Type in your name

2. High technology treatment methods Treatment of neuropathic pain Type in your name Type in the nameof your institution

3. General aspect of management of neuropathic pain

4. IASP definition of neuropathic pain Neuropathic pain is a pain caused by a lesion or disease of the somatosensory system. www.iasp-pain.org/resources/painDefinition

5. Examples of causes of neuropathic pain Peripheral nervous system alcohol? • Radiculopathies related to spinal column diseases • Nerve traumas • Infectious diseases • HIV • Herpes zoster • Leprosy • Cancer-related • Polyneuropathies • Diabetes • Drug induced (e.g., antiretroviral drugs, neurotoxic chemotherapy) • Vitamin deficiency • Immune mediated

6. Examples of causes of neuropathic pain Central nervous system • Stroke • Spinal cord injury • Multiple sclerosis Both the disease itself and neuropathic pain can cause disability.

7. Neuropathic pain: underlying mechanisms Peripheral mechanisms Central mechanisms Membrane hyperexcitability Ectopic discharges Wind up Central sensitization Denervation hypersensitivity Loss of inhibitory controls • Membrane hyperexcitability • Ectopic discharges • Na+ channel expression  • Neuropeptide release  • Peripheral sensitization In neuropathic pain there is increased activity and decreased inhibition in the somatosensory system. Pharmacotherapy is based on modulation of these phenomena by decreasing the spontaneous activity and transmitter release and enhancing the inhibitory mechanisms.

8. Mechanism-based treatment? Individualized mechanism-based treatment is currently not possible. Trial and error -testing of the evidence-based drugs, individual tailoring. Etiology Mechanisms Symptoms

9. What is expected from a doctor? • To know the concept of neuropathic pain • To be able to recognize neuropathic pain • To be able to diagnose the causative disease and to treat it, if possible (e.g., diabetes) • To be able to start the first line medication to relieve neuropathic pain • To be able to refer the patient to a specialist, if needed (for diagnostic procedures or treatment)

10. Diagnosis of neuropathic pain Radicular pain (C6) Painful polyneuropathy

11. Diagnosis of neuropathic pain • Diagnosis of lesion or disease of the somatosensory system • Without this the pain cannot be neuropathic! • Location of pain is neuroanatomically logical (pain drawing is useful) Character of pain (e.g., burning, electric shock like pain), presence of other sensory symptoms (paresthesia, dysesthesia) and abnormal findings in sensory testing (hypo- or hyperesthesia, allodynia) • Neuropathic pain screening tools (e.g., DN4) are based on pain descriptors, and some include also simple sensory testing

12. Diagnosis of neuropathic pain • Measurement of pain intensity and impact of pain on functional capacity and well-being • Treatment effect is assessed by improvement in these aspects

13. What are we treating? Pain Causative disease and its treatment? Functional impairment? Sleep disturbance? Elderly? Anxiety? Depression? Concomitant diseases? Multiple drug use? Disability?

14. Information, follow-up, case management • The patient needs information of the character of the pain and of the causative disease and its treatment • Follow-up and a possibility of the patient to contact the doctor or nurse (the “case-manager”) is important to ensure compliance and safe treatment • Support of the patient is an essential part of the management • Team work is recommended

15. Pharmacotherapy of neuropathic pain Pharmacotherapy is the most important treatment for those with moderate or severe pain* • Goals: • (partial) pain relief (>50%, >30%) • Complete pain relief is exceptional; hence some pain relief is a realistic goal, which needs to be explained to the patient. • functional improvement and better quality of life • better sleep and mood, relief of anxiety • Many patients have some, moderate or intolerable side effects. • There are many refractory patients * See evidence of efficacy of pharmacotherapy in systematic reviews, e.g. Cochrane reviews, Finnerup et al. Pain 2005;118:289-305, Finnerup et al. Pain 2010 ;150:573-81

16. Principles of pharmacotherapy of neuropathic pain 1) Individual drug selection Cause of neuropathic pain • Most evidence comes from studies of painful polyneuropathies and postherpeticneuralgia, but in less studied conditions, the drugs with evidence from the best studied conditions are tested Other medical problems and their medication • Be careful with the contraindications and precautions • cardiac conduction disturbances: don’t select TCAs • urinary retention: don’t select TCAs or duloxetine • uncontrolled blood pressure: don’t select venlafaxine or duloxetine • Check possible interactions with the patient’s current medication (e.g., antiretroviral drugs, SSRIs) Previous drug trials • If some drug has been adequately tested previously with poor result, repetition of trial with the same drug is not rational

17. Principles of pharmacotherapy of neuropathic pain 2) Rational dosing and sufficient information • Tailored dosing • Clear information of dosing and possible side effects • “Start low, go slow, reach high” • Escalate to effective or maximal tolerated dose • Adequate drug trial? Slow up-titration • to the recommended maximal dose • to the maximal tolerated dose • to the dose providing relevant pain relief

18. Principles of pharmacotherapy of neuropathic pain 3) Assessment of efficacy and adverse effects Assess efficacy • pain relief • relief of comorbidities (e.g., better sleep, better mood, relived anxiety) • functional improvement • better quality of life Assess adverse effects • patients are usually ready to tolerate mild adverse effects • with slow titration side effects are usually relieved (e.g., dizziness caused by gabapentinoids or tiredness caused by TCAs) Taper of useless or harmful medications

19. Principles of pharmacotherapy of neuropathic pain 4) Rational polypharmacy, if needed • If one drug provides some pain relief, another drug with different mechanism of action can be combined with the first drug • an antidepressant combined with gabapentin or pregabalin • a systemic drug combined with a topical drug • The doses in combination therapy may be a bit lower than in monotherapy

20. Evidence-based drugs for neuropathic pain: mechanism(s) of action In combination treatment drugs with different mechanism of action can be combined.

21. Evidence-based drugs for neuropathic pain: dosing

22. Algorithm for treatment of neuropathic pain Peripheral neuropathic pain Trigeminal neuralgia Central neuropathic pain Topical lidocaine Central post-stroke pain Local allodynia Carbamazepine or oxcarbazepine Amitriptyline Spinal cord injury pain Gabapentin /pregabalin SNRI TCA Neuro-surgery Capsaicin plaster? Pregabalin Opioids? Multiple sclerosis pain (Cannabinoids) Abbreviations: SNRI = serotonin and noradreanalin reuptake inhibitors TCA = tricyclic antidepressants

23. Questions patients often ask about treatment • Are the drugs harmful to my liver, kidneys, stomach? • Are the drugs harmful to my brain? • Will they affect my mood? • Will they affect my sex life? – individual importance • Will I still be able to drive? • Are they addictive? • Can I use alcohol with them? • Can I change the dose if needed? • Is it ok to stop taking them abruptly? • Are they expensive?

24. Pain and cognitive performance • Revise previous medication, if needed • Start with low dose, titrate individually, follow up carefully • Evaluate effect on pain, comorbidities and cognitive performance • Inform patient of possible deleterious effect of drugs on alertness; driving is not recommended during titration of drugs with possible sedative effect Medication Disturbed sleep COGNITIVE PERFORMANCE PAIN Anxiety and stress Depression

25. Detailed information about drugs for neuropathic pain

26. Tricyclic antidepressants (TCAs) Efficacy • The efficacy of TCAs has been established in peripheral neuropathic pain (pain diabetic neuropathy, postherpetic neuralgia) and in central post stroke pain • The pain relieving effect of TCAs in independent of their antidepressant effect (comes quicker and with lower dose)

27. Tricyclic antidepressants (TCAs) Dosing • Starting: 10–25 mg in a single dose at bedtime • Effective dosages vary from 25–150 mg from case to case • The average dosage for amitriptyline is 75 mg/day • Monitoring of serum drug concentrations may be helpful

28. Contraindications and precautions of TCAs • TCAs cannot be used in recovery phase of myocardial infarction or in patients with cardiac conduction disturbances. • TCAs should be used with caution in patients with history of seizures, prostatic hypertrophy, urinary retention, chronic constipation, narrow-angle glaucoma, increased intraocular pressure, suicidal ideations and in patients receiving concomitant SSRI, SNRI or tramadol treatment.

29. Adverse effects of TCAs • Anticholinergic adverse effects are common • Dry mouth: drink water, salivation-producing resoriblets • Constipation: bulk laxatives • Blurred vision or urinary retention: taper TCA off • Cardiovascular adverse effects: • Orthostatic hypotension: monitor blood pressure (supine and standing) • Prolongation of PR and QTc intervals: ECG screening • Increased heart rate: taper TCA off • Sedation, confusion and sweating can also occur • Imipramine and nortriptyline cause fewer anticholinergic effects and less sedation

30. Venlafaxine • Efficacy of venlafaxine has been shown in painful polyneuropathy • Dosing: start with 75 mg once daily, and escalate the dose with 75 mg at 2 weeks interval. Effective dosage is 150-225 mg/day. • Venlafaxine is contraindicated in patients with uncontrolled hypertension, and blood pressure monitoring is recommended during the treatment

31. Venlafaxine • Venlafaxine should be used with caution in patients with history of mania, seizures and bleeding tendency • Adverse effects: nausea, dry mouth, headache and sweating, abnormal dreams, decreased libido, dizziness, insomnia, nervousness, sedation, tremor, visual disturbance, hypertension, palpitations, anorexia and urination hesitancy

32. Duloxetine • Efficacy of duloxetine has been shown in painful diabetic polyneuropathy • Dosing: start with 60 mg once a day, and increase the dose with 30-60 mg until 120 mg, when needed (effective dose is 60-120 mg/day) • Adverse effects: nausea, somnolence, dry mouth, constipation, reduced appetite, diarrhoea, hyperhidrosis, and dizziness • Duloxetine is contraindicated in unstable arterial hypertension.

33. Carbamazepine (slow release) • Is a drug of choice for primary trigeminal neuralgia (but no evidence of efficacy in other NP conditions) • Dosing: slowly raise the initial dosage of 100 mg twice daily until freedom from pain is achieved (often 600-800 mg daily, even 1200 mg daily) • Adverse effects: Sedation, dizziness, gait abnormalities, liver and blood changes, hyponatraemia, enzyme induction • Blood count, liver enzyme and plasma sodium monitoring is recommended

34. Carbamazepine (slow release) • Carbamazepine has lots of interactions with other drugs (e.g., oral contraceptives) • Check the possible interactions before prescribing carbamazepine • Check serum drug concentration in suspected enzyme induction • Once the neuralgia is in remission, try to decrease the dose slowly

35. Oxcarbazepine • Is a drug of choice for primary trigeminal neuralgia (but no evidence of efficacy in other NP conditions) • Has fewer interactions and is better tolerated than carbamazepine • Dosing: slowly raise the initial dosage of 150mg twice daily until freedom from pain is achieved (600-1800 mg daily) • Adverse effects: somnolence, headache, dizziness, diplopia, nausea, vomiting and fatigue • Hyponatremia is possible; check plasma sodium level before commencing the treatment and after some weeks of use of oxcarbazepine

36. Tramadol • Tramadol itself has serotoninergic and noradrenergic effect, and its active metabolite (after metabolism by CYP2D6 enzyme) is opioid agonist • Dosing: test with a 50 mg capsule, and if it is well tolerated, escalate the dose gradually up to 300-400 mg/day • Depot and short-acting capsules can be combined • Adverse effects: nausea, sedation, excessive sweating, dizziness, constipation, headache • Use with caution in patients with epilepsy or SSRI or SNRI medication

37. Gabapentin • The efficacy of gabapentin has been established in painful diabetic neuropathy and postherpetic neuralgia • Dosing: start with 300 mg at bedtime, and escalate with 300 mg/day or more slowly until sufficient pain relief • Effective dose: 900-3600 mg/day (divided in 3 doses) • Adverse effects: dizziness, somnolence, peripheral oedema, weight gain, asthenia, headache, dry mouth and blurred vision • If renal function impaired, reduce the dose • No pharmacokinetic interactions

38. Pregabalin • The efficacy of pregabalin has been established in painful diabetic neuropathy, postherpetic neuralgia and spinal cord injury pain • Dosing: start with 75 mg at bedtime and increase the dose with 75 mg every 3 days until pain relief or maximal dose (600 mg/day) • Effective dose: 150-600 mg/day (divided in 2 doses) • Adverse effects: include dizziness and somnolence, peripheral edema, weight gain, asthenia, headache, dry mouth and blurred vision • If renal function impaired, reduce the dose • No pharmacokinetic interactions

39. Strong opioids (e.g., oxycodone) • Are regarded as the last option* • Can be combined with antidepressants, antiepileptics or topical treatment * National guidelines on use of opioids for non-cancer pain are available for many countries

40. Strong opioids (e.g., oxycodone) Preconditions for an opioid trial • The cause of pain is known (neuropathic or nociceptive & neuropathic pain) • Pain is severe in spite of other treatments (which continue during opioid trial) • The patient has no previous dependence or abuse problems • Psychiatric problems (depression, anxiety) are adequately treated • The patient consents to have a trial with pre-set dose schedule and tapering off of the drug, if pain relief and improved function are not achieved.

41. Strong opioids (e.g., oxycodone) • Use only slow-release preparations • Starting dose 10-20 mg b.i.d., dose escalation with 10-20 mg/day every 3-5 days until pain relief, intolerable side effects or maximal dose (80-120 mg oxycodone for neuropathic pain)# • Pre-treatment of constipation with lactulose # Oxycodone is the opioid with best evidence in RCTs, but equivalent doses of slow-release morphine can also be used due to availability and cost

42. Referral to a neurosurgeon? Primary trigeminal neuralgia Refer to a neurosurgeon if carbamazepine or oxcarbazepine fail to relive pain. Ganglion thermocoagulation and microvascular decompression are the most common techniques.

43. Referral to a neurosurgeon? Other neuropathic pains: Consider referral to a specialist for spinal cord stimulation, if a patient has chronic (> 6 months) peripheral neuropathic pain, complex regional pain syndrome or neuropathic pain associated with partial spinal cord injury (with preserved dorsal column) and the pain is severe in spite of adequate drug trials.

44. Patient cases

45. Leo 78 years, history and clinical examination • Retired taxi-driver, widow, lives in a remote village • The only medication is tamsulosin due to prostatic hyperplasia • Herpes zoster at left 5th thoracic dermatome for 1 year ago was treated with acyclovir • Severe pain, tenderness, disturbed sleep • Dynamic mechanical allodynia and pinprick hyperalgesia at the anterior part of the painful dermatome

46. Leo 78 years, pharmacotherapy • Topical lidocaine: abolished allodynia but not the continuous spontaneous pain • Amitriptyline was considered but not started due to prostate hyperplasia and old age (relative contraindications) • Gabapentin: (initial dose 300 mg at bed-time, maintenance dose 600 mg t.i.d.) alleviated pain to mild • Allodynia recurred with the cessation of topical lidocaine; continues with combination medication • Medication well tolerated, drives a car Take home message: especially in the elderly living alone topical treatments are recommended due their safety and tolerability, but on their own they may not provide sufficient pain relief.

47. Anna 52 years, history and examination findings • A previously healthy nurse who has had low back pain, which radiculates to the left L5 dermatome, for 2 months • Clinical findings: Laseque -/+70°, no limitation of range of movements, no motor abnormalities, tendon reflexes normal, in sensory testing pinprick hypoalgesia at left L5 • In MRI scan a small prolapse in L IV-L V, no compression of neural structures  conservative treatment • In ENMG an aftermath of a mild L5 root lesion

48. Anna 52 years, treatment • Information from the doctor • No indication for surgery • There is a mild root lesion, but the pain may be relieved with time • No need to restrict physical activity (“do what you can without essentially exacerbating the pain”) • If needed, a drug trial to relive neuropathic pain is possible

49. Anna 52 years, treatment • Counselling by a physiotherapist • Ergonomy • Suitable physical activity not exacerbating the pain • Pharmacotherapy: amitriptyline up to 70mg/day • Good pain relief (average pain from 8 to 3 on NRS 0-10) • The only adverse effect was mild constipation controlled with diet • Take home messages: • Sufficient and uniform information from the health care professionals • Monotherapy with a cheap first-line drug for neuropathic pain was successful

50. Summary • Tailored medication • Choice of the drug(s) • Careful dose escalation • Sufficient information for the patient and family members • Close follow-up • Psychosocial support, non-pharmacological methods • Realistic goal-setting