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

3. General aspects of managingof 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 • 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. Characteristics of neuropathic pain • Typical for neuropathic pain: • spontaneous and provoked pain (often different from previous familiar pains) • other positive symptoms such as paresthesiae • negative signs (sensory deficits) • Depending on the site of the lesion, there may be other symptoms and clinical findings (e.g., motor paresis, muscle cramps, autonomic nervous symptoms)

11. Definitions of common features suggestive of neuropathic pain

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

13. Diagnosis of neuropathic pain • Location of pain is neuroanatomically plausible.Pain drawing is useful! • Abnormal sensory function is found in clinical examination. • The disease causing the neuropathic pain can be identified by: • General examination • Neurological examination (findings  location of the lesion) • Referral to further examinations, if needed.

14. Neurological examination:sensory testing Testing of mechanical allodynia: • Dynamic: brush • Static: compression with finger or algometer

15. Neurological examination:sensory testing • Sensory testing is performed on unclothed skin • Sensory testing is directed according to the information from the history and pain drawing • The findings in the painful area are compared with findings in the contralateral area in unilateral pain and in other sites on the proximal-distal axis in bilateral pain

16. Neurological examination: motor testing • Inspection: muscular wasting, movements • Palpation of muscles (tension, tenderness) • Muscle strength • 0 = total paralysis • 1 = flicker • 2 = movement with gravity eliminated • 3 = movement only against gravity • 4 = movement can be overcome by resistance • 5 = full power • Tone (spasticity, rigidity) • Gait

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

18. 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

19. 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

20. Principles of pharmacotherapy of neuropathic pain 1) Individual drug selection Cause of neuropathic pain • Most evidence comes from studies of painful polyneuropathies and postherpetic neuralgia, 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 Previous drug trials • If some drug has been adequately tested previously with poor result, repetition of trial with the same drug is not rational

21. 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 • the maximal tolerated dose • to the dose providing relevant pain relief

22. 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 useless or harmful medications

23. 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 • e.g. an antidepressant combined with gabapentin or pregabalin • e.g. a systemic drug combined with a topical drug • The doses in combination therapy may be a bit lower than in monotherapy.

24. Evidence-based drugs for neuropathic pain: mechanism(s) of action In combination treatment - drugs with different mechanisms of action can be given together.

25. Evidence-based drugs for neuropathic pain: dosing

26. Algorithm for treatment of neuropathic pain Peripheralneuropathic pain Trigeminalneuralgia Central neuropathic pain Topical lidocaine Central post-stroke pain Localallodynia Carbamazepine or oxcarbazepine Amitriptyline Spinalcordinjury pain Gabapentin /pregabalin SNRI TCA Neuro-surgery Capsaicinplaster? Pregabalin Opioids? Multiplesclerosis pain (Cannabinoids) Abbreviations: SNRI = serotonin and noradreanalin reuptake inhibitors TCA = tricyclic antidepressants

27. 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?

28. 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 Medication Disturbed sleep COGNITIVE PERFORMANCE PAIN Anxiety and stress Depression

29. Detailed information about drugs for neuropathic pain

30. 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)

31. 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

32. 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.

33. 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

34. Adverse effects of TCAs • Sedation, confusion and sweating can also occur • Imipramine and nortriptyline cause fewer anticholinergic effects and less sedation

35. 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

36. 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

37. 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.

38. 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

39. 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

40. Oxcarbazepine • Is a drug of choice for primary trigeminal neuralgia • 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 oxacarbazepine

41. Tramadol • Tramadol itself has serotoninergic and noradrenergic effect, and its active metabolite (after metabolism by CYP2D6 enxyme) is opioid agonist • Dosing: testi 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

42. 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

43. Patient cases

44. Case 1: Afghan housewife

45. Case 1 • Patient comes to visit a psychiatric outpatient clinic, escorted by her husband. • Complains of continuous burning and lancinating pain in her left arm and on the right side of the face. • Pain is much more severe in the face than in the arm.

46. Case 1 History • Less than 3 years earlier, patient had suffered an attack of severe vertigo and vomiting, slurred speech and clumsiness of left hand • most of her symptoms had subsided within a week but slight clumsiness of left hand persisted • she had not consulted a doctor that time • pain in face and left arm had started gradually after about 2 months of this episode

47. Case 1 Clinical examination • slight drooping of right eyelid • slight clumsiness, ataxia and dysmetria of right arm • normal and symmetric muscle strength, normal speech • loss of pinprick and temperature sensation on right cheek and diminished pinprick and temperature sensation in left arm • cardiac auscultation: normal

48. Case 1 Diagnosis • (highly probable) post stroke pain due to right lateral medullary infarction (Wallenberg syndrome); posterior inferior cerebellar artery occlusion? • Spino- and trigeminothalamic tract are injured in Wallenberg syndrome (denervation sensitivity) • Pain may start in acute or chronic (months after stroke) stage • Many patients have swallowing difficulties in acute stage

49. Lateral medullary syndrome

50. Case 1 Treatment • Nortriptyline was started (initiation 10 mg/day and increase up to maximum tolerated dose) • Later combined with carbamazepine (100 mg bid and increased up to 300 mg bid) (lancinating, electric shock like pain on the right side of the face).