 mg is approximately equivalent to 7 mg ofmethadone)

� If morphine 90–300 mg (oral) use ratio of 8:1 (for instance,morphine 300 mg (oral) is approximately equivalent to 35 mgmethadone (oral))

� If morphine �300 mg (oral) use ratio of 12:1 (for instance,morphine 400 mg (oral) is approximately equivalent to 35 mgmethadone (oral))

� If previous morphine dose is much higher than 300 mg, the doseratio will be higher than 12:1

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Difficult pain

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particular intervention may be. Further planned oncologicaltreatment may require short term use of interventions forpain control

� Pathology—The site and extent of disease will affect theresponse to analgesics and direct which interventions have ahigh chance of improving pain control. Plexus or nerve rootinvolvement is common, as is incident pain

� Personnel—Early involvement of pain specialists in amultidisciplinary setting is important for planning analgesicstrategies. This can help to minimise the length of stay inhospital and reduce problems with severe uncontrolled pain.Local availability of expertise and adequate training of staffand relatives must be considered when technique is selected.

A basic rule is that the technique with the least likelihoodof severe side effects should be chosen by using simpletechniques before progression to more complex strategies.

In general, neurodestructive techniques should be reservedfor when other measures have failed or when life span isobviously limited.

Spinal routes of drug deliveryWith improvements in catheter and pump technology, use ofspinal lines is becoming more common in pain control. If thetechnique is carried out by appropriately trained personnel,complication rates are low, allowing flexible, long termanalgesia that can be used in an outpatient setting. Catheterscan be inserted either into the epidural space or into thesubarachnoid (intrathecal) space, where the cerebrospinal fluidis found. The line may be tunnelled subcutaneously to reducerisks of infection and movement of the catheter. The choice oftechnique depends on several factors.

DrugsAs the patients who need this technique tend to have complexpain problems, multimodal analgesia has the best results. Acombination of low dose local anaesthetic, opioid, andclonidine is effective for most patients. Midazolam can beuseful as an additional agent, particularly if there are problemswith opioid tolerance. If ketamine is used then it should bepreservative-free to reduce problems with neurotoxicity. Theinitial conversion of opioid dose from oral or systemic opioid isvariable and depends on the opioid used and comorbidity ofthe individual patient. Long acting opioids should be stoppedbefore the line is inserted and the patient converted to shortacting agents. An approximate dose calculation fromsubcutaneous diamorphine is:

� Epidural: 1/10 of systemic dose� Intrathecal: 1/10 of epidural dose

Thus, if a patient was on 100 mg of subcutaneous diamorphine aday, the equivalent epidural dose would be 10 mg and theequivalent intrathecal dose would be 1 mg per 24 hours.

The initial solution used for epidural infusion is normally:

� 9 ml 0.5% bupivacaine� 75–150 �g clonidine� Diamorphine according to individual patient.

This gives a total volume of 10 ml infused over 24 hours.Should there be a major problem with pump malfunction,

and the whole syringe were accidentally given at once, this shouldnot give a major life threatening overdose. Education andtraining of staff is important to minimise potential complications.

The futureAgents not currently widely available in the UK that may behelpful in managing patients with cancer pain include:

Examples of invasive analgesic techniques

Peripheral CentralPeripheral nerve block Non-destructive� Intercostal � Epidural� Femoral � Intrathecal� SciaticMajor nerve block Neurosurgical/destructive� Brachial plexus � Rhizotomy� Psoas � Cordotomy� Paravertebral sensory nerve root � Intrathecal phenol

ablation� Coeliac plexus

Spinal cord

Inferior vena cava

Vertebra

Aorta

Kidney

Coeliac plexus nerve block

Factors affecting choice of regional techniqueEpidural IntrathecalProcedural� Simple procedure—local � Sedation or general anaesthesia

anaesthetic with or without usually requiredsedation � Deep fixation at time of

� Fixation can be difficult insertion� Catheters not designed for � Silastic catheter designed for

long term use long term use� Drug spread may be limited, � Drug spreads within CSF, unless

especially if there is tumour obstruction to flow; lipid in the epidural space, or solubility determines degree scarring related to of spreadradiotherapy � Safety—catheter can only

� Safety—catheter migration to migrate OUT of intrathecal intrathecal space delivering spacepotential overdose

PrognosisShort term use: Longer term use:� Limited prognosis � Several different options—for � Other definitive treatment example, external or fully

planned—for example, implantableradiotherapy

� Trial for intrathecal line

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ABC of palliative care

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� Lidocaine patches—These are currently available in the US butnot in the UK. They have a good side effect profile andstudies have shown efficacy in neuropathic pain. We have alsoused them in our centre for bone pain, particularly vertebralmetastases, with some success.

� Pregabalin—This agent is a 3-alkylated analogue of GABA (�-amino butyric acid), with a similar pharmacological profile togabapentin, acting via the �2/� subunit on voltage gatedcalcium channels in the central nervous system. However, ithas greater potency than gabapentin. Randomised controlledtrials to date have shown efficacy against some forms ofneuropathic pain and an improved sleep pattern. Side effectsseem similar to those seen with gabapentin. Titration of doseis easier than with gabapentin.

� N-methyl-d-aspartate (NMDA) subtype selective agents—Currentlyavailable agents are non-selective. There is evidence fromanimal models that particular subtypes of the NMDAreceptor may have potential for analgesia with reduced sideeffects and opioid sparing effects. These include agentsacting at the glycine-B modulatory site or the NR2B subunit.

� Calcitonin gene-related peptide (CGRP) antagonists—CGRP isfound in sensory neurones. Non-peptide analogues with afavourable pharmacokinetic profile may have potential asanalgesics.

Potential complications of spinal line

Complication Sign/symptom ActionCSF leak Severe headache Lie flat, encourage

(postural) fluid intake (iv ifnecessary); bloodpatch

Infection Local signs, pyrexia Avoid—aseptictechnique for anydressing changes,line changes etc;antibiotics

Cord compression— Signs of cord Rare, may needmay be secondary to compression— surgical treatmenttumour, haematoma, sensory level,abscess weakness, may be

painCatheter block or Acute increase in Replace catheterfracture pain, may be leakage

of infusion fluidCatheter Leakage of infusion Wrap in sterile salinedisconnection fluid from soaked swab

disconnection site immediatelyReplace syringe, line,and distal filter

Complications related to drugs

Complication Sign/symptom ActionOpioid withdrawal Agitation, insomnia, Increase opioid dose

etc either via catheter orshort acting oral dose

Opioid toxicity Hallucinations, Decrease dose, stopsedation, twitching, opioids by otherrespiratory routes, use naloxonedepression if clinically important

respiratorydepression

Acute opioid Requiring rapid Add midazolam totolerance dose escalation infusion mixture,

despite stable situation switch to differentwith tumour opioid

Pruritus— Itching—often nasal Naloxone (low dose),uncommon with change or stoplong term use opioidUrinary retention— Unable to pass urine Catheterisemore common inmenExcess motor block Leg weakness Decrease local

anaesthetic dose

Further reading� Hanks GW, Conno F, Cherny N, Hanna M, Kalso E, Mc Quay HJ,

et al. Morphine and alternative opioids in cancer pain: the EAPCrecommendations. Br J Cancer 2001;84:587–93.

� Mercadante S, Radbruch L, Caraceni A, Cherny N, Kaasa S,Nauck F, et al. Steering Committee of the European Associationfor Palliative Care (EAPC) Research Network. Episodic(breakthrough) pain: consensus conference of an expertworking group of the European Association for Palliative Care.Cancer 2002;94:832–9.

� Portenoy R, Forbes K, Lussier D, Hanks GW. Difficult painproblems: an integrated approach. In: Doyle D, Hanks GW,Cherny N, Calman K, eds. Oxford textbook of palliative medicine. 3rded. Oxford: Oxford University Press, 2003:438–58.

� World Health Organization. Cancer pain relief. Geneva: WHO,1996.

� Zech DF, Grond S, Lynch J, Hertel D, Lehmann KA. Validation ofWorld Health Organization Guidelines for cancer pain relief: a10-year prospective study. Pain 1995;63:65–76.

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