Management of pain in diabetic neuropathy

1. Management of pain in diabetic neuropathy F. Beno�t

2. Management of pain in diabetic neuropathy Definition of diabetic neuropathy : heterogeneous group of diseases that affect the autonomic and peripheral nervous systems of patients suffering from diabetes. Incidence : - unknow, estimated 220 million people in 2010 - 28 to 50 % of patients suffer from diabetes - > 50% of individuals aged > 60years

3. Management of pain in diabetic neuropathy Pathophysiology : - multifactorial - role of persistant hyperglycemia (polyols pathway) - ? nerve sorbitol ? ? nerve flow ? capillary pathology ? - ? decrease nerve myoinisitol ? ? nerve Na/K ? ? ? nerve velocity ? signs and symptoms neuropathy - Autoimmune mechanisms ( antineuralantibodies, antiphospholipid antibodies) - microvascular mechanisms - other mechanisms ( genetic, environmental factors, structural changes,�)

4. Management of pain in diabetic neuropathy Evaluation of pain in diabetic neuropathy : Diagnosis of diabetic neuropathy Evaluate the intensity of pain (scale) Distinguisch - the location of attempt (symetric or focal and multifocal) on basis of sensitive or motor topography - adverse consequences : depression, decreased socialisation, sleep disturbance, impaired ambulation and increased health care resource use and costs. JAGS MAY 1998 vol.46 NO.5

5. Management of pain in diabetic neuropathy Presentation : - focal - peripheral or thoracic location - pain: sudden, acute, severe - resolve inexplicably - truncal - coincide .extreme glycemia (hypo/hyper) .weight (gain/lost) - pain: severe dysesthesic, worse at night - spontaneously resolve ( 6/12 months)

6. Management of pain in diabetic neuropathy Presentation : - mixed symmetrical distal - sensory, autonomic and motor nerves - symmetrical involvement of extremities - sensory loss, dysesthesia, painfull paresthesia - worse at night - deep tendon reflexes disappear - motor involvment, weakness, atrophy

7. Management of pain in diabetic neuropathy Treatment : - preventive measures : - control of blood sugar ( UKPDS, DCCT ) - prevention of trauma (careful,skin,�) - orthotics devices (orthoses) - promptly treat skin ulcers or infections

8. Management of pain in diabetic neuropathy Treatment : - Nonpharmacological : - streching exercices - electrotherapy (tens) - psychological aspect - acupunture - pharmacological : 2 pathways ? target the different steps of physiopathologics disorders by hyperglycemia ? target pain symptoms

9. Management of pain in diabetic neuropathy Treatment : ? neurodestructive effect by

10. Treatment : ? treat diabetic neuropathy - aldose reductase inhibitors : - decrease the accumulation of sorbitol - sorbinil ( adenopathies, cytopenia) - tolrestat, zenarestat : some improvements in symptoms (renal toxicity, hepatic dysfunction) - fidarestat : well tolerate, Eparlestat use in japan only. - no evidence to support their use - linoleic acid : - ? symptoms, best electromyography - no evidence to support their use Diabetes Care vol.24 NO 10, oct.2001 Management of pain in diabetic neuropathy

11. Management of pain in diabetic neuropathy Treatment : ? treat diabetic neuropathy

12. Treatment : ? treat diabetic neuropathy - neurotropins : - nerve growth factors, insulin like growth factor - no evidence to support their use - immunoglobulins : - proximal or/and motor nerves inflammatory location - cost - no evidence to support their use Management of pain in diabetic neuropathy

13. Management of pain in diabetic neuropathy Treatment : ? target pain symptoms - antidepressants - tricyclic : - most effective, blockade postsynaptic norepinephrine and serotonin reuptatake - cholinergic side effects (hypotension, retention,�) - 10 mg at bed time ( ami or nor-triptyline) titrate up to 25 mg as side effects permit. - alone or in addition with gabapentin. - desipramine (pertofran�), nortriptyline : fewer adverse effects and sedative effects pharmacotherapy 2001; 21 (9): 1070-1081

14. Management of pain in diabetic neuropathy Treatment : ? target pain symptoms - antidepressants : - serotonin reuptake inhibitors : - less side effects - less effective than tricyclics - maprotiline ( ludiomil�) : - less effective than tricyclics and similar adverse side effects. - trazodone : - effective but limited by the absence of placebo control studies. - venlafaxine : -minimal histaminic, muscarinic and adrenergic side effects - no placebo control study

15. Management of pain in diabetic neuropathy Treatment : ? target pain symptoms - anticonvulsants : - gabapentin : - action unknow - well tolerated ( somnolence, ataxia,�) - resuts similar in comparison with amitriptyline - no mean dosage ( between 900 mg/d to 3600 mg/d) - eliminated by renal route - carbamazepine : - blocks presynaptic action, decrease the release excitatory neurotansmitters and blocking postsynaptic repetitive discharge. - rapid onset of analgesic action - 50-100 2X/d max. 1200mg/d - adverse effects ( aplasic anemia, agranulocytosis,...) pharmacotherapy 2001; 21 (9): 1070-1081

16. Management of pain in diabetic neuropathy Treatment : ? target pain symptoms - anticonvulsants : - phenytoin : - improvement in pain and paresthesia (100 mg 3 or 4/d) - titration of 5 to 20 mg/L same than placebo ?conflicting evidence - numerous adverse effects ( blood dyscrasias, hepatotoxicity,...) - benzodiazepines : - more studies needed - lamotrigine (Lamictal�) : - induced dose dependent analgesia in rat - no more efficacy than placebo. The cochrane library 2002 issue 2

17. Management of pain in diabetic neuropathy Treatment : ? target pain symptoms - anticonvulsants : - valproic acid :- used in neuropatic pain due to peripheral disorders. more randomised trials are necessary for diabetes antiarrythmics : - mexiletine : - block sodium channels, unable to give pain signals - useful when pain manifests as sharp lancinating or burning pain. (150 to 200 mg2x/d) - poorly tolerated - lidocaine : - sodium channel-blocking effect, - intraenously 5mg/kg (30 to 45 min.) - more studies needed

18. Management of pain in diabetic neuropathy Treatment : ? target pain symptoms - analgesics : - tramadol : - pain relief unknown and not correlated with serum concentration - potential abuse and development of pain tolerance - NSAIDs : - some pain relief - gastrointestinal and renal side effects - opoids : - adjuvant therapy relief pain more quickly - analgesic tolerance - high doses needed to relieve pain - side effects

19. Management of pain in diabetic neuropathy Treatment : ? target pain symptoms - antiparkinsonism agents : - levodopa :- effective (100 mg/d), no patient with side effect in a little study (25 patients) - alpha-agonists : - clonidine : - 20 % response vs placebo for sharp and shooting pain.(0.1 mg 2x/d to 0.�3mg 2x/d) - transdermal administration (1x7d) - side effects limit the use

20. Management of pain in diabetic neuropathy Treatment : ? target pain symptoms - others : - pentoxifylline : study limited by lack of placebo control improve de viscosity and the blood flow ? symptoms scores, side effects (arrythmias,�) ? Conflicting results - dextromethorphan : - low affinity antagonist properties to the glutamate receptor (when activated it induces a sensation of dull and pain) - average dosage 381 mg/d ? more studies with different dosis needed

21. Management of pain in diabetic neuropathy -Treatment : ? target pain symptoms - others : - protein kinase C : - isoforms prevent the development of diabetic nerve dysfunction - attractive drug discovery but more studies needed to demonstrated precise mechanism expert opin.investig.Drugs 2001 10 : 1653-1664 capsaicin : topical agent : - depletion of substance P. - few systemic adverse effects - pain reduction (40 % vs 27.8% placebo) - good option if oral agents not tolerated - optimal efficacity with 3 or 4 /d

22. Management of pain in diabetic neuropathy Take home messages : - good blood glucose control - Tricyclics are the most studied and considered as first-line therapy - desipramine is considered as first choise for elderly - anticonvulsants are second-line agents : gabapentin

23. Management of pain in diabetic neuropathy Take home messages : Capsaicin good alternative or adjuvant Other drugs have shown some efficacy in trials with small number of patients The adverse effect profile of a drug should be weighed against possible benefits

24. Management of pain in diabetic neuropathy References�: 1 .Ivo W. Tremont-lukats, Carla Megeff and Misha-Miroslav Backonja�: Anticonvulsants for neuropathic pain syndromes. Drugs 2000 Nov. 60(5)�: 1029 - 1052. 2. Diabetes Control and Complication Trial Research Group. (DCCT)�: The effect of intensive treatment of diabetes on the development and progrssion of long-term complications in insulin-dependent diabetes mellitus. N.Engl.J.Med. 1993�;329�:977-86. 3. UK Prospective Diabetes Study (UKPDS) Group�: Intensive blood-glucose control with sulfonylureascor insulin compared with conventional treatment and risk of complications in patients with 2 diabetes (UKPDS 33) Lancet 1998�; 352�:837-853. 4. Management of hyperalgesic diabetic neuropathy. Journ. Annu. Diabetol. Hotel Dieu. 2000�; 139-44 review. 5. Patrick G. Jensen and Jennifer R. Larson�: Management of painful diabetic neuropathy drugs and aging 2001�; 18(10) 737-749.