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Ovid: Oxford Handbook of Palliative Care

Editors: Watson, Max S.; Lucas, Caroline F.; Hoy, Andrew M.; Back, Ian N. Title: Oxford Handbook of Palliative Care, 1st Edition Copyright ©2005 Oxford University Press > Table of Contents > Symptom Management > Chapter 6a – The management of pain > Treatment of other causes of poorly controlled pain Treatment of other causes of poorly controlled pain Malignant bone pain

  • Radiotherapy—around 50 per cent will experience less pain within two weeks and 85 per cent within four weeks of treatment. In around 5 per cent a ‘pain flare’ is described with the pain worsening in the first few days after treatment before settling
  • NSAID e.g. diclofenac 50mg t.d.s.
  • Strong opioids (morphine)
  • Corticosteroids
  • Bisphosphonates

Bisphosphonates Bisphosphonates have a rôle in a long-term strategy to reduce skeletal complications, including pain, from bone metastases of any origin (most data available for myeloma, breast and prostate cancer). Bisphosphonates may also have a rôle in the ‘acute’ management of metastatic bone pain. Patients may experience a ‘flu-like reaction post treatment. Doses may need to be altered in renal failure. Treatment Bisphosphonates

  • Analgesic effect should be expected within 14 days. Disodium pamidronate, sodium clodronate, and ibandronic acid need to be given every three to four weeks, but zoledronic acid has a longer duration of action (four to six weeks)
  • It is not clear for how long bisphosphonates should be continued. The rôle of oral bisphosphonates has yet to be clarified in patients with metastatic bone disease

Treat

  • Zoledronic acid 4mg i/v over 15 minutes. Calcium levels must be watched closely as hypocalcaemia may need treatment with calcium and vitamin D supplements
  • Disodium pamidronate 90mg i/v infusion diluted to 500ml in sodium chloride 0.9 per cent (minimum 375ml), infuse over 2–4h
  • Sodium clodronate i/v infusion 1500mg (can exceptionally be given SC)
  • Ibandronic acid 6mg i/v every 3–4 weeks. (2–4mg for hypercalcaemia.)

Radiotherapy

  • Radionuclides such as strontium are absorbed at areas of high bone turnover. They may take 12 weeks to have full effect and 80 per cent will experience pain relief. External beam hemi-body irradiation is an alternative for multiple-site bone pain

Surgery

  • Surgical techniques. The pain of bone metastases may respond to local infiltration or intra-lesional injection with depot corticosteroid ± local anaesthetic. Consideration should be given to prophylactic pinning of osteolytic metastases in long bones. Vertebroplasty, in which injection of acrylic cement is administered percutaneously, into unstable fractures of the vertebrae may be worth considering if the patient is relatively well. Spinal or epidural anaesthetic blocks may also be needed

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Bisphosphonates and bone pain Disodium pamidronate

  • Inj. 15mg, 30mg 90mg (dry powder for reconstitution)

Sodium clodronate

  • Inj. 300mg/5ml 300mg/10ml

Starting dose: 800mg or 520mg b.d. p.o. Zoledronic acid

  • Inj. 4mg

Ibandronic acid

  • Inj. 6mg
  • p.o. 50mg daily

Treatment of poorly controlled pain

Pain Possible co-analgesics
Headache due to cerebral oedema dexamethasone
Painful wounds metronidazole
Intestinal colic hyoscine butylbromide or hydrobromide (Kwells)
Gastric mucosa lansoprazole
Gastric distension asilone + domperidone
Skeletal muscle spasm baclofen/diazepam
Cardiac pain nitrates/nifedipine
Oesphageal spasm nitrates/nifedipine

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Renal impairment/renal failure1, 2 Palliative care teams may be involved in the care of patients with different degrees of renal failure. Many drugs and their metabolites accumulate in uraemic patients and cause significant side-effects. Degree of Renal Impairment

  GFR Serum Creatinine
Mild 20–50ml/min 150–300 mmol/l
Moderate 10–20ml/min 300–700 mmol/l
Severe <10ml/min >700 mmol/l

Drugs in renal failure

  • Metabolites of morphine accumulate in renal failure and can cause neurotoxic side-effects such as myoclonus and confusion
  • Oxycodone and hydromorphone have active metabolites which are renally excreted, and their value in renal failure is less clear. However, case reports suggest they may be better than morphine, at least in individual patients switched from morphine because of problems with metabolite accumulation. In health, there is a large reserve of renal function, urea and creatinine remaining at normal values until there is a reduction of 50–60 per cent in glomerular filtration rate
  • Paracetamol is safe in renal failure but should be reduced to 3g every 24 h if the patient has severe renal impairment. Paracetamol is dialysed out by haemodialysis but not by peritoneal dialysis

Factors associated with altered handling of drugs in renal failure

  • Loss of plasma protein binding capacity occurs due to uraemia itself, which may be relevant for drugs which are highly protein-bound such as diazepam
  • Changes in hydration may affect the distribution of drugs in the body causing overdosage
  • Oral absorption of drugs may be reduced because of vomiting, diarrhoea and gastrointestinal oedema
  • Increased permeability of the blood brain barrier in uraemia may exaggerate the unwanted central nervous system effects associated with certain drugs
  • Codeine and Dihydrocodeine can both cause prolonged narcosis but can be used if necessary in a combined preparation with paracetamol (e.g.co-codamol/co-dydramol) in reduced doses. There is an increase in the CNS side effects of weak opioids in renal failure
  • Co-proxamol should be used with caution in patients with severe renal impairment
  • Diamorphine is metabolized to morphine which is itself metabolized to morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). Accumulation of M3G may cause clinical excitation or agitation P.219
    Accumulation of M6G, the useful analgesic metabolite, may account for symptoms of drowsiness, nausea and vomiting, respiratory depression and even coma. Haemodialysis may produce significant falls in morphine concentration leading to pain during or shortly after dialysis. The complex nature of opioid usage in renal failure requires that, particularly in the opioid naïve, very small doses are used and then only with the ready availability of naloxone. For similar reasons the use of long-acting preparations should be avoided. Opioids which do not have active metabolites may be more suitable for patients in renal failure than morphine or diamorphine. (Alfenanil or fentanyl.)
  • Fentanyl is mainly metabolized in the liver to inactive metabolites and it has a short half-life, making it a useful drug in renal impairment
  • Alfentanil is a short acting opioid metabolized by the liver to inactive compounds. It is 10 times more potent than diamorphine when given subcutaneously and there are some case studies showing less agitation when changed from diamorphine
  • Twenty per cent of methadone is excreted unchanged in urine. With its long half-life the dose should be reduced in renal impairment.
  • Hydromorphone has been used in patients with renal failure even though it is metabolized to a metabolite which can potentially accumulate causing neuroexcitatation and cognitive impairment
  • Oxycodone is 90 per cent metabolized in the liver. In severe renal impairment, it is contra-indicated because the 10 per cent which is normally excreted unchanged in the urine, may then accumulate. For patients with mild or moderate renal failure, oxycodone can be used with caution, so long as the dose is titrated up slowly
  • NSAIDS should be avoided, if possible, in patients with any degree of renal impairment, though this counsel of perfection may not necessarily be appropriate in the palliative care setting. Where appropriate, sulindac is the NSAID of choice as it is reported to have renal sparing effects. These effects are lost with doses above 100mg twice daily. In patients with total renal failure on dialysis NSAIDs should not be forgotten if kidney protection is no longer an issue.

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Table 6a.11 Commonly used palliative care medication in different degrees of renal failure
Drug Mild Creat. 150–300mmol/l GFR 20–50ml/min Moderate Creat. 300–700mmol/l GFR 20–50ml/min Severe Creat. >700mmol/l GFR <10ml/min
Analgesics
Paracetamol ND ND 500mg–1g every 8 h
NSAIDs Avoid if possible Avoid if possible Avoid
Weak opioids
Co-codamol,
Co-dydramol ND 6 Tabs. in 24h 4 Tabs. in 24h
Co-proxamol ND 6 Tabs. in 24h 4 Tabs. in 24h
Tramadol ND 50–100mg every 12h 50mg every 12h
Strong opioids
Morphine 75% of ND 2.5–5mg every 6–8 h** 1.25–2.5 every 6–8 h*
Oxycodone Start at a low dose and titrate slowly Avoid
Diamorphine 75% of ND** 2.5mg SC every 6 h** 2.5mg SC every 8 h*
Hydromorphone ND** 1.3mg every 6–8 h** 1.3mg every 8 h*
Methadone ND** ND** 50% of ND
Fentanyl ND** 75% of ND** 50% of ND
Alfentanil ND** ND** ND**
Antiemetics
Metoclopramide ND 75% of ND 50% of ND
Haloperidol ND but avoid repeated dosaging as haloperidol may then accumulate.
Cyclizine ND ND ND
Levomepromazine ND ND ND
Domperidone ND ND ND
Ondansetron ND ND ND
Anticholinergics
Hyoscine butylbromide ND ND ND
Hyoscine hydrobromide ND ND ND
Central nervous system
Baclofen Max. 5mg o.d. Max. 5mg o.d. Max. 5mg o.d.
Benzodiazepines Start with very small doses. Increased cerebral sensitivity
Gabapentin 300mg b.d. 300mg o.d.
Amitriptyline ND ND ND
Fluoxetine ND ND ND on alternate days
Citalopram ND ND No information available
Mirtazepine ND 15mg o.d. 15mg
Paroxetine ND 20mg o.d. 20mg o.d.
**Titrate
ND normal dose
From: Bunn R., Ashley C. (1999) The Renal Drug Handbook. Oxford: Radcliffe Medical Press
With thanks to the Renal Pharmacists at the Belfast City Hospital Pharmacy Department.

Footnotes 1 Kirkham S. R., Pugh R. (1995) Opioid analgesia in uraemic patients. Lancet, 345, 8958: 1185. 2 Farrell A., Rich A. (2000) Analgesic use in patients with renal failure. Eur J Pall Care, 7, 6: 201-5. P.222
Anaesthetic procedures in palliative care Presently she cast a drug into the wine of which they drank, to lull all pain and anger and bring forgetfulness of every sorrow –Homer’s Odyssey Introduction The majority of patients with cancer can have their pain needs met by following the WHO three-step analgesic ladder. For the minority of patients who do not gain satisfactory pain relief, a ‘fourth step’ (interventional pain management) can be useful in helping to control pain, maintain psychomotor performance and improve quality of life. As with all interventions, patient selection is vital for success. General selection criteria include:

  • Patient competent/consented
  • Patient compliant
  • Absence of systemic infection
  • Absence of specific allergy
  • Absence of significant coagulopathy
  • Adequate support for post-procedural care and maintenance

Patients with palliative care needs are often debilitated, have limited mobility and have a limited life span. It is therefore imperative that measures to alleviate their pain are minimally disruptive. Many spinal procedures can easily be done at the bedside, while more involved interventions such as chemical neurolysis necessitate radiological guidance, usually in a hospital setting. With this in mind, patients should be selected for procedures acceptable to them and appropriate to their level of disability. Intrathecal and epidural (neuraxial) techniques Direct delivery of opioids to the spinal cord via epidural and intrathecal techniques has become increasingly popular in recent decades, and has proven an effective and reversible way to provide profound analgesia with reduced systemic side-effects. Intrathecal opioids bind to the mu and kappa opioid receptors in the substantia gelatinosa of the spinal cord. This is achieved to a lesser extent with epidural opioids, which exert a simultaneous systemic and intrathecal effect (10 per cent and 90 per cent respectively). Common indications for the use of neuraxial techniques:

  • Unacceptable side-effects despite successful analgesia with systemic opioids
  • Unsuccessful analgesia despite escalating doses and use of sequential opioids
  • Intolerable neuropathic pain which may be amenable to spinal adjuvants
  • Sympathetically mediated pain amenable to sympathetic blockade
  • Incident pain which may benefit from numbness (local anaesthetic)

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Possible contra-indications to neuraxial techniques (risk-benefit decision):

  • Platelet count of <20 × 109/l with clinical symptoms of poor clotting
  • Full anti-coagulation or INR>1.5
  • Active infection with concurrent septicaemia
  • Concurrent chemotherapy likely to cause neutropenia
  • Occlusion of epidural space by tumour at the site of catheter tip placement (epidural catheters only)
  • Allergy or unmanageable side-effects from anticipated treatment
  • Psychosocial issues that make technique untenable
  • Inadequate professional support to resolve ongoing problems

There is a growing body of evidence favouring intrathecal over epidural administration of opioids in the palliative setting.

Fig. 6a.5 Schematic diagram of lumbosacral anatomy showing needle placement for lumbar subarachnoid, and epidural spaces.

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Table 6a.12 Comparing the two routes of administration
Factors Intrathecal Epidural
Infection rate Same as epidural Same as intrathecal
Pain relief Better for long-term Good only for short-term
Dose Lower (10–20% of epidural dose) Higher
Pump refills Less frequent More frequent (higher volumes)
Side-effects Fewer More
Technical difficulty Easier to place, less likely to become displaced Potentially more difficult, and catheter may migrate
Long-term complications Less (approx. 5%) More (approx. 55%)
Catheter occlusion and fibrosis Minimal Higher frequency (leading to loss of analgesia/pain on injection)
Epidural metastases Less affected More affected (may compromise drug delivery)
Overall advantage Effective analgesia with fewer complications

Catheters may be externalized through the skin at the puncture site or may be tunnelled subcutaneously away from the spine. Alternatively, a totally implantable pump system may be employed if the patient has a life expectancy of several months.

Table 6a.13 Comparison of continuous versus bolus techniques
Factor Continuous Intermittent bolus
Dose escalation Higher Lower
Analgesic quality Better Fair
Local anaesthetic combinations Minimal motor or haemodynamic complications Higher risk of motor or haemodynamic complications (Not recommended for intraspinal administration)

Ideally, the continuous infusion technique should be used, with a familiar delivery system e.g. standard Graseby syringe pump delivering the infusion solution over 24 h. P.225
Technical complications of neuraxial catheters

  • Mechanical problems
  • Skin breakdown at insertion site
  • Infection-local/catheter infection/epidural abscess/meningitis/systemic infection
  • CSF leak, causing headache
  • CSF seroma
  • Haematoma
  • Catheter dislodgement, occlusion or migration
  • Nerve damage (rare but possible).

Adverse effects attributable to spinal opioids

  • Minor sedation (opioid dose excessive)
  • Urinary retention (commonest in males in first 24 h)
  • Persistent nausea
  • Pruritus
  • Respiratory depression (may be severe and insidious if opioid-naïve)
  • Hyperalgesia (at higher doses)
  • Myoclonus (higher doses, indicating toxicity)
  • Constipation.

Management of adverse affects

  • Sedation: reduce dose of opioid
  • Urinary retention: usually requires once-only catheterization
  • Nausea: regular antiemetic
  • Pruritus:
    • consider adding spinal bupivacaine
    • i/v ondansetron 8mg has been shown to be effective
    • i/v nalbuphine may be effective
  • Respiratory depression: (R.R. less than 8/minute or excessive drowsiness)
    • naloxone 100–400mcg
    • stop intrathecal infusion
    • reduce infusion dose
  • Hyperalgesia:
    • reduce opioid dose
    • consider addition of adjuvant agent
  • Myoclonus:
    • reduce opioid dose
    • check renal function
    • encourage rehydration
    • Consider low dose benzodiazepine therapy (myoclonus may not be opioid dose-dependent)
  • Constipation: regular laxatives from the outset of therapy.

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Choice of drug: Opioids, local anaesthetics, clonidine Opioids Morphine is one of the least lipid soluble opioids available, and when given in the spinal space, it has the slowest rate of uptake into the surrounding vasculature, which gives it a longer and primarily spinal site of action. Intrathecal morphine is regarded as 100 times more potent than a systemically given dose. Data from postoperative pain studies suggest that morphine is twice as potent as diamorphine by the intrathecal route. Intrathecal morphine should be preservative free. Diamorphine can be administered intrathecally, with a potency ratio of 1:100 (intrathecal:systemic). Diamorphine should be reconstituted in sodium chloride 0.9 per cent. Alternatives to morphine and diamorphine are used less frequently. Hydromorphone is an effective and affordable option for the morphine-intolerant patient. The potency of intrathecal hydromorphone is five times that of morphine. Of the lipophilic drugs, both fentanyl and sufentanil are used. Greater lipid solubility may be an advantage for rapid onset of action, but rapid systemic absorption means shorter duration of action with less dose-sparing effect when compared to systemic administration. There is no published data on dose equivalences. Typical dosing schedule

  • If opioid-naïve, start with intrathecal diamorphine 0.5–1mg/24h or epidural diamorphine 2.5–5mg/24h
  • If the patient is established on a systemic opioid, the following regimen may be used to minimize the withdrawal phenomenon during route conversion
    • Give half of the systemic opioid by the established route
    • Convert the remaining half dose to equivalent dose of diamorphine, and then divide by 100 to get the intrathecal dose
  • Add 2ml of 0.5 per cent bupivacaine to diamorphine
  • Add sodium chloride 0.9% up to total of 10ml
  • Infuse solution over 24 h
  • After 24 h, reduce the systemic dose by 50 per cent again and titrate upwards the intrathecal dose (usually in increments of 10–30 per cent)
  • Attempt to discontinue the systemic opioid by day two (may not always be possible)

Local anaesthetics Local anaesthetic agents are sodium channel blockers and are unique in their ability to block nerve impulses conducted proximally (pain relief) and impulses conducted distally (motor blockade). The conduction blockade produced is both painless and reversible. Side-effects of local anaesthetics

  • Postural or overt hypotension—sympathetic block
  • Numbness—sensory block
  • Leg weakness—motor block
  • Altered proprioception in low doses, even when motor weakness is not apparent
  • Urinary retention
  • ‘Total spinal’—this potentially catastrophic event can occur if a large dose of local anaesthetic is delivered to the subarachnoid space P.227
    erroneously. A profound drop in blood pressure is accompanied by motor paralysis of the lower limbs, spreading to the upper limbs and respiratory muscles and ultimately the brain. Both cardiovascular and ventilatory support are required until the local anaesthetic effects wear off
Table 6a.14 The most frequently used local anaesthetic agents
Agent Lidocaine Bupivacaine Ropivacaine
Onset Rapid Slower Similar to bupivacaine
Duration Short (h) 2–3 times longer than lidocaine Slightly longer than bupivacaine
Typical dosage 2ml 2% over 24 h 2ml 0.5% over 24 h 2ml 0.75% over 24 h
Advantages Rapid onset and offset
Synergism with opioids
Synergism with opioids May preferentially block sensory nerves
Two-thirds as potent as bupivacaine
Synergism with opioids

Spinal adjuvants Clonidine Clonidine is an α-2adrenergic agonist and appears to act at the level of the spinal cord. It acts synergistically with opioids but is also a powerful analgesic when used alone in the management of neuropathic pain. It is a lipophilic compound and its spinal effect may be more pronounced with intrathecal rather than epidural administration. The dose of clonidine is often limited by the appearance of side-effects such as sedation, hypotension and bradycardia. Nausea, pruritus and urinary retention have also been reported. Starting doses range from 10–20mcg/24h and should be titrated for analgesic effect and minimal side-effects. Doses above 150 mcg/24h should not be necessary. Other analgesics have been tried as intrathecal agents, including midazolam, ketamine, octreotide, calcium channel blockers and neostigmine. As yet, there is no convincing body of evidence to support their use. Guidelines for percutaneous intrathecal catheter insertion

  • Patient consent
  • Nurse assistant present
  • Adequate space for aseptic trolley
  • Patient in sitting or lateral position, with their head and knees curled toward their abdomen
  • Skin asepsis (eg. chlorhexidine)
  • Local anaesthetic infiltration of skin at chosen level of insertion
  • 18G Tuohy needle inserted into spinal space, piercing the dura, until CSF is free-flowing
  • Aseptic epidural catheter inserted to 15cm, and free-flow of CSF confirmed
  • Catheter secured and dressing applied to insertion site (one which allows daily visual inspection)
  • P.228

  • An antibacterial filter should be connected and may remain attached for up to a month
  • Connection made to infusion pump or syringe driver

Follow-up care

  • All staff involved in aftercare of the patient should be familiar with the possible side-effects and complications listed, and should be vigilant for signs of infection or problems developing
  • The catheter insertion site should be inspected on a daily basis
  • A pain chart should be kept initially until the analgesia is considered sufficient
  • If the patient is being discharged to the community, there should be liaison with the key members of the primary care team (GP, district nurse and community specialist palliative care nurse) prior to discharge and written guidelines should accompany the patient home
  • Patients should not be discharged home until dose escalation have been stabilized

Chemical neurolysis for cancer pain Neurolysis of nerves by chemical means is indicated for patients with limited life expectancy. The use of neurolytic techniques has diminished over recent years due to advancements in spinal analgesia and increased life expectancies in cancer patients. However, neurolysis should be considered in the following circumstances:

  • the pain is severe, intractable and has failed to respond to other measures
  • the nociceptive pathway is readily identified and related to a peripheral nerve pathway or sympathetic chain
  • a trial block of local anaesthetic has been successful
  • the effects of the local anaesthetic block are acceptable to the patient

The goals of neurolysis include reduction in pain, and reduction in the need for other pharmacotherapy. Neurolysis is rarely permanent and pain returns as a consequence of regrowth of neural structures or disease progression in the treated area. When used centrally, there is a risk of motor paralysis and sphincter weakness, which are generally unacceptable to most patients. For that reason, patients should be fully consented by the practitioner prior to the procedure. Neurolytic agents Alcohol and phenol are the two most commonly used agents. Effects of alcohol:

  • Burning sensation upon injection along the distribution of the nerve, followed by warm numbness
  • Pain relief increases over a few days and is maximal by one week
  • Alcohol is hypobaric, hence the patient should be able to tolerate a position that allows the alcohol solution to float upwards to the affected nerve root

Effects of phenol:

  • Following injection, an initial local anaesthetic effect subsides to neurolysis which may take 3–7 days to become apparent
  • Density and duration of block is felt to be less than that of alcohol
  • Since phenol is hyperbaric, the patient should be able to tolerate a position that allows the phenol to sink down to the nerve roots P.229
    Visceral cancer pain is often produced by a combination of visceral afferent stimulation, as well as somatic and neuropathic elements. The sympathetic chain carries much nociceptive information, and blockade of the sympathetic chain may improve both visceral and sympathetically-mediated pain. Visceral cancer pain can often be alleviated by a combination of oral medication and neurolytic blockade of the sympathetic axis. Since neurolytic techniques have a narrow risk/benefit ratio, they should only be performed by experienced pain clinicians in appropriate surroundings.

Coeliac plexus block The coeliac plexus is responsible for transmission of nociceptive information from the entire abdominal contents, excluding the descending colon and pelvic structures. It has been successfully used to combat pain from pancreatic cancer and other upper abdominal viscera. For an experienced operator it is a relatively safe and simple technique, performed under CT guidance. Patients referred for this procedure should be able to tolerate lying on an X-ray table, and should have no coagulopathy or local infection. Possible complications include:

  • Orthostatic hypotension (may persist for days)
  • Backache at the site of needle insertion (if backache and hypotension persist, observe serial haematocrit measurements to rule out retroperitoneal haemorrhage haematoma)
  • Diarrhoea
  • Abdominal aortic dissection
  • Paraplegia and motor paralysis (rare)

Superior hypogastric block The superior hypogastric sympathetic ganglion transmits nociceptive information from the pelvis, excluding the distal Fallopian tubes and ovaries. It has been successfully used to manage pain of pelvic origin, other than ovarian pain. Neurological complications have not been reported with this block. Ganglion of impar block This ganglion marks the end of the sympathetic chains and is situated at the sacrococcygeal junction. Visceral pain in the perineal area has been successfully treated with neurolytic blockage of this ganglion. These patients often present with a vague, poorly localized perineal pain, accompanied by burning or urgency, and oral medication alone is often inadequate. No complications have been reported with this block. Other neurolytic blocks Pleural phenol block Insertion of an epidural catheter into the pleural space and infusion of local anaesthetic or phenol has been described in the management of visceral pain associated with oesophageal cancer and rib invasion by bony metastases. It is a relatively simple technique with few complications. These include:

  • Pneumothorax (avoid bilateral blocks)
  • Phrenic nerve palsy
  • Trauma to local structures caused by the needle, catheter or as a consequence of the phenol injection

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Fig. 6a.6 (a) Positioning for coeliac plexus block; (b) Deep anatomy showing placement of needles for coeliac placement block

Saddle block This is a modified low spinal technique where phenol is injected into the CSF in the lumbar area, with the intention of causing chemical neurolysis of the low sacral nerve roots that serve the perineum and perianal area. It is useful for patients complaining of pain in the ‘saddle’ area, but carries the potential risk of sphincter compromise (<10 per cent). P.231

Fig. 6a.7 Technique of intra-pleural block

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Further reading Borgeat A., Stirnemann H. R. (1999) Ondansetron is effective to treat spinal or epidural morphine-induced pruritis. Anesthesiology, 90: 432–6. Buchheit T., Rauck R. (1999) Subarachnoid techniques for cancer pain therapy: When, Why and How? Current Pain and Headache Reports, 3, 3: 198–205. Cohen S. E., Ratner E. F., Kreitzman T. R. et al. (1992) Nalbuphine is better than naloxone for treatment of side effects after epidural morphine. Anesth Analg, 75: 747–52. de Leon-Casasola O. (2000) Critical evaluation of chemical neurolysis of the sympathetic axis for cancer pain. Cancer Control, 7, 2: 142–8. Hill D. A. (2003) Peripheral nerve blocks: practical aspects. In H. Breivik et al. (eds.) Clinical Pain Management, Practical Applications and Procedures, pp. 197–232. London: Arnold. Lema M. J., Myers D. P., de Leon-Casasola. (1992) Interpleural phenol therapy for the treatment of chronic oesophageal cancer pain. Rge Anesth, 17: 166–70. Mercadante S. (1999) Neuraxial techniques for cancer pain: an opinion about unresolved therapeutic dilemmas (review). Regional Anesthesia and Pain Medicine, 24, 1: 74–83. Miguel R. (2000) Interventional Treatment of Cancer Pain: the fourth step in the World Health Organization analgesic ladder? Cancer Control, 7, 2: 149–56. Schnitzer T. J., Burmester G. R., Mysler E. et al. (2004) Comparison of lumiracoxib with naproxen and ibuprofin in the Therapeutic Arthritis Research and Gastrointestinal Event Trial (TARGET), reduction in ulcer complications. Lancet, 364: 665–74. Simpson K. H., Russon L. (2000) The use of intrathecal drug delivery systems in pain management. CME Bulletin Palliative Medicine, 2: 17–20. Twycross R. et al. (2003) Itch. QJM, 96: 7–26. Zeppetella G. et al. (2004) Topical opioids for painful skin ulcers—do they work? European Journal of Palliative Care, 11: 93–6.

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