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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 > Neuropathic pain Neuropathic pain Neuropathic pain: Pain which is transmitted by a damaged nervous system, and which is usually only partially opioid sensitive. Up to 40 per cent of cancer-related pain may have a neuropathic mechanism involved. Neuropathic pain may be difficult to control. A wide variety of treatments may be needed: Management

Table 6a.7 Examples of treatments used for patients with neuropathic pain
Opioids Ketamine
Antidepressants (tricyclic) Spinal (epidural and intrathecal)
Anticonvulsants Methadone
NSAID trial Lidocaine patch/infusion
TENS Accupuncture Neurolytic procedures e.g. coeliac plexus block, cordotomy
Radiotherapy Capsaicin
Corticosteroids

Remember that most cancer pains which seem to be predominantly neuropathic will also probably have a nociceptive opioid responsive element. i.e. try WHO analgesic ladder first. Classes of drugs used in neuropathic pain Opioid analgesics Opioids may be effective in both cancer-related and non-malignant neuropathic pain. Opioids other than morphine/diamorphine have been shown to be effective including tramadol, fentanyl, and oxycodone. Opioids are used in cancer-related neuropathic pain as:

  • many patients will have a different, coexisting nociceptive pain
  • there may be a nociceptive element to the pain
  • opioids alone may control a third of neuropathic pains, and partially control a further third

If the pain seems to be resistant to first-line opioid (or opioid toxicity is a problem):

  • an alternative opioid analgesic may be tried for better tolerance
  • medication can be given to counteract side-effects (e.g. psychostimulants for drowsiness)
  • the pain may be morphine-resistant

Methadone can be considered different from the other opioids with respect to neuropathic pain. It can either be tried as an alternative to a first-line opioid, or introduced later, when other options have failed which is more usual.

Figure. No caption available.

See p. 196.

Figure. No caption available.

P.207
Tricyclic Antidepressants The mechanism of analgesic action is principally by facilitation of descending inhibitory pain pathways. e.g. amitriptyline 25–100mg dosulepin 25–100mg Note that amitriptyline can increase the bioavailability of morphine leading to opioid side-effects.

  • Start with amitriptyline 25mg (10mg in the elderly) nocte
  • If no response by day five, increase the dose (or, according to clinical circumstances, consider changing to anticonvulsant)
  • Some patients do not see benefit until after 4–6 weeks of treatment, and/or doses of up to 50mg/day
    • severity of pain and the patient’s prognosis will dictate how long to persevere with antidepressants
    • many patients do not tolerate amitriptyline especially in higher doses, therefore consider changing to dosulepin
  • Use lofepramine for frail, elderly, or those already suffering antimuscarinic side-effects from other drugs:
    • start at 70mg nocte
    • may increase to 70mg b.d. on day 5–7

Lower doses of tricyclic antidepressants than those commonly required in depressive illness are reported to be effective in neuropathic pain, and faster responses are to be expected.1 Other less sedating tricyclic antidepressants (e.g. imipramine) may be more useful for certain patients. Newer antidepressants are being used,2 but their rôle is as yet unclear and there is growing concern about withdrawal reactions and cardiotoxicity, particularly with venlafaxine. Mirtazapine is a noradrenergic and specific serotonergic antidepressant (NaSSA); there are a few reports of its use in neuropathic pain. Topical tricyclics such as doxepin cream have also been tried. Amitriptyline

  • Tabs. 10mg, 25mg, 50mg
  • Syrup 25mg/5ml, 50mg/5ml

Starting dose: 25mg nocte p.o. Dosulepin

  • caps. 25mg
  • Tabs. 75mg (Prothiaden)

Starting dose: 25mg nocte p.o. Lofepramine

  • Tabs. 70mg
  • Susp. 70mg/5ml

Starting dose: 70mg nocte p.o. Doxepin

  • Cream 5% 30g

Starting dose: Apply t.d.s to q.d.s., maximum 12g daily Footnotes 1 McQuay H. J. (1996) A systematic review of antidepressants in neuropathic pain. Pain 68: 217–27. 2 Pernia A., Mico J. A., Calderon E., Torres L. M. (2000) Venlafaxine for the treatment of neuropathic pain (letter). Journal of Pain and Symptom Management, 19, 6: 408–10. P.208
Anticonvulsants3 e.g. sodium valproate 100–600mg b.d. gabapentin 100–600mg t.d.s. carbamazepine 100–400mg b.d. Anticonvulsants have for a long time been considered better than tricyclic antidepressants for lancinating or paroxysmal pain, but evidence from studies does not support this. There is little to choose overall between antidepressants and anticonvulsants for neuropathic pain in terms of efficacy or adverse effects. There is little data to compare anticonvulsants in terms of efficacy, although in one trial comparing the efficacy of different anticonvulsants for lancinating pain, the results suggested that clonazepam was superior to phenytoin, sodium valproate and carbamazepine.4

  • Carbamazepine has been used most extensively, but is often tolerated poorly by elderly, frail or ill patients. It has numerous drug interactions and tends to result in more side-effects, particularly when used in combination with other drugs. Doses should be built up slowly to minimize adverse effects
  • Sodium Valproate has therefore been recommended by many in palliative care, but more data on its efficacy is needed
  • Clonazepam has been used in cancer-related pain and has the advantage of subcutaneous administration
  • Lamotrigine has had mixed results
  • Gabapentin is the only drug licenced for all types of neuropathic pain. Trials have shown it to be effective in non-malignant and cancer-related pain. It appears to be well tolerated in palliative care patients. Doses up to 2.4g/24h have been used successfully
  • Pregabalin has recently been introduced and is thought to work in a similar way to Gabapentin. It is unclear if patients who are unresponsive to Gabapentin may gain benefit from Pregabalin apart from its simpler dose regime (Pregabalin—for neuropathic pain November 2004, http://www.druginfozone.org)

Unlike the antidepressants, anticonvulsants are pharmacologically diverse in their actions, and there is good theoretical reason to try alternative anticonvulsants if one is ineffective. All anticonvulsants are used in their typical ‘anticonvulsant’ doses.

  • Start with gabapentin: day one—300mg nocte, day two—300mg b.d., day three—300mg t.d.s.
  • If no response by day five, either increase dose in 300mg increments every few days (maximum 1800–2400mg/day), use an alternative anticonvulsant, or move on to another method:
  • Some patients do not see full benefit from anticonvulsants until after 4–6 weeks of treatment
  • The severity of pain and the patient’s prognosis will dictate how long to persevere with gabapentin, or with anticonvulsants in general

P.209
Gabapentin

  • caps. 100mg, 300mg, 400mg
  • Tabs. 600mg 800mg

Starting dose; Day 1–300mg nocte, day 2–300mg b.d., day 3–300mg t.d.s. p.o. Usual maintenance: 0.9–1.2g/24h. Maximum recommended dose 1.8g/24h, but doses up to 2.4g/24h (and even higher) have been used. Sodium valproate

  • Tabs. 200mg, 500mg
  • Syrup 200mg/5ml

Starting dose; 200mg t.d.s. p.o. or 500mg nocte p.o. Increase 200mg/day at 3-day intervals. Usual maintenance 1–2g/24h. Max. 2.5g/24h in divided doses. Supps. are available as special orders. Carbamazepine

  • Tabs. 100mg, 200mg, 400mg
  • Liquid 100mg/5ml
  • Supps. 125mg, 250mg

Starting dose; 100mg b.d. p.o. Increase from initial dose by increments of 200mg every week. Usual maintenance dose 0.8–1.2 g/24h in two divided doses. Max. 1.6–2g/24h. Equivalent rectal dosage: 125mg PR [approximate, equals] 100mg p.o. Carbamazepine levels are increased (risk of toxicity) by dextropropoxyphene (co-proxamol), clarithromycin, erythromycin, fluoxetine, fluvoxamine. Clonazepam

  • Tabs. 500mcg, 2mg
  • Inj. 1mg/1ml

Starting dose; 1mg nocte for 4 nights Increase gradually to usual maintenance dose 4–8mg/24h. Oral solutions in various strengths are available from several sources. Pregabalin

  • Caps. 25mg, 50mg, 75mg, 100mg, 150mg, 200mg, 300mg

Starting dose; 75mg b.d. Increase after three days to 150mg b.d. Increase after seven days to 300mg b.d. Footnotes 3 McQuay H. J. (1995) Anticonvulsant drugs for management of pain: a systematic review. BMJ, 311: 1047–52. 4 9. Swerdlow M., Cundill J. G. (1981) Anticonvulsant drugs used in the treatment of lancinating pain. A comparison. Anaesthesia 36, 12: 1129–32. P.210
Corticosteroids Corticosteroids (usually dexamethasone) may help cancer-related neuropathic pain, either by reducing inflammatory sensitisation of nerves, or by reducing oedema which may cause pressure on nerves. A high initial dose is used to achieve rapid results (dexamethasone 8mg/day will work in 1–3 days); the dose should then be rapidly reduced to the minimum that maintains benefit. Although long-term corticosteroids may be best avoided, they can sometimes buy useful time whilst allowing other methods (e.g. radiotherapy or antidepressants) time to work.

  • Hydrocortisone has a high mineralocorticoid effect
  • Dexamethasone has a relatively high equivalent corticosteroid dose per tablet and less mineralocorticoid effects than prednisolone, or methylprednisolone with consequently less problems with fluid retention
  • Prednisolone causes less proximal myopathy than dexamethasone.5

If steroids are not helpful for pain within five days, consider stopping

Table 6a.8 Relative anti-inflammatory steroid doses (approximate)
Steroid Administration Equivalent dose
Dexamethasone Oral/SC 2mg
Prednisolone Oral/Rectal 15mg
Hydrocortisone Oral/i/m/i/v 60mg
Methylprednisolone Oral/i/m/i/v 12mg

NSAIDs NSAIDs are sometimes effective in cancer-related neuropathic pain, either because there is mixed nociceptive pain or because they reduce inflammatory sensitization of nerves. NSAIDs exert an anti-inflammatory action by inhibiting prostaglandin synthesis. There is considerable variation in individual patient tolerance and response. Pain relief starts soon but an anti-inflammatory effect may take a few weeks. The main differences between NSAIDs are in the incidence and type of side-effect, and efficacy should be weighed against the possible side-effects. NSAIDs vary in their selectivity for inhibiting different types of cyclo-oxygenase; selective inhibition of cyclo-oxygenase-2 (e.g. celecoxib) improves gastrointestinal tolerance but significant cardiac side-effects have created recent concerns and lead to the withdrawal of some preparations, most notably rofecoxib (vioxx). Ibuprofen has fewer side-effects than other non-selective NSAIDs. e.g. ibuprofen 200–400mg t.d.s. p.o. diclofenac 50mg t.d.s. (can be used p.o. SC or Supps.) celecoxib up to 200mg b.d. p.o. naproxen 250–500mg b.d. (p.o. or PR) ketorolac 10–30mg SC every 4–6 h p.r.n. Max. 90mg daily (max. 60mg for elderly). Max. duration 2 days parecoxib 40mg, then 20–40mg every 6–12 h p.r.n. Max. 80mg daily (max. 40mg for elderly). P.211
Elderly patients or those with a past history of peptic ulceration may be more at risk from side-effects. A proton pump inhibitor such as lansoprazole has been shown to reduce this risk. Aspirin causes long acting inhibition of platelet coagulability and its unique cardiovascular protective effect makes joint prescribing of low dose aspirin and a non selective NSAID appropriate for patients in need of aspirin prophylaxis. However, the reduction in gastrointestinal side-effect risks gained by use of a selective COX2 inhibitor is obviated if given with low dose aspirin. Risk factors for GI bleed with NSAID

  • Age ≥ 75
  • Corticosteroids
  • Aspirin
  • Anticoagulant
  • Platelets < 50×109/t
  • Dyspepsia on NSAIDs now or in the past
  • Peptic ulceration/ bleed in last year

Footnotes 5 Kingdon R. T. et al. (1998) Handbook for pain management. London: Saunders. P.212
Other drugs Topical lidocaine (Lignocaine) Topical lidocaine may be useful for superficial localized areas of pain such as fungating wounds for short periods of time.6 A combination of lidocaine gel with diamorphine may also help pain. Prolonged use may lead to skin sensitization. A lidocaine 5 per cent patch has been shown to reduce pain and allodynia from post herpetic neuralgia. Up to three patches for periods of up to 24 h seems to be safe. An adequate trial over several weeks may be required. Mild to moderate skin redness, rash or irritation may occur. While the systemically absorbed dose from topical lidocaine will be small care should be exercised with patients susceptible to cardiac problems. Oral flecainide and mexiletine These medications should only be used under specialist supervision and are rarely used in palliative care. Infusions of lidocaine (lignocaine) have been claimed as effective in neuropathic pain, and have been used long-term over many weeks. As a continuous infusion is not always acceptable, oral drugs with similar sodium-channel blocking properties have been used (flecainide and mexiletine). A positive response to lidocaine infusion may predict a response to mexiletine, and possibly therefore flecainide. That neuropathic pain is particularly challenging to treat is illustrated by the very large number of strategies which have been tried to a greater or lesser extent.

  • Hypomagnesaemia should be looked for and corrected
  • Baclofen may specifically help paroxysmal pain; up to 60mg daily has been used
  • Levomepromazine appears to have intrinsic analgesic activity. The sedative/anxiolytic effect may also benefit distressed patients
  • Clonidine is used extensively in spinal infusions. Given by mouth, its tolerance is limited by hypotension and sedation. Doses of 25mcg t.d.s. increasing to 100 mcg t.d.s. have been used
  • Capsaicin cream has proved useful in neuropathic pain, especially post herpetic neuralgia. The application of the cream can itself cause stinging which can be relieved by the use of Emla cream applied prior to the capsaicin. Capsaicin is a derivative of chilli pepper and must be applied with gloves five times a day. The pain may increase to start with but perseverance may provide relief. Studies suggest its mode of action is mediated by reducing the amount of substance P available for neurotransmission
  • Cannabinoids may have a place in neuropathic pain, or pain associated with muscle spasm

Capsaicin

  • Cream 0.075% 45g (Axsain)

Starting dose: Apply topically 3–4 times daily Clonidine

  • Tabs. 25mg. Tabs. 100mg, 300mg
  • caps. m/r 250mg

Starting dose: Neuropathic pain 25mg t.d.s. p.o. increasing to 100 mg t.d.s. Baclofen

  • Tabs. 10mg; Liquid 5mg/5ml

Starting dose: 5mg t.d.s. p.o. P.213
N-methyl-D-aspartate (NMDA) receptors The NMDA receptor is thought to be involved in the development of the ‘wind-up’ phenomenon of neuropathic pain. Ketamine and methodone are NMDA antagonists which may explain their efficacy in neuropathic pain. The site of action of opioid analgesics is closely related to the NMDA receptor, and anecdotal reports suggest that opioid analgesics may be needed for NMDA receptor antagonists to work. Wind up is the phenomenon of central sensitization when the experience of unchanged chronic pain stimulation worsens as nerve fibres become ‘trained’ to deliver pain signals better. Footnotes 6 Back I. N., Finlay I. (1995) Analgesic effect of topical opioids on painful skin ulcers. Journal of Pain and Symptom Management, 10, 7: 493. Ketamine Ketamine is a dissociative anaesthetic with strong analgesic properties. Its analgesic effect may be partly due to NMDA receptor blocking and may be useful clinically in sub-anaesthetic doses for treating neuropathic, inflammatory or ischaemic pain. In higher doses approaching anaesthetic doses, it may be useful for treating terminal uncontrolled overwhelming pain. It has been used byp.o., CSCI and i/v routes, and in a very wide range of doses.

  • CSCI in doses of 50–360mg/24h ± a loading dose of 10mg SC
  • p.o. starting doses between 2mg and 25mg t.d.s. have been used, and up to 50mg q.d.s. or 240mg/day
  • i/v bolus doses of 0.1–0.5mg/kg (approx. 5–25mg)

Dysphoric effects including hallucinations are reported quite commonly in higher doses. They are more common in anxious patients, and small doses of benzodiazepines may help. Anaesthetic experience suggests pre-treatment may help reduce the incidence. Neuropathic pain Use oral route if possible:

  • Diazepam 2mg p.o. 2 h before first dose then 2mg nocte for 3 days
  • Start ketamine 10mg q.d.s. p.o.
  • Increase by 10mg increments once or twice daily, up to 50mg q.d.s. as appropriate

If parenteral route appropriate:

  • Ketamine 10mg SC stat. may be given if indicated for severe pain
  • Start infusion of ketamine 50–100mg/24h CSCI
  • Add midazolam 5mg/24h CSCI to reduce dysphoric effects, or higher dose if patient is very anxious
  • Increase ketamine dose by 50–100mg increments as indicated to maximum 500mg/24h CSCI

Oral versus Parenteral doses Ketamine is effective orally and in view of the wide dose ranges used, it is difficult to assess the potency ratio. It undergoes first-pass hepatic metabolism to an active metabolite, and one study suggests it may be more potent given orally than parenterally. In general, equivalent daily doses should initially be used when changing route. P.214
Ketamine for procedures Ketamine can be used as an analgesic to allow patients to be positioned for epidural or certain procedures (e.g. dressing changes). It carries a high incidence of dysphoric effects at these doses.

  • Ketamine 0.5mg/kg by slow i/v injection (for 50kg man=25mg), or
  • Ketamine 1.5mg/kg i/m (for 50kg man=75mg)
  • Pre-treatment with a benzodiazepine to reduce the incidence of dysphoric effects:
    • midazolam 2.5mg SC given 30 min before, or
    • midazolam 1-3mg slow i/v immediately before (N.B. Anaesthetic dose for 50kg man is 50–150mg i/v over 1 min or 300–600mg i/m)

Terminal overwhelming pain

  • Give ketamine 25–50mg slow i/v or SC for immediate effect if needed
  • Midazolam 5mg SC stat
  • Start ketamine 300–600mg/24h CSCI
  • Add midazolam at least 20mg/24h to prevent hallucinations
  • Increase ketamine to a maximum of 1,200mg/24h CSCI (up to 3.2g/24h have been given)

Methadone (Figure see p. 220)

Figure. No caption available.
Table 6a.9 Efficacy of drugs for neuropathic pain (NNT)7
  Diabetic neuropathy Postherpetic neuralgia
Oxycodone 2.7 2.5
Tramadol 3.4
Tricyclic antidepressants 2.4 2.3
SSRIs 6.7
All antidepressants 3.4 2.1
Carbamazepine 3.3
Gabapentin 3.7 3.2
All anticonvulsants 2.7 3.2
Mexiletine 10.0
Baclofen 1.4
Capsaicin 5.9 5.3
NNT is the number of patients who have to be treated for one to achieve the specified level of benefit, in this case benefit in terms of pain relief.

P.215

Table 6a.10 Examples of treatments used for patients with neuropathic pain
Opioids Ketamine
Antidepressants (tricyclic) Spinal (epidural and intrathecal)
Anticonvulsants Methadone
NSAID trial Lidocaine patch/infusion
TENS Accupuncture Neurolytic procedures e.g. coeliac plexus block, cordotomy
Radiotherapy Capsaicin
Corticosteroids

Footnotes 7 Sindrup S. H. and Jensen T. S. (1999) Efficacy of pharmacological treatments of neuropathic pain: an update and effect related to mechanism of drug action. Pain, 83: 389–400.

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