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Shawn Jorgensen, MD
Albany Medical Center
AAPM&R Annual Assembly
October 2015
 No financial disclosures
 Neuropathic pain
 Estimated 4-8% prevalence (Moulin 2014)
 Diabetics – 16% with painful neuropathy (Bril 2011)
 Sources
 Central nervous system
 Peripheral nervous system
 Focal peripheral mononeuropathies
 Radiculopathies
 Plexopathies
 Generalized peripheral neuropathies
 Disorders of sensation associated with peripheral neuropathy -
definitions
 Neuropathic pain
 “Pain arising as a direct consequence of a lesion or disease affecting the
somatosensory system.” (Treede 2008)
 Peripheral neuropathic pain
 Only the peripheral portion of the somatosensory system (e.g. not
central poststroke pain)
 Dysethsesia
 An unpleasant abnormal sensation, whether spontaneous or evoked.
(IASP 1994)
 Hyperalgesia
 Increased pain from a stimulus that normally provokes pain.
(IASP 1994)
 Allodynia
 Pain due to a stimulus that does not normally provoke pain.
(IASP 1994)
 Neuropathies
 Breaking down neuropathies - Axes
 Time of onset
 Fiber size
 Small, large
 Modality
 sensory, motor, autonomic
 Neuron / myelin
 If neuron, which aspect (soma, axon)
 Length-dependence
 Fiber Size
 Small fiber
 Symptoms
 Pain, burning (dysesthesia)
 Physical exam:
 Normal strength
 Normal vibration, proprioception, light touch
 Abnormal pinprick, temperature, crude touch
 Normal reflexes
 NCS
 Normal
 Fiber Size
 Large
 Symptoms
 Tingling (parasthesia)
 Physical exam
 Possibly decreased strength
 Decreased vibration, proprioception, light touch
 Normal pinprick, temperature, crude touch
 Diminished reflexes
 NCS
 Abnormal NCS
 Length-dependence
 Length-dependent (distal symmetrical)
 Most neuropathies
 Non-length dependent
 Multifocal neuropathies
 Mononeuropathy mutliplex
 Lewis-Sumner syndrome (MADSAM)
 HNPP
 Autoimmune demyelinating
 CIDP, AIDP
 Ganglionopathy/neuronopathy
 Other jobs of physician treating patients with
peripheral neuropathy
 Manage acute illness if severe
 Give disease-modifying treatment (when possible)
 Make sure it is not evidence of something medically
important
 Prevent injury
 Charcot joint
 Diabetic foot care/monitoring
 Manage ataxia
 Manage weakness
 Potentially reversible neuropathies
 B12 deficiency
 Copper deficiency
 Vasculitic neuropathy
 Guillain-Barre syndrome
 CIDP
 MMN
 Alcoholic neuropathy
 Uremic neuropathy
 Hypothyroid neuropathy
 Neuropathies that herald important medical
conditions
 Diabetes/pre-diabetes
 MGUS
 Multiple myeloma
 POEMS
 Waldenstrom’s Macroglobulinemia
 Small cell lung cancer (paraneoplastic sensory
neuronopathy)
 Other jobs of physician treating patients with
Peripheral neuropathy
 Work up for underlying cause
 AAPM&R, AANEM, AAN (England 2010)
 Highest yield
 Fasting glucose, B12, methylmalonic acid +/- homocysteine, SPEP (level C
evidence)
 If fasting glucose normal, 2 hour GTT
 Modifications?
 Change SPEP to serum immunofixation (SIFE) – more sensitive
(Katzmann 2006)
 Add HbA1c
 Treatment
 4 classes of anti-neuropathic pain medications
 Antidepressents
 SNRI
 TCA
 SSRI (lesser)
 Antiepileptics
 Gabapentoids
 Others
 Opioids
 Miscellaneous
 Topical
 Modalities
 Treatment
 3 big questions:
 (1) Severity
 Is it bad enough to require treatment?
 (2) Is topical on the table?
 Does the distribution of symptoms make topical treatment
practical?
 (3) If oral, what can’t they take?
 Treatment
 What can’t they take?
 (1) Can’t take because of medications they are on
 (2) Can’t take because of medical condition
 (3) Can’t take because of life condition
 Treatment
 What can’t they take?
 (1) Because of medications they are on
 Tryptans, TCA – caution with using other antidepressants
(seratonin syndrome)
 Tramadol – caution with using SNRI/SSRI – lowers seizure
threshold
 Treatment
 What can’t they take?
 (2) Because of medical conditions they have
 Glaucoma – avoid duloxetine
 Liver disease – avoid duloxetine
 Increased intraocular pressure – avoid TCA
 Cardiac conditions – avoid TCA
 Urinary retention – avoid TCA (PDR.net 2015)
 Treatment
 What can’t they take?
 (2) Because of life conditions they have
 Heavy drinker – avoid duloxetine
 Sedation
 Can’t be sedated
 Sedation not important
 Commercial truck
 Mattress tester
driver
 Fighter pilot
 Rodeo clown
 Shark feeder
 Insurance MRI
authorization agent
 Hospital administrator
 Rehabilitation resident
 Treatment
 Which meds are best?
 Efficacy
 AAPM&R, AANEM, AAN Consensus statement- Painful
diabetic neuropathy (Brill 2011)
 Levels of evidence
 I = a randomized controlled clinical trial with masked or
objective outcome assessment in a representative population
that meet multiple specific criteria
 II = a randomized, controlled clinical trial in a representative
population with masked or objective outcome assessment
lacking one of the criteria aove or a prospective matched cohort
study with a masked or objective outcome assessment in a
representative population.
 III = all other controlled trials (including well-defind natural
history controls or patients serving as their own controls) in a
representative population where outcome is independently
assessed or independently derived by objective outcome
measurements that is unlikely to be affected by an observer’s
expectation or bias
 IV = studies not meeting class I, II or III criteria including
consensus or expert opinion
 AAPM&R, AANEM, AAN Consensus statement-
Painful diabetic neuropathy (Brill 2011)
 Levels of evidence
 A = established as effective, ineffective, or harmful
 At least two consistent class I studies
 B = probably effective, ineffective, or harmful
 At least one class I study or two class II studies
 C = probably effective, ineffective, or harmful
 At least one class II study or two consistent class III studies
 U = Data inadequate or conflicting
 AAPM&R, AANEM, AAN Consensus statement-
Painful diabetic neuropathy (Brill 2011)
 Level A
 Pregabalin
 AAPM&R, AANEM, AAN Consensus statement-
Painful diabetic neuropathy (Brill 2011)
 Level B
 Venlafaxine
 Duloxetine
 Amitryptiline
 Gabapentin
 Valproate
 Dextramethorphan
 Morphine sulfate
 Tramadol
 Oxycodone controlled-release
 Capsaicin
 Isosorbide dinitrate spray
 Percutaneous electrical nerve stimulation
 AAPM&R, AANEM, AAN Consensus statement-
Painful diabetic neuropathy (Brill 2011)
 Level C
 Lidoderm patch
 AAPM&R, AANEM, AAN Consensus statement-
Painful diabetic neuropathy (Brill 2011)
 Level U
 Topiramate
 Desipramine
 Imipramine
 Fluoxetine
 Vitamins
 Alpha-lipoic acid
 AAPM&R, AANEM, AAN Consensus statement-
Painful diabetic neuropathy (Brill 2011)
 Should not be used (Level B)
 Oxcarbazepine
 Lamotrigine
 Lacosamide
 Clonidine
 Pentoxifylline
 Mexilitine
 Electromagnetic field treatment
 Reiki
 Low-intensity laser treatment
 Consensus statement from Canadian Pain Society
(Moulin 2014)
 General
 Reviewed randomized controlled trials, systematic reviews
and existing guidelines
 Primary goal is to make pain bearable, not gone – keep
reasonable expectations
 Consensus statement from Canadian Pain Society (Moulin
2014)
 Numbers needed to treat (NNT) for neuropathies
 The number of patients that need to be treated with a a drug to
provide one additional patient with at least 50% pain relief relative
to the comparator group
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TCA
Opioids
Cannabinoids
Pregabalin
Tramadol
Duloxetine
Capsaicin 0.04%
Gabapentin
SSRI
2.1
2.6
3.4
4.5
4.9
5.1
6.2
6.5
6.8
 Consensus statement from Canadian Pain Society
(Moulin 2014)
 Algorithm
 1st line – Gabpentoids, TCA, SNRI
 2nd line – tramadol, opioids
 3rd line – cannabinoids
 4th line – topical lidocaine, methadone, lamotrigine,
lacosamide, tapentadol, botulinum toxin
 Consensus statement from Canadian Pain Society
(Moulin 2014)
 Other considerations
 TCA
 adverse effects – drowsiness, dry mouth, constipation, urinary
retention – caution with elderly
 Nortryptiline and desipramine better tolerated then
amitrpytiline and imipramine
 Gabapentoids
 Few drug interactions
 Opioids
 Tolerance develops to some side effects but not constipation
 IASP (Finnnerup 2015)
 Meta-analysis of randomized, double blind studies
 General principles
 No evidence of efficacy of specific medications to specific
disorders (possible exception of trigeminal neuralgia)
 HIV related neuropathy and radiculopathy may be more
refractory than other types of neuropathic pain
 IASP (Finnnerup 2015)
 NNT (number needed to treat)
 NNT - 30-50% reduction in pain intensity
 NNH – number needed to harm – number of patients who needed
to be treated for one patient to drop out because of adverse effects

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Botulinum toxin A
Tricyclics
Tramadol
Gabapentin
SNRI
Pregabalin
Strong opioids
Capsaicin 8%
NNT
1.9
3.6
4.7
7.2
6.4
7.7
10.6
10.6
NNH
13.4
12.6
(“good”)
11.8
13.9
11.7
 IASP (Finnerup 2015)
 First line
 Gabapentin (including extended release or encarbil)
 Pregabalin
 Duloxetine
 Venlafaxine XR
 Tricyclics (caution at high doses)
 Second line
 Capsaicin 8% patches
 Lidocaine patches (low effect size)
 Tramadol (lower tolerability)
 Botulinum toxin A SQ (weak evidence)
 Strong opioids (safety concerns)
 IASP (Finnerup 2015)
 Inconclusive recommendations – discrepant findings
 Combination therapy
 Capsaicin cream
 Carbemazapine
 Topical clonidine
 Lacosamide
 Lamotrigine
 NMDA antagonists
 Oxcarbazepine
 SSRI
 Tapentadol
 Topiramate
 Zonisamide
 IASP (Finnerup 2015)
 Recommendations against use
 Because of generally negative trials or safety concerns
 Weak recommendations against
 Cannabinoids
 negative results, potential misuse, diversion, and long-term mental health
risks in particulary susceptible individuals
 Valproate
 Strong recommendations against
 Levetiracetam
 Mexilitine
 Summary
 Pain is one of many aspects of a neuropathy that have to
be addressed
 Consider side effects first when treating neuropathic
pain
 Most guidelines, reviews, and meta-analysis rank
Gabapentoids, SNRIs and TCAs as first line for
neuropathic pain, including those in neuropathies
Thank you!!
 Bibliography
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Bril V, England J, Franklin GM, Backonja M, et al: American Academy of Neurology; American Association of
Neuromuscular and Electrodiagnostic Medicine; American Academy of Physical Medicine and Rehabilitation.
Evidence-based guideline: Treatment of painful diabetic neuropathy: report of the American Academy of Neurology,
the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical
Medicine and Rehabiliation. PM R. 2011 Apr; 3(4): 345-352.
England JD, Gronseth GS, Franklin G, Carter GT, et al. Practice Parameter: Evaluation of distal symmetric
polyneuropathy: Role of laborataory and genetic testing (an evidence-based review): Report of the American
Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American
Academy of Physical Medicine and Rehabilitation. Neurology 2009;72:185-192.
Finnerup NB, Attal N, Haroutounian S, McNicol E, et al. Pharmocotherapy for neuropathic pain in adults: a systematic
review and meta-analysis. Lancet Neurol:2015;162-173.
Katzmann JA, Dispenzieri A, Kyle RA, Snyder MR, et al. Elimination of the need for urine studies in the screening
algorithh for monoclonal gammopathies by using serum immunofixation and free light chain assays. Mayo Clin Proc
2006;81:1575-1578.
Merskey H, Bogduk N. Classification of Chronic Pain. Second edition, IASP Task Force on Taxonomy. “Part III: Pain
Terms, A Current List with Definitions and Notes on Usage” pp 209-214. IASP Press, Seattle 1994.
Moulin D, Boulanger A, Clark AJ, Clark H, et al. Pharmocological management of chronic neuropathic pain: revised
consensus statement from the Candian Pain Society. . Pain Res Manag. 2014 Nov-Dec;19(6):328-335.
"PDR Search." PDR.Net. 2015. Web. 4 Sept. 2015.
Treede RD, Jensen TS, Campbell JN, Cruccu G, et al. Neuropathic pain: Redefinition and a grading system for clinical
and research purposes. Neurology 2008;70: 1630-1635.