Opioid analgesics in the management of acute pain

Clinical Guideline

Guidelines for the Treatment of

Neuropathic pain in adults

Change history

Date Change details Approved by

Document detail Document location West Kent and MTW Formulary &

MTW Trust Wide Version 1.0 Effective from July 2017 Review date July 2020 Owner Directorate of Critical Care Author CNS Leslie Harman – Lead Nurse

Pain Management Team

Approved by Date

MTW Pain Management Steering Group June 2017 MTW Drugs & Therapeutic Committee May 2017 West Kent CCG Medicines Optimisation Group May 2017

Ratified by Date

Trust Clinical Governance Committee 14th September 2017

Superseded documents - Related documents Opioid Acute Pain Guidelines

Opioid Chronic Pain Guidelines Palliative Care Pain Guidelines

The following staff have given consent for their names to be included in this document

Leslie Harman

Guidelines for the treatment of neuropathic pain in adults Author: Lead Nurse Pain Management Team Review date: July 2020 RWF-THT-CHP-GUI-1 Version no.: 1.0 of 13

Contents Page Abbreviations 2 Aim of guidelines 3 Neuropathic Pain Analgesic Flow Chart 4 Amitriptyline 5 Carbamazepine 5 Duloxetine 5 Gabapentin 6 Pregabalin 6 Imipramine 7 Nortriptyline 7 Venlafaxine 7 Topical Capsaicin cream 0.075% 8 Lidocaine Patches ‘Versartis’ 8 Codeine 8 Buprenorphine 9 Tramadol 9 Appendix: 1 Neuropathic Pain diagnostic questionnaire – DN4 2 LANSS; Leeds assessment of neuropathic symptoms and signs

11 12

References 13

Abbreviations PRN Pro re nata (as required) SSRI Selective Serotonin Reuptake

Inhibitor SNRI Selective Noradrenaline Reuptake

Inhibitor AKI Acute Kidney Injury CKD Chronic Kidney Disease


Aim of guideline

• To provide a general framework that should be widely applicable when prescribing neuropathic analgesia for the management of neuropathic pain in adults

• To standardise clinical practice as far as possible - safe and effective practice is likely to be achieved by familiarity

• Not to undermine the autonomy or freedom of clinicians to make their own decisions regarding the clinical management of patients in their care.

Neuropathic pain is a type of chronic pain associated with injury to nerves and nervous system. Types of neuropathic pain include sciatica following disc prolapse, nerve injury following spinal surgery, pain after infection such as shingles or HIV/AIDS, pain associated with diabetes, pain after amputation (phantom limb pain or stump pain) and pain associated with multiple sclerosis or stroke. Neuropathic pain is usually severe and unpleasant. Medication may be used to treat neuropathic pain but are usually not very effective and work for a small proportion of people. Patients may not benefit from the first drug tried and may need to try more than one drug to improve symptoms. Pharmacology is only part of the treatment of neuropathic pain. Full assessment with clear diagnosis well explained is equally important. Appendix;

1 Neuropathic Pain diagnostic questionnaire – DN4 2 LANSS; Leeds assessment of neuropathic symptoms and signs

Aim of treatment: Functional restoration is more important than total pain relief; most neuropathic pain medication reduces but does not abolish pain. Improving function will improve quality of life. Measurement of effectiveness of medication can be measured by using VAS; visual analogue scores 0 -10, a reduction of pain score by 2 is positive with improved function. If side-effects of medication lead to reduced function and decline in quality of life consider reduction of dose of medication, or cessation of the medication, or consider a switch to alternative medication if available. If all options have been tried do not offer further trials.


Neuropathic Analgesic flowchart

Fourth Line: Mild - Strong Opioids Limited benefit, prescribe at low dose only, please refer to Acute and Chronic Opioid guidelines.

First Line

Second Line

Third Line

Amitriptyline 10mg OD - up to 75mg OD

If amitriptyline not tolerated (not if poor response) then:

Duloxetine 60mg OD - up to 120 mg daily (give maximum dose as 60mg BD) 1st line for Diabetic Neuropathy.

Carbamazapine 100mg BD – up to 800mg BD 1st line for Trigeminal Neuralgia only

Titrate all drugs at weekly intervals or longer if dose increase not tolerated

Gabapentin Day 1 – 100mg OD Day 2 – 100mg BD

Day 3 – 100mg TDS and continue at this dose Up to 1200mg TDS

If poor response or significant side effects

Pregabalin 25mg BD – up to 150 mg BD

Titrate all drugs at weekly intervals or longer if dose increase not tolerated

Other alternatives only available

Following Pain Team review:

Imipramine 10mg ON -75mg ON (TCA) – unlicensed Nortriptyline 10mg ON – 75mg ON (TCA)

Venlafaxine 37.5mg OD – 150mg OD (◊ do not use in patients with cardiac disease or in pregnancy) – unlicensed

Topical Capsaicin 0.075% cream QDS (licensed for post herpetic neuralgia and diabetic neuropathy only)

Lidocaine Plaster 5% 12 hours on/ 12 hours off (licensed for post herpetic neuralgia only)


Amitriptyline • Tricyclic antidepressant (TCA) • NICE (2013): analysis appeared consistent in demonstrating pain

reduction compared to placebo, Side effects such as sedation may be considered intolerable by some patients, but conversely may be considered beneficial by patients who have problems with sleeping

• (unlicensed) neuropathic pain, diabetic neuropathy • Caution in patients with cardiovascular, epilepsy, diabetes,

increased intra-ocular pressure, urinary retention, glaucoma, psychosis or bipolar disorders.

Initially 10 mg at Night; gradually increase if necessary to 75 mg, higher doses under Pain Team supervision. Amitriptyline has a long half-life so once-daily administration, 1 – 2 hrs before bedtime. Most common side-effects: dry mouth, abdominal pain, palpitations, oedema, hypertension, restlessness, fatigue, raised intraocular pressure and mydriasis. High rate of fatality in overdose. Increased risk of CNS toxicity with Tramadol.

Pharmacokinetics: SPC, Martindale, AHFS,

Carbamazepine • Anti-epileptic • (unlicensed) Trigeminal neuralgia and Diabetic neuropathy • Caution in patients with cardiac disease, skin reactions, advanced

liver disease, Renal impairment, Initially 100 mg 1 – 2 times a daily, increase gradually according to response ; usual dose 200 mg 3 – 4 times daily. Patient will require 6 monthly blood tests Most common side-effects: headache, ataxia, drowsiness, nausea, vomiting, blurred vision, skin reactions, dry mouth, fatigue, hyponatraemia, blood disorders. Oxcarbazepine may be less likely to cause blood disorders, regular blood tests may not be required. Pharmacokinetics: SPC, Martindale, AHFS

Duloxetine

• Antidepressant ( SNRI) • NICE ( 2013) : analysis appeared consistent that duloxetine

reduces pain compared with placebo • Inhibits the re-uptake of both serotonin and noradrenaline is

licensed to treat major depressive orders • Licensed only for the management of diabetic peripheral

neuropathic pain only. • Caution in patients with cardiac disease, elderly, history of mania,

history of seizures, raised intra-ocular pressure, bleeding disorders. Hepatic impairment – avoid.

Initially 60 mg daily, increase gradually according to response. Max 120 mg. Discontinue after 2 months if inadequate response.


Most common side-effects: nausea, vomiting, diarrhoea, constipation, abdominal pain, hepatoxicity, headaches, dizziness, drowsiness, sleep disturbance, fatigue, anxiety, sweating, dry mouth, palpitations, hot flushes, sexual dysfunction and pruritus. Pharmacokinetics: SPC, Martindale, AHFS

Gabapentin

• Anti-epileptic • NICE (2013): analyses consistent that gabapentin reduced pain

compared with placebo • Licensed for the treatment of peripheral neuropathic pain, so use for

other conditions would be off label. Effective treatment for migraine prophylaxis

• Caution in the elderly, diabetes, mixed seizure, history of psychotic illness, renal impairment. (Gabapentin can be safely combined with a TCA or SNRI)

• Gabapentin is secreted in breast milk – should be avoided during nursing

• Avoid with antacids – reduce bioavailability by 20%, administer ≥ 2 hrs after antacids

Initially 100 mg at night, increase gradually to 100mg TDS. If effective increase further according to response Max 1200 mg TDS. NB increases should be via Pain team only. Most common side-effects: nausea, vomiting, gingivitis, diarrhoea, abdominal pain, dyspepsia, constipation, dry mouth, flatulence, weight gain, vasodilation, oedema, confusion, depression, vertigo, anxiety, speech disorders, visual disturbance Pharmacokinetics: SPC, Martindale, AHFS

Pregabalin • Anti-epileptic • Licenced for peripheral and central neuropathic pain, generalized

anxiety disorders • Caution severe congestive heart failure, renal impairment, elderly,

diabetes, mixed seizure, history of psychotic illness Initially 25 – 50 mg at night, increase gradually to 150 mg BD. Further increases ( max 600mg) should be via the pain team only (Pregabalin can be safely combined with a TCA or SNRI) Most common side-effects: dry mouth, constipation, vomiting, flatulence, dizziness, drowsiness, irritability, impaired attention, speech disorder, impaired memory, malaise, insomnia, weight gain, sexual dysfunction and visual disturbance Pharmacokinetics Onset of action 1 hour Time to peak plasma conc .steady state 24 – 48 hrs


Imipramine • Tricyclic antidepressant ( TCA) • (unlicensed) neuropathic pain • Caution in patients with cardiovascular, epilepsy, diabetes,


Initially 10 mg at Night; gradually increase if necessary to 75 mg, higher doses under Pain Team supervision. Most common side-effects: dry mouth, palpitation, flushing, restlessness, headache and fatigue Pharmacokinetics: SPC, Martindale, AHFS

Nortriptyline • Tricyclic antidepressant ( TCA) • NICE (2013): analysis generally consistent that nortriptyline reduces

pain compared with placebo. However, there was much uncertainty around these estimates

• (unlicensed) neuropathic pain, diabetic neuropathy • Caution in patients with cardiovascular, epilepsy, diabetes,


Initially 10 mg at Night; gradually increase if necessary to 75 mg, higher doses under Pain Team supervision Most common side-effects: dry mouth, abdominal pain, diarrhoea, palpitations, oedema, hypertension, restlessness, fatigue, raised intraocular pressure and mydriasis. High rate of fatality in overdose. Pharmacokinetics: SPC, Martindale, AHFS

Venlafaxine • Antidepressant • Major depression, generalized anxiety but may be helpful

(unlicensed) for neuropathic pain and diabetic neuropathy • Caution in patients with heart disease arrhythmia, uncontrolled

hypertension, and diabetes, history of epilepsy, history or family of mania, glaucoma, bleeding disorders, hepatic impairment, and renal impairment. Pregnancy – avoid present in milk.

Initially 37.5 mg daily, increase gradually according to response. Max 150 mg. Discontinue after 2 months if inadequate response. Most common side-effects: constipation, nausea, anorexia, weight changes, palpitation, vasodilation, chills, dizziness, dry mouth, insomnia, headache, abnormal dreams, anxiety, confusion, hypertonia, tremor, sexual dysfunction, menstrual disturbance, sweating. Pharmacokinetics: SPC, Martindale, AHFS


Topical Capsaicin cream 0.075% • Topical application • NICE (2013) : some evidence that capsaicin cream is better than

placebo at reducing pain. Alternative treatment for patients with localised peripheral pain who are unable to, or prefer not to , use oral medication

• O.075% licenced for symptomatic relief of post herpetic neuralgia after lesions have healed and for relief of painful diabetic neuropathy, adjunct in hand and knee osteoarthritis

• Apply using gloves • Caution avoid mucous membranes, inflamed or broken skin, the

face and scalp. Apply to affected area 3 – 4 times daily. Wear gloves. Wash hands after each application. Burning sensation and skin redness is normal, can take 2 – 4 weeks before pain is reduced. Most common side effect: transient burning and erythema Pharmacokinetics: SPC, Martindale, AHFS

Lidocaine Patches • Local Anaesthetic • Lidocaine 5% (versartis) medicated plaster. Licenced for the

treatment of post herpetic neuralgia but may be helpful in other axial pain

• Caution avoid inflamed or broken skin Apply to intact, dry, non-hairy, non-irritated skin once daily for 12 hours followed by a 12 hour plaster free period, discontinue if no response after 4 weeks, up to 3 plasters may be used to cover large areas, plasters may be cut. Most common side effects: erythema and blisters. Pharmacokinetics: SPC, Martindale, AHFS

Mild - Strong Opioids Limited benefit, prescribe at low dose only, please refer to Acute and Chronic Opioid guidelines Evidence for strong opioids may be equivalent to that for other anti-neuropathic agents. However, it is advised these are reserved for later stages in the treatment of neuropathic pain. Codeine

• A weak opioid • Codeine is metabolised to morphine in order to relieve pain; individuals

can vary from poor metabolisers (little or no pain relief) to ultra-rapid metabolisers (excessive amounts of morphine in the blood).

30-60mg 4-6 hourly PRN (max 240mg/hours for pain)


Codeine is a Weak opioid and weak mu agonist Primary action is by metabolism by CYP2D6 by de-methylation - approximately 10% is metabolised to morphine Large variability in metabolism so hypermetabolisers (~5%) get excessive effects and are at risk of narcosis Hypometabolisers (~7.5%) get little benefit from drug but may still get side effects As a result of this highly varied metabolism leading to potential toxicity or lack of effect codeine is no longer recommended for breast feeding mothers or for children as per NPSA warnings. We would recommend that it is not used as first line analgesia for in hospital acute pain. Dose = 30-60mg qds Pharmacokinetics: Bioavailability 40% po Onset of action 30 - 60 min Time to peak plasma conc. 1 - 2 hours Plasma half life 2.5 - 3.5 hours Duration of action 4 - 6 hours

Buprenorphine

• A partial opioid agonist • Do not prescribe concurrently with other high dose opioids (can

potentially precipitate withdrawal) • 200micrograms buprenorphine is equivalent to 15mg morphine.

200 - 400micrograms sublingually TDS PRN Drug Patch Size (micrograms/hour) Oral Morphine equivalent/ 24 hours Buprenorphine 5 12mg 10 24mg

20 48mg

Pharmacokinetics: SPC, Martindale, AHFS Tramadol

• Weak opioid + modulates serotonin/noradrenaline pathways • Caution in patients prescribed other medicines which can inhibit

serotonin reuptake – potential risk of serotonin syndrome (SSRIs, SNRIs, mirtazapine, MAOs, tricyclic antidepressants)

• Caution in patients with epilepsy and in patients with other seizure threshold lowering drugs (SSRI, SNRIs, antipsychotics)

Tramadol 50-100mg QDS PRN


Tramadol is a Synthetic centrally-acting analgesic with opioid and non-opioid properties

Opioid agonist, serotonin and NA reuptake inhibitor Can be effective treatment for neuropathic pain Can potentiate serotonin syndrome - theoretical risk of precipitating serotonin syndrome if used with other drugs which increase serotonin levels, (SSRIs, TCAs, Pethidine). Presents with tachycardia, myoclonus, dilated pupils, sweating, shivering & hyper-reflexia. Pro-convulsant: caution with epilepsy, particularly with tramadol IV Can lead to hyponatraemia

Dose = 50-100mg up to QDS Pharmacokinetics: SPC, Martindale, AHFS Other Opiates could be trailed at low doses as analgesic efficacy of opioids in chronic neuropathic pain is subject to considerable uncertainly.

Appendix:

1 Neuropathic Pain diagnostic questionnaire – DN4 2 LANSS; Leeds assessment of neuropathic symptoms and signs


References: http://www.nice.org.uk/guidance/CG173 Clinical Guideline 173. Neuropathic pain – pharmacological management: The pharmacological management of neuropathic pain in adults in non-specialist settings. 2013 Cochrane Reviews: Tramadol for neuropathic pain. Duehmke RM, Hollingshead J, Cornblath DR. Cochrane Database of Systematic Reviews2006, Issue 3.

Opioids for neuropathic pain. Eisenberg E, McNicol ED, Carr DB. Cochrane Database of Systematic Reviews 2006, Issue 3.

Amitriptyline for neuropathic pain and fibromyalgia in adults. Moore RA, Derry S, Aldington D, Cole P, Wiffen PJ. CochraneDatabase of Systematic Reviews 2012, Issue 12.

Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults. Gill D, Derry S, Wiffen PJ, Moore RA. Cochrane Database of Systematic Reviews 2011, Issue 10.

Duloxetine for treating painful neuropathy or chronic pain. Lunn MPT, Hughes RAC, Wiffen PJ. Cochrane Database ofSystematic Reviews 2009, Issue 4

Carbamazepine for acute and chronic pain in adults. Wiffen PJ, Derry S, Moore RA, McQuay HJ. Cochrane Database ofSystematic Reviews 2011, Issue 1.

Topical lidocaine for the treatment of postherpetic neuralgia. Khaliq W, Alam S, Puri NK. Cochrane Database of Systematic Reviews 2007, Issue 2.

Pregabalin for acute and chronic pain in adults. Moore RA, StraubeS,Wiffen PJ, Derry S, McQuay HJ. Cochrane Databaseof Systematic Reviews 2009, Issue 3

Pharmacokinetics: SPC, Martindale, AHFS. http://.medicines.org.uk/emc/company/2380/martindale%20pharma


http://www.nice.org.uk/guidance/CG173

http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD003726.pub3/pdf

http://onlinelibrary.wiley.com/doi/10.1002/14651858.CD006146/pdf








Opioid analgesics in the management of acute pain

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