GUIDELINES FOR THE MANAGEMENT OF CANCER-RELATED NEUROPATHIC PAIN
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1 GUIDELINES FOR THE MANAGEMENT OF CANCER-RELATED NEUROPATHIC PAIN 28.1 GENERAL PRINCIPLES Neuropathic pain may be relieved in the majority of patients by multimodal management. 1, 2 A careful history and examination are essential. 1 Investigations such as computerised tomography (CT) or magnetic resonance imaging (MRI) may be appropriate. 2 It is important to have a logical and rational approach to prescribing. Chemotherapy or radiotherapy may be indicated if the tumour is chemosensitive or radiosensitive. 3, 4, 5, 6, 7 Non-pharmacological approaches should be considered including: transcutaneous electrical nerve stimulation (TENS); acupuncture; hydrotherapy and psychological interventions. 8, 9, 10 Interventional techniques may be indicated and should always be discussed at an early stage with an Anaesthetic Pain Specialist. 11, GUIDELINES The WHO analgesic ladder should be followed. 13 [ Level 2-] Strong opioids should be titrated against response. Adjuvants and non-opioids should be used as appropriate. 14 [Level 1-] The endpoint of titration is pain relief or intolerable side effects. If dose-limiting side effects occur despite the use of adjuvants or other interventions, a switch of opioid should be considered. 15 [Level 3] Figure 28.1 features a flow diagram which may be a useful guide for adjuvant prescribing in neuropathic pain. 16, 17 [ Level 1+] If nerve compression is suspected, a trial of corticosteroids should be considered e.g. dexamethasone 8mg for 5 days. 18, 19, 20 [Level 1-] Pain relief following the use of corticosteroids often predicts a favourable response to radiotherapy. 21 [ Level 4] Anaesthetic techniques may be indicated. They should always be discussed early with an Anaesthetic Pain Specialist whilst the patient remains fit enough to tolerate any appropriate procedure (see Guidelines on Interventional Pain Techniques). 11, 12 [ Level 3] Topical treatment with capsaicin cream may be of benefit in patients intolerant of other treatments. 22 [ Level 1-] In patients with symptoms that are difficult to control or who have severe allodynia / hyperalgesia, consider admission to a specialist centre. 23 [Level 4]
2 Figure 28.1 Approaches to the use of adjuvant analgesics in neuropathic pain 16, 17 [Level 4] Start amitriptyline or gabapentin and titrate dose. NO PARTIAL COMPLETE Stop chosen drug Continue chosen drug Switch to gabapentin or amitriptyline. Add gabapentin or amitriptyline. Stop chosen drug. NO PARTIAL COMPLETE Continue chosen drug(s). Consider alternative anticonvulsant from drugs listed in Table 28.1 Refer for specialist management. Methadone is a potent µ agonist and acts as a non-competitive antagonist at the N-methyl-Daspartate (NMDA) receptor. It has also been shown to inhibit the re-uptake of serotonin and noradrenaline. Morphine, hydromorphone, fentanyl and oxycodone do not exhibit this additional action. Methadone is therefore often used as a broad-spectrum opioid in the treatment of resistant cancer-related neuropathic pain, where there have been dose-limiting side effects and rapid development of tolerance to the previous opioid. Methadone should only be initiated in a specialist unit (see Guidelines on the Use of Methadone). 24 [ Level 1-] Ketamine may be given as an infusion prior to conversion to an oral preparation where appropriate. It should only be initiated under specialist supervision. It can be given intravenously 25 [Level 1-] or subcutaneously. Various regimens have been described and the choice will depend on the preference of the specialist team. 26, 27 [ Level 3]
3 Anaesthetic approaches (see Guidelines on Interventional Pain Techniques) If the pain is escalating despite the use of recommended guidelines, or if urgent control is required, consider early referral for an Anaesthetic Pain Specialist opinion. 11 [Level 4] The use of peripheral nerve blocks using local anaesthetic and / or corticosteroids may be effective for the relief of pain in the distribution of one or more peripheral nerves. 28, 29 [Level 3] Neurolytic procedures such as a saddle block using phenol may relieve some painful sacral neuropathies. 11, 30 However this may cause significant problems with bladder and bowel function. Some experts favour epidural catheters as an alternative. [Level 4] Epidural opioids +/- bupivicaine may be of use in patients with neuropathic pain, particularly in patients with intractable radicular pain or where systemic opioids have caused severe side effects. However, they may cause significant problems with bladder and bowel function. 31, 32 [Level 4] If unilateral pain below the shoulder and prognosis between three months and twelve months, consider referral for percutaneous cordotomy. 33, 34, 35 [Level 3] 28.3 STANDARDS 1. All patients with neuropathic pain should be monitored with a pain diary. 2, 23, 36 [Grade D] 2. Patients with poorly controlled neuropathic pain should have at least weekly follow up if an outpatient, and 48 hourly reassessment if an inpatient. 23 [Grade D] 3. If neuropathic pain is escalating, an Anaesthetic Pain Specialist should be contacted for advice within 48 hours. 11 [Grade D]
4 Table 28.1 Adjuvant oral analgesics used in the management of neuropathic pain Drug Name Initial dose Titration Side effects Notes Amitriptyline 16 [Level 1+] Capsaicin 0.075% cream 22 [Level 1-] Carbamazepine 37 [Level 1+] Clonazepam 38 [Level 3] Dexamethasone 21 [ Level 1-] Gabapentin 17 [Level 1+] 10mg-25mg at night. 10mg at night in the elderly. Median preferred dose of 75mg daily. Apply topically three or four times daily. 200mg daily. 100mg daily in elderly. 500 micrograms nocte. 8mg daily. 300mg nocte. 100mg nocte if elderly. Increase every 3 days as tolerated. Increase by 100mg- 200mg every three days. Give in divided doses. Increase by 500microgrammes every third day. Maximum dose is 8 mg. Give for 5 days. Discontinue if no response. Reduce to lowest dose to maintain effect (see Guidelines on Corticosteroids). Increase after 3 days to 300mg bd. Increase to 300mg tds after further 3 days. Maximum dose is 2400mg. Occur in 33% of patients. Include drowsiness and dry mouth. Skin burning and redness. Nausea, drowsiness, confusion and ataxia. Sedation. Sedation, dizziness. Speed of onset 1-7 days. May get improved sleep pattern and mood. Use with caution in the following: cardiac disease; arrhythmias; epilepsy; concurrent use of SSRIs; angle closure glaucoma; history of urinary retention. May take up to 10 days to have an effect. Always wear gloves when applying. Beware of drug interactions. May be given subcutaneously via a syringe driver. May adsorb to PVC so use non PVC equipment for infusions. A CSCI containing clonazepam should only run for a maximum of 12 hours as stability of diluted clonazepam currently only confirmed for 12 hours. If good response then may benefit from radiotherapy. Monitor blood sugar levels. Consider gastric protection. Reduce dose in renal failure/ impairment. Use with caution in patients with CCF. Diabetic patients may need to adjust hypoglycaemic treatment as weight gain may occur. Lidocaine plaster 39 [Level 1-] Pregabalin 40 [Level 1-] One strength. Apply for 12 hours daily over painful area and then remove. Day 1: 25mg od Day 2: 25mg bd Increase every two days by 25 mg bd. Note: May need to use slower titration regimen e.g. start at 100mg od and increase by 100mg every two days. Can use up to 3 patches at any one time 150mg-600mg daily in two divided doses. Avoid tds dosing. Treatment costs increase with no benefit. Skin reaction Sedation, dizziness. Current evidence is for post herpetic neuropathic pain. May be useful for post thoracotomy pain. Potential pharmacodynamic interactions with all opioids and sedatives. 42 Caution may be required in patients with chronic heart failure. 43 Diabetic patients may need to adjust hypoglycaemic treatment as weight gain may occur. Sodium valproate 41 [Level 2-] 200mg at night. Increase by 200mg every third day. Maximum dose is 1000mg daily. Nausea, ataxia. NB. Choice of adjuvant analgesic will depend on clinician experience and the side effect profile of individual drugs.
5 28.4 REFERENCES 1. Chong MS, Bajwa ZH. Diagnosis and treatment of neuropathic pain. J Pain Symptom Manage 2003; 25(5 Suppl): S4-S Herr K. Neuropathic pain. A guide to comprehensive assessment. Pain Manag Nurs 2004; 5(4 Suppl 1): Back I. Palliative Medicine Handbook. 3 rd ed. Aberystwyth, Ceredigon: Cambrian Printers Casper ES, Green MR, Kelsen DP, Heelan RT, Brown TD, Flombaum CD et al. Phase II trial of gemcitabine (2,2 difluorodeoxycytidine) in patients with adenocarcinoma of the pancreas. Invest New Drugs 1994; 12(10): Carmichael J, Fink U, Russell RCG, Spittle MF, Harris AL, Spiessi G et al. Phase II study of gemcitabine in patients with advanced pancreas cancer. Br J Cancer 1996; 73(1): cited in Storniolo AM, Enas NH, Brown CA, Voi M, Rothenberg ML, Schilsky R. An investigational new drug treatment program for patients with gemcitabine. Cancer 1999; 85(6): Storniolo AM, Enas NH, Brown CA, Voi M, Rothenberg ML, Schilsky R. An investigational new drug treatment program for patients with gemcitabine. Cancer 1999; 85(6): Hughes RAC, Britton T, Richards M. Effects of lymphoma on the peripheral nervous system. J Soc Med 1994; 87(9): Cruccu G, Aziz TZ, Garcia-Larrea L, Hansson P, Jenson TS, Lefaucheur JP et al. EFNS guidelines on neurostimulation therapy for neuropathic pain. Eur J Neurol 2007; 14: Han JS. Acupuncture and endorphins. Neurosci Let 2004; 361: Rapson LM, Wells N, Pepper J, Majid N, Boon H. Acupuncture as a promising treatment for below-level central neuropathic pain: a retrospective study. J Spinal Cord Med 2003; 26(1): Swarm RA, Karanikolas M, Cousins MJ. Anaesthetic techniques for pain control. In: Doyle D, Hanks G, Cherny N, Calman K (eds). Oxford Textbook of Palliative Medicine. 3 rd edition. Oxford; Oxford University Press, 2004: p Lipton S. Pain relief in active patients with cancer: the early use of nerve blocks improves the quality of life. Br Med J 1989; 298: Grond S, Radbruch L, Meuser T, Sabatowski R, Loick G, Lehmann KA. Assessment and treatment of neuropathic cancer pain following WHO guidelines. Pain 1999; 79: Eisenberg E, Mc Nichol E, Carr DB. Opioids for neuropathic pain. Cochrane Database of Systematic Reviews 2006, Issue 3. Art No: CD DOI: / CD Quigley C. Opioid switching to improve pain relief and drug tolerability. Cochrane Database of Systematic Reviews 2004, Issue 3 Art No: CD DOI: / CD Saarto T, Wiffen PJ. Antidepressants for neuropathic pain. The Cochrane Database of Systematic Reviews Issue 4. Art No: CD DOI: / CD pub Wiffen PJ, McQuay HJ, Edwards JE, Moore RA. Gabapentin for acute and chronic pain. Cochrane Database of Systematic Reviews 2005, Issue 3. Art No: CD DOI / Hanks GW, Trueman T, Twycross RG. Corticosteroids in terminal cancer - a prospective analysis of current practice. Postgrad Med J 1983; 59:
6 19. Bruera E, Roca E, Cedaro L, Carraro S, Chacon R. Action of oral methylprednisolone in terminal cancer patients: a prospective randomized double-blind study. Cancer Treat Rep 1985; 69: Vecht CJ, Haaxma-Reiche H, van Putten WL, de Visser M, Vries EP, Twijnstra A. Initial bolus of conventional versus high-dose Dexamethasone in metastatic spinal cord compression. Neurology 1989; 50: Makin MK, Smith J. Scientific evidence and expert clinical opinion for the utility of coanalgesia. In: Hillier R, Finlay I, Welsh J, Miles A (eds. Key Advances in the Effective Management of Cancer Pain. London: Aescupulis Medical Press, Mason L, Moore RA, Derry S, Edwards JE, McQuay HJ. Systematic review of topical capsaicin for the treatment of chronic pain. Br Med J 2004; 328: Merseyside and Cheshire Palliative Care Network Audit Group. Management of Cancerrelated Neuropathic Pain. Expert Consensus. July Morley JS, Bridson J, Nash TP, Miles JB, White S, Makin MK. Low dose methadone has an analgesic effect in neuropathic pain: a double-blind randomised controlled crossover trial. Palliat Med 2003; 17(7): Mercadante S, Arcuri E, Tirelli W, Casuccio A. Analgesic Effect of Intravenous Ketamine in Cancer Patients on Morphine Therapy: A Randomized, Controlled, Double-Blind, Crossover, Double-Dose Study. J Pain Symptom Manage 2000; 20(4): Mercadante S, Lodi F, Sapio M, Calligara M, Serrett R. Long-term ketamine subcutaneous infusions in neuropathic cancer pain. J Pain Symptom Manage 1995; 10(7): Benitez-Rosario MA, Feria M, Salinas-Martin A. A retrospective comparison of the dose ratio between subcutaneous and oral ketamine. J Pain Symptom Manage 2003; 25(5): Boys L, Peat SJ, Hanna MH, Burn K. Audit of neural blockade for palliative care patients in an acute unit. Palliat Med 1993; 7(3): Chambers WA. Nerve blocks in palliative care. Br J Anaesth 2008; 10(1): Slatkin N, Rhiner M. Phenol saddle blocks for intractable pain at the end of life: Report of four cases and literature review. Am J Hosp Palliat Care 2003; 20(1): Day R. The use of epidural and intrathecal analgesia in palliative care. Int J Palliat Nurs 2001; 7(8): Burton AW, Rajagopal A, Shah HN, Mendoza T, Cleeland C, Hassenbusch SJ et al. Epidural and intrathecal analgesia is effective in treating refractory cancer pain. Pain Med 2004; 5(3): Crul BJP, Blok LM, van Egmond J, van Dongen RT. The present role of percutaneous cervical cordotomy for the treatment of cancer pain. J Headache Pain 2005; 6(1): Jackson MB, Pounder D, Price C, Matthews AW, Neville E. Percutaneous cervical cordotomy for the control of pain in patients with pleural mesothelioma. Thorax 1999; 54(3): Lahuerat J, Lipton S, Wells JCD. Percutaneous cervical cordotomy: results and complications in a recent series of 100 patients. Ann R Coll Surg Engl 1985; 67(1): Hansson P. Neuropathic pain: clinical characteristics and diagnostic workshop. Eur J Pain 2002; 6 (Suppl 1): S Wiffen PJ, McQuay HJ, Moore RA. Carbamazepine for acute and chronic pain. Cochrane Database of Systematic Reviews 2005, Issue 3. Art No: CD DOI: / CD
7 38. Hugel H, Ellershaw JE, Dickman A. Clonazepam as an adjuvant analgesic in patients with cancer-related neuropathic pain. J Pain Symptom Manage 2003; 26: Galer BS, Jensen MP, Ma T, Davies PS, Rowbotham MC. The lidocaine patch 5% effectively treats all neuropathic pain qualities: Results of a randomized, double-blind, vehiclecontrolled, 3-week efficacy study with use of the Neuropathic Pain Scale. Clin J Pain 2002; 18(5): Finnerup NB, Otto M, Jensen TS, Sindrup SH. An evidence based algorithm for the treatment of neuropathic pain. Med Gen Med 2007; 9(2): Hardy JR, Rees AJ, Gwilliam B, Ling J, Broadley K, A hern R. A phase II study to establish the efficacy and toxicity of sodium valproate in patients with cancer-related neuropathic pain. J Pain Symptom Manage 2001; 21(3): Ben-Menachem E. Pregabalin pharmacology and its relevance to clinical practice. Epilepsia 2004; 45 (Suppl 6): S13-S Murphy N, Mockler M, Ryder M, Ledwidge M, McDonald K. Decompensation of chronic heart failure associated with pregabalin in patients with neuropathic pain. J Card Fail 2007; 13(3): CONTRIBUTORS Lead Contributors Dr H Emms Consultant in Palliative Medicine St Johns Hospice Wirral Dr C Douglas Specialist Registrar in Palliative Medicine Royal Victoria Hospital Dundee External Reviewer Dr A Jones Consultant Anaesthetic Pain Specialist Royal Liverpool and Broadgreen University Hospitals NHS Trust and Marie Curie Hospice Liverpool Dr M Makin Chief of Staff ( Cancer Services) Consultant and Visiting Professor in Palliative Medicine Betsi Cadwaladr University Health Board and Glyndwr University Wales
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