Guideline Name: Neuropathic Pain Neuropathic pain is defined by the International Association for the Study of Pain, Neuropathic Special Interest group as pain arising as a direct consequence of a lesion or disease affecting the somatosensory system. It can be caused by lesions of the peripheral or central nervous system or both. The nerves involved can then transmit abnormal or incorrect messages to the brain resulting in increased intensity of pain, pain over a larger area or persistent pain. Neuropathic pain episodes can be divided into spontaneous or stimulus-evoked pain i.e. sensory changes. It is estimated that neuropathic pain could be a significant feature in up to 40% of cancer pain syndromes and in one case series it was found that 79% of neuropathic pain cases result from nerve compression, 16% from nerve injury and 5% are sympathetically mediated 1. Nerve injury in cancer has 3 main causes: 1. Tumour infiltration of individual nerves, nerve plexuses or the spinal cord. 2. As a result of surgery (post-operative incisional pain and phantom limb pain). 3. Radiotherapy and chemotherapy can also damage nerves and alter nerve function. Other classical forms of neuropathic pain include diabetic peripheral neuropathy, trigeminal neuralgia and postherpetic neuralgia. Clinical Features Neuropathic pain may include some of the following features: Pain in the distribution of a nerve or dermatome Burning or stinging Deep aching pain Spontaneous stabbing/lancinating pain Numbness Allodynia (pain in response to a normally non-painful stimulus eg. Unable to tolerate clothes on the area) Dysaesthesia (altered sensations such as pins and needles) Hyperaesthesia (unpleasant increased sensitivity) Hyperalgesia (increased pain response to a normally painful stimulus) Occasionally a sympathetic component manifesting as cutaneous vasodilatation and/or sweating. The diagnosis of neuropathic pain is based mainly on the patient s history and physical examination. The essential elements are to identify painful symptoms, altered sensation and a clinical history that all match a neuroanatomical or dermatomal pattern. Examination may also identify specific functional neurological deficits. The LANSS scale is a useful screening tool (appendix 1), although it is not a substitute for good clinical assessment. Palliative care patients usually have a combination of neuropathic and nociceptive pain and it can be useful to consider whether there is a neuropathic component to an individual s pain. Page 1 of 9
Management As well as the pain, other physical and emotional aspects should be addressed including improving poor sleep as well as treating depression and anxiety. Non-pharmacological approaches should also be considered (see below). A multi-disciplinary approach is often the most successful. General recommendations for the medical management of neuropathic pain in non-palliative care patients would suggest the use of a tricyclic antidepressant or an anticonvulsant as first line analgesics. In palliative care, because a patient s pain is rarely purely neuropathic in origin, it is usually recommended to follow the WHO analgesic ladder with early consideration of adjuvant medications in addition. If pain is due to an infiltrating cancer, a combination of opioid and NSAID should be tried first, before adding an anti-depressant or anti-convulsant 2. About half of nerve injury pains caused by cancer respond to the combined use of a NSAID and a strong opioid; the rest need adjuvant analgesics 3. Responsiveness of the pain to medications may be reduced if pain has been present for a prolonged period prior to instigation of treatment. In one systematic review, the benefits of adjuvant analgesics greatly outweigh their adverse effects in patients with neuropathic cancer pain. No one adjuvant analgesic was better than another and none caused more side effects than another 4. 1. WHO Analgesic Ladder Opioids and Adjuvants Morphine should be 1 st line opioid of choice. There is no evidence that oxycodone or other opioids are superior to morphine in the management of neuropathic pain. Opioids are comparable to tricyclic antidepressants in number needed to treat (NNT) in non-cancer neuropathic pain (approx 2.5) 5. Tramadol - Do not use with antidepressants due to risk of serotonin toxicity. Limited evidence suggests NNT of approx 3.9 5. Non-steroidal anti-inflammatory drugs can be tried as adjuvant analgesics. 2. Corticosteroids Steroids are only recommended for use in neuropathic pain caused by an infiltrating cancer. They can be very useful in reducing neuropathic pain due to nerve compression by reducing oedema and inflammation 6. They should be considered at any stage if nerve compression is felt likely. Starting dose 8mg od (but adjusted depending on the clinical situation). Remember gastric protection if needed and be vigilant for oral thrush and steroid induced diabetes. 3. Antidepressants Tricyclic Antidepressants (TCAs) eg. Amitriptyline, Nortriptyline, Imipramine, Lofepramine. Although very well established in palliative medicine, TCAs are unlicensed for neuropathic pain. The NNT for the different types of neuropathic pain that respond to TCAs ranges from 2.0 to 3.0 5. The different types of tricyclic antidepressant have differing effectiveness and side effect profiles 5. Amitriptyline may cause a more significant morning hangover effect than nortriptyline 7. Side effects include dry mouth, constipation, postural hypotension, urinary retention and cardiac arrhythmias. They should be avoided in patients with glaucoma and used with caution in patients with a cardiac or diabetic history. TCAs should be the first line agent for treatment of neuropathic pain in patients with renal impairment. They should not be withdrawn abruptly. Page 2 of 9
Amitriptyline should be started at 10mg nocté. If tolerated it can be increased to 25mg after 3-7 days, then increased by 25mg every 1-2 weeks (up to maximum dose of 150mg od). Nortriptyline could be tried if amitriptyline is helpful but poorly tolerated (if total dose amitriptyline 100mg or less the same dose can be given without tapering or a wash-out period). Lofepramine has a lower incidence of side effects and may therefore be safer in patients with history of cardiac arrhythmias. Selective Serotonin Reuptake Inhibitors (SSRIs)/Serotonin & Noradrenaline Reuptake Inhibitors (SNRIs) eg. Venlafaxine, Duloxetine, Paroxetine, Citalopram, Trazodone. Venlafaxine is the first-line antidepressant of choice in neuropathic pain from causes other than diabetic neuropathy 6. Side effects include nausea, constipation, hypertension, increased bleeding risk (if combined with NSAID) and should be avoided in patients with cardiac arrhythmias, severe renal or liver disease. They may be less likely to predispose to cardiac problems than TCAs. Venlafaxine should be started at a dose of 37.5mg daily and titrated up at weekly intervals to 150mg maximum dose. There is a risk of withdrawal syndrome and as such the dose should be reduced over several weeks. Duloxetine is the drug of choice in and only licensed for diabetic neuropathic pain. It should be started at 30mg daily and increased to a maximum of 120mg daily. 4. Antiepileptics Gabapentin or Pregabalin These should be considered as an alternative 1 st line therapy to tricyclic antidepressants (in patients without renal impairment) as there is no good evidence to suggest either class of drug is more effective. Advantages include the fact that they are licensed for neuropathic pain and have fewer anti-cholinergic side effects than amitriptyline. Side effects include dizziness, drowsiness, peripheral oedema and a dry mouth. Gabapentin: Pregabalin: It can involve a large tablet load and require careful titrating. Start at 100mg the first night then 100mg tds and titrate up to recommended maximum dose of 1200mg/day, (in certain circumstances this can be increased to 3600mg /day). Titration should be slow in elderly, frail patients (refer to PCF 4). It must be used in caution in renal failure (see appendix 2). The duration of an adequate trial of Gabapentin is 3-8 weeks titration plus 2 weeks at maximum dose. The brand name Lyrica is licensed for neuropathic pain but not the generic drug; it has lower NNH (number needed to harm) than Gabapentin in some studies 5 but can still have significant side effects. Starting dose is 25 to 50mg bd for most patients, titrating to 300mg bd maximum. Also use with caution in renal failure as the drug is excreted unchanged by the kidneys, and cardiac failure. Recommendations are for doses to be given once daily when egfr <30 (see appendix 2). NICE guidelines 6 recommend offering either Amitriptyline, Duloxetine, Gabapentin or Pregabalin as first line initial treatment for NP, and titrating the dose until either a therapeutic effect is achieved or side effects limit further titration. If the initial drug is ineffective or side effects are not tolerated, the recommendation is to switch to one of the remaining 3 drugs and repeat the process to find a drug that is effective and tolerated. If it is necessary to combine adjuvant analgesics then avoid combining two adjuvants with the same action. Page 3 of 9
Other Antiepileptics Sodium Valproate disadvantage is monitoring levels/bloods. Lamotrigine maybe useful. Is not licensed. Levetiracetam Carbamazepine first-line choice in Trigeminal Neuralgia but may be a useful alternative in some patients 7. Starting dose 100mg BD and titrate weekly to a maximum of 1.2 to 1.6mg daily. Oxcarbazepine may be less likely to cause blood disorders. 5. Consider Other Medications Clonazepam: Lidocaine: This is a benzodiazepine with long half-life. It can be useful when spasms or anxiety are associated with the pain. Start at 0.5mg nocté and titrate up to 2mg. A local anaesthetic available in 5% patches. Patch must be placed over the painful area to be effective. Leave in place for 12 hours & then remove for 12 hours to prevent tolerance. A two week trial is enough to assess efficacy 7. Can use up to 3 patches at any one time. (NB There is limited evidence for the effectiveness of such patches so it may be worth considering this as a trial only). NMDA receptor channel blockers: Ketamine: Methadone: Capsaicin Cream: Can cause opioid sparing and render patients opioid toxic so usually introduced as inpatient. Can be used orally (start at 10mg qds up to 200mg qds) or as a continuous subcutaneous infusion (CSCI). (Starting dose 0.1-0.5mg/kg/hr up to 2.4g/24hrs). Side effects include vivid dreams and hallucinations which can be controlled by haloperidol This is an opioid agonist, NMDA receptor blocker and serotonin re-uptake inhibitor with a possible role in reducing wind-up. It has a very long half-life and accumulates in tissues due to high lipid solubility 8. Hospice admission is suggested to convert a patient to methadone but it can be used in low dose (e.g. 5mg bd) as an adjuvant analgesic. 0.075% can be useful to localise NP in those patients who wish to avoid or can t tolerate oral treatment 6. Tramadol: Might be useful as a breakthrough remedy while other drugs are being titrated 6. 6. Non-Drug Measures TENS: Discuss with Physiotherapist 7. Consult with Chronic Pain Team for Anaesthetic Interventions The Chronic Pain Team are located at Maidstone Hospital and can be contacted on 01622 224955/224411 (Mon- Fri). Patients can be referred for out-patient appointments (at Maidstone, Tunbridge Wells or Sevenoaks Hospitals) or to be seen on IPU for assessment for a procedure. Procedures include nerve blocks, epidural or intrathecal injections, indwelling epidural or intrathecal infusions and nerve stimulation. Page 4 of 9
References 1. Stute P, Soukup J, Menzel M, Sabatowski R, Grond S. Analysis and treatment of different types of neuropathic cancer pain. J Pain and Symptom Management 2003; 26(6):1123-31. 2. Palliative Care Formulary 4 rd edition. Twycross R, Wilcock A. 3. Symptom Management in Advanced Cancer. Twycross R, Wilcock A, Stark Toller C, 2009. 4. Jongen JLM et al. The Evidence for Pharmacological Treatment of neuropathic pain: beneficial and adverse effects. 5. Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment: an evidence-based proposal. Pain 2005; 118: 289-305. 6. NICE Guidelines: CG96173 Neuropathic pain - pharmacological management, Pub Nov. 2013. 7. West Kent CCG Neuropathic Pain Prescribing Guidelines, June 2014. 8. Moulin DE et al. Pharmacological management of chronic neuropathic pain consensus statement and guidelines from the Canadian Pain Society. Pain Research and Management 2007; 12(1): 13-21 Related policies and guidelines Epidural guideline (Inpatient Unit and Community) Date Originated: October 2007 Original Author: Date of last review: October 2012 Date of this review: April 2015 Reviewed By: Dr Diane Kooiman, Specialty Doctor Date of next review: January 2019 Issuing Authority: Dr Helen McGee, Consultant & Medical Director Page 5 of 9
The LANSS Pain Scale Leeds Assessment of Neuropathic Symptoms & Signs Appendix 1 Name Date. This pain scale can help to determine whether the nerves that are carrying your pain signals are working normally or not. It is important to find this out in case different treatments are needed to control your pain. A. PAIN QUESTIONNAIRE Think about how your pain has felt over the last week. Please say whether any of the descriptions match your pain exactly. 1) Does your pain feel like strange, unpleasant sensations in your skin? Words like pricking, tingling, pins and needles might describe these sensations. a) NO My pain doesn t really feel like this (0) b) YES I get these sensations quite a lot (5) 2) Does your pain make the skin in the painful area look different from normal? Words like mottled or looking more red or pink might describe the appearance. a) NO My pain doesn t affect the colour of my skin (0) b) YES I ve noticed that the pain does make my skin look different from normal (5) 3) Does your pain make the affected skin abnormally sensitive to touch? Getting unpleasant sensations when lightly stroking the skin, or getting pain when wearing tight clothes might describe the abnormal sensitivity. a) NO My pain doesn t make my skin abnormally sensitive in that area (0) b) YES My skin seems abnormally sensitive to touch I that area (3) 4) Does your pain come on suddenly and in bursts for no apparent reason when you re still. Words like electric shocks, jumping and bursting describe these sensations. a) NO My pain doesn t really feel like this (0) b) YES I get these sensations quite a lot (2) 5) Does your pain feel as if the skin temperature in the painful area has changed abnormally? Words like hot and burning describe these sensations. a) NO I don t really get these sensations (0) b) YES I get these sensations quite a lot (1) B. SENSORY TESTING Skin sensitivity can be examined by comparing the painful area with a contralateral or adjacent non-painful area for the presence of allodynia and an altered pin-prick threshold (PPT). 1) ALLODYNIA Examine the response to lightly stroking cotton wool across the non-painful area and then the painful area. If normal sensations are experienced in the non-painful site, but pain or unpleasant sensations (tingling, nausea) are experienced in the painful area when stroking, allodynia is present a) NO normal sensation in both areas (0) b) YES allodynia in painful area only (5) 2) ALTERED PIN-PRICK THRESHOLD Determine the pin-prick threshold by comparing the response to a 23 gauge (blue) needle mounted inside a 2ml syringe barrel placed gently onto the skin in a non-painful and then painful area. If a sharp pin prick is felt in the non-painful area, but a different sensation is experienced in the painful area, eg non/blunt only (raised PPT) or a very painful sensation (lowered PPT), an altered PPT is present. If a pin prick is not felt in either area, mount the syringe onto the needle to increase the weight and repeat. a) NO equal sensation in both areas (0) b) YES altered PPT in painful area (3) SCORING: Add values in parentheses for sensory description and examination findings to obtain overall score. TOTAL SCORE (maximum 24) If score <12, neuropathic mechanisms are unlikely to be contributing to the patient s pain. If score >12, neuropathic mechanisms are likely to be contributing to the patient s pain. Page 6 of 9
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Appendix 2 Page 8 of 9
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