TREATMENT OF NEUROPATHIC PAIN Philip Siddall

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TREATMENT OF NEUROPATHIC PAIN Philip Siddall
The pharmacological management of
neuropathic pain
Philip Siddall
Department of Pain Management, HammondCare, Greenwich Hospital, Sydney
Sydney Medical School – Northern, University of Sydney
Disclosures
In the last 5 years:
›
I have received grant funding from the NH&MRC,
ANZCA, NSW Lifetime Care and Support Authority, and
NSW Government Spinal Cord Injury & Other
Neurological Conditions Research Grants Program.
›
I have not received any direct or indirect benefits from
any pharmaceutical company.
Outline
› Pharmacological treatment
- Antidepressants
- Anticonvulsants
- Opioids
- Others
› Putting it all together
› What’s around the corner
Review of neuropathic pain studies
› Under the auspices of IASP Neuropathic Pain SIG
› Led by Nanna Finnerup and Nadine Attal
› All drug treatments since 1966
› Randomized, double blind, placebo-controlled studies
(N>10)
› Uses GRADE (Grading of Recommendations
Assessment, Development and Evaluation) system to
evaluate level of evidence and strength of
recommendations
› 229 studies including 33 unpublished
Outline
› Pharmacological treatment
- Antidepressants
- Anticonvulsants
- Opioids
- Others
› Putting it all together
› What’s around the corner
Antidepressants
› Tricyclic antidepressants
amitriptyline, nortriptyline, desipramine,
imipramine, clomipramine
› Selective serotonin reuptake inhibitors (SSRIs)
fluoxetine, escitalopram
› Mixed reuptake inhibitors (SNRIs)
venlafaxine, desvenlafaxine, duloxetine
Tricyclic Antidepressants
amitriptyline, imipramine, clomipramine, desipramine
› Effective in some neuropathic pain conditions
(postherpetic neuralgia, diabetic neuropathy, central
post stroke pain, trigeminal neuralgia, postmastectomy
pain, HIV sensory neuropathy) but not others (spinal
cord injury pain, HIV neuropathy)
› Good efficacy (NNT all TCAs 3.6, amitriptyline 3.4)
› Often intolerable side effects - dry mouth, constipation,
drowsiness, dizziness (NNH 13.4)
Selective reuptake inhibitors
(SSRIs, SNRIs)
fluoxetine, venlafaxine, duloxetine
› SSRIs have a better side effect profile and but are less
effective than tricyclic antidepressants (NNT around 7)
› SNRIs (venlafaxine and duloxetine) may be more
effective than SSRIs (combined NNT 6.4)
› Moderate incidence of adverse effects – nausea,
drowsiness, constipation (NNH 11.8)
Outline
› Pharmacological treatment
- Antidepressants
- Anticonvulsants
- Opioids
- Others
› Putting it all together
› What’s around the corner
Anticonvulsants
› “Older” antiepileptics
- phenytoin
- sodium valproate
- carbamazepine
- clonazepam
› “Newer” antiepileptics
- gabapentin
- pregabalin
- lamotrigine
- topiramate
- oxcarbazepine
Older Anticonvulsants
valproate, carbamazepine
› Many studies are negative
› Valproate – 3/6 studies positive result (NNT 4.3)
› Carbamazepine/oxcarbazepine – 1/5 studies positive result
(NNT 5.7)
› Moderate-high incidence of adverse effects (valproate NS,
carbamazepine NNH 5.5)
Newer Anticonvulsants
› Gabapentin
› 14 studies- PHN, diabetic neuropathy, SCI, amputation, HIV
› Combined NNT 6.3, combined NNH 25.6
› Pregabalin
› 25 studies - PHN, diabetic neuropathy, SCI, amputation, HIV,
CPSP
› Combined NNT 7.7, combined NNH 13.9
Other Anticonvulsants
lamotrigine, topiramate
› Topiramate
› 3 trials - diabetic neuropathy, radiculopathy
› Combined NNT 6.0, combined NNH 6.3
› Lamotrigine
› 10 trials - diabetic neuropathy, HIV, CPSP, SCI
› Combined NNT 17.8, combined NNH 17.3
Outline
› Pharmacological treatment
- Antidepressants
- Anticonvulsants
- Opioids
- Others
› Putting it all together
› What’s around the corner
Parenteral opioids
EFFECTIVENESS (RCTs)
“relatively ineffective in neuropathic pain”
› intravenous morphine, buprenorphine, alfentanil, fentanyl
are effective for a range of neuropathic pain conditions
- SCI pain (Eide et al., 1995)
- “non-cancer neuropathic” (Dellemijn and Vanneste, 1997)
- “neuropathic” (affective) (Kupers et al., 1991)
- “neuropathic” (Jadad et al., 1992)
- postherpetic neuralgia (Rowbotham et al., 1991)
- postherpetic neuralgia (-ve) (Eide et al., 1994)
Oral opioids
› Tramadol
› 7 trials – diabetic neuropathy, cancer, SCI (-ve), mixed
› Combined NNT 4.7, combined NNH 12.6
› Oxycodone (10-120mg/day), morphine (90-240 mg/day),
tapentadol (200-500 mg/day), methadone (10 mg)
› 13 trials – peripheral neuropathic pain
› Combined NNT 4.3, combined NNH 11.7
› No additional benefit >180mg/day morphine equivalent
› All studies 12 weeks or less
Combination therapy
OPIOID
ANTI
EPILEPTIC
ANTI
DEPRESSANT
Gabapentin (2400 mg max) + morphine (60 mg max) (PHN, diabetic neuropathy)
> gabapentin or morphine or placebo (NNT 2.2, NNH NS) (Gilron et al 2005)
Nortriptyline 100 mg + morphine 90 mg (radiculopathy)
> morphine or nortriptyline (Khoromi et al. 2007)
Lower doses for combination and no increase in side effects
Outline
› Pharmacological treatment
- Antidepressants
- Anticonvulsants
- Opioids
- Others
› Putting it all together
› What’s around the corner
Local Anaesthetics
› Lignocaine
› effective parenterally
› RCTs - SCI pain, central post stroke pain, diabetic
neuropathy, postherpetic neuralgia
› Mexiletine
› 8 trials - SCI, diabetic neuropathy, HIV, amputation,
peripheral nerve injury
› 1/8 studies positive (peripheral nerve injury, 1200 mg)
Botulinum toxin type A
› Botulinum toxin type A
- 5 trials - PHN, diabetic neuropathy, TN, mixed
- Combined NNT from small studies (n=161) -1.9
- Large unpublished study negative
- No NNH data but generally minimal side effects
NMDA antagonists
› Ketamine
› Only evaluated in short term with parenteral administration
› Dextromethorphan
› 5 trials – facial neuralgia -ve, PHN -ve, diabetic
neuropathy (2/3 +ve, 960 mg and 45 mg with 30 mg
quinidine)
› Memantine
› 5 trials – amputation, PHN diabetic neuropathy - all –ve
› Magnesium
› 1 trial – mixed -ve
Cannabinoids
› Sativex spray (delta 9 THC,
cannabidiol), dronabinol
› 9 trials – MS, diabetic
neuropathy, SCI, mixed
› Only 2 positive (MS, mixed)
› Combined NNT NS,
› Combined NNH 12.1
Topical Preparations
› lignocaine patch
- Up to 3 patches/day in the painful area for 12
consecutive hours
- 3 trials > 3 weeks - postherpetic neuralgia, postsurgical
- Postsurgical negative, PHN studies positive
- Well tolerated, low incidence side effects
- Low quality of evidence, high patient preference and SE
profile
› capsaicin (8%)
- Up to 4 patches for 30-60 minutes, repeated after > 3
months
- 7 trials – postherpetic neuralgia, HIV (8% vs 0.04%)
- Combined NNT 10.6, NNH NS
- High quality of evidence, potential concerns with long
term use
Topical Preparations
› clonidine
- 3 trials – diabetic neuropathy (all –ve)
› nutmeg
- 1 trial – diabetic neuropathy (- ve)
› nitrates (isosorbide dinitrate, glyceryl trinitrate)
- 3 trials - diabetic neuropathy (all +ve) (small numbers)
› amitriptyline 2%
- 1 trial – mixed with allodynia/hyperalgesia (-ve)
› ketamine 1%
- 1 trial – mixed with allodynia/hyperalgesia (-ve)
› amitriptyline 4% + ketamine 2%
- 2 trials – diabetic neuropathy, PHN (-ve)
Trigeminal neuralgia
Cruccu G, Gronseth G, Alksne J, Argoff C, Brainin M, Burchiel K, Nurmikko T, Zakrzewska JM.
AAN-EFNS guidelines on trigeminal neuralgia management. Eur J Neurol, 2008; 15: 1013-28.
› First line
› Carbamazepine 200-1200 mg/day (better evidence)
NNT 1.7 NNH 3.4
› Oxcarbazepine 600-1800 mg/day (better tolerability)
› Insufficient evidence for other drugs
› Cruccu & Truini 2013
“On the basis of the available evidence we suggest that no oral
treatment other than carbamazepine or oxcarbazepine is useful.”
Outline
› Pharmacological treatment
- Antidepressants
- Anticonvulsants
- Opioids
- Others
› Putting it all together
› What’s around the corner
Comparative effectiveness of drug treatments
Finnerup NB et al. (2010). The evidence for pharmacological treatment of neuropathic pain. Pain, 150(3), 573-581.
“Despite a 66% increase in
published trials [since 2005],
only a limited improvement
of neuropathic pain
treatment has been
obtained.”
Summary of recommendations
Quality of
evidence
Effect size (NNT)
Tolerability &
safety (NNH)
Gabapentin
high
moderate (6.3)
high (25.6)
Pregabalin
high
moderate (7.7)
moderate (13.9)
SNRIs
high
moderate (6.4)
moderate (11.8)
Amitriptyline
moderate
moderate (3.6)
low-moderate (13.4)
Tramadol
moderate
moderate (4.7)
low-moderate (12.6)
Capsaicin patch 8%
high
low (10.6)
moderate-high
Topical lignocaine
low
unknown
high
Opioids
moderate
moderate (4.3)
low-moderate (11.7)
BTX-A
low
moderate (1.9)
high
First line
Second line
Third line
General GRADE recommendations
Strong +ve
gabapentin
1200-3600
pregabalin
150-600
SNRIs
60-120
TCAs
25-150*
Weak +ve
Weak -ve
Strong -ve
AED+TCA or SNRI
lidocaine patch
local NP
capsaicin patch 8%
local NP
tramadol
200-400
strong opioids
BTX-A
cannabinoids
-ve + safety
valproate
-ve + safety
levetiracetam
- ve
mexiletine
-ve + safety
General GRADE recommendations
Inconclusive
Reason
Valproate
Inconsistent effects
Carbamazepine
Inconsistent effects
Capsaicin cream (low
conc)
weak evidence
Topical clonidine
SSRIs
Inconsistent effects
dextromethorphan
Inconsistent effects
Finnerup et al. Pharmacotherapy of neuropathic pain: systematic review, meta-analysis and NeuPSIG recommendations (in press)
Outline
› Pharmacological treatment
- Antidepressants
- Anticonvulsants
- Opioids
- Others
› Putting it all together
› What’s around the corner
What’s around the corner?
Salat K, et al. New investigational drugs for the treatment of neuropathic pain.
Expert opinion on investigational drugs, 2014; 23: 1093-104.
› N and T- type calcium channel blockers
(conotoxins)
› Selective sodium channel blockers (Nav1.7)
› Anti nerve growth factor antibody (tanuzemab)
- Phase I and II in low back pain
- but concerns about worsening peripheral neuropathies
› Angiotensin 2 receptor antagonists (EMA401)
- Phase I and II in postherpetic neuralgia but only tested
to 4 weeks
- placebo-like CNS adverse effects,
- few drug-drug interactions
- convenient dosage regimen (twice daily dosing as
tablets or capsules)
Summary
› We have very little information in paediatrics
- “The treatment of neuropathic pain in children is a neglected area
and recommendations only apply to adults.” Howard RF, Wiener S,
Walker SM. Neuropathic pain in children. Arch Dis Child 2014; 99:
84-9.
› There is emerging support for some drugs as first line
› Efficacy is modest for most drugs (NNTs 3-10)
› Side effect profile is often poor
› There is no strong evidence to support the use of specific
drugs for specific conditions (except TN)
› The move to phenotypic profiling
› There are some promising drugs in the pipeline
References
1.
Haanpää M, et al. NeuPSIG guidelines on neuropathic pain assessment.
Pain, 2011; 152: 14-27.
2.
Finnerup NB, Sindrup SH, & Jensen TS. The evidence for pharmacological
treatment of neuropathic pain. Pain, 2010, 150(3), 573-581.
3.
Dworkin RH et al. Interventional management of neuropathic pain: NeuPSIG
recommendations. Pain, 2013; 154: 2249-61.
4.
Cruccu G, Gronseth G, Alksne J, Argoff C, Brainin M, Burchiel K, Nurmikko
T, Zakrzewska JM. AAN-EFNS guidelines on trigeminal neuralgia
management. Eur J Neurol, 2008; 15: 1013-28.
5.
Cruccu G, Truini A. Refractory Trigeminal Neuralgia: Non-Surgical Treatment
Options. CNS Drugs, 2013; 27: 91-6.
6.
Salat K, Kowalczyk P, Gryzlo B, Jakubowska A, Kulig K. New investigational
drugs for the treatment of neuropathic pain. Expert opinion on investigational
drugs, 2014; 23: 1093-104.
Suggested algorithm
Finnerup NB, Otto M, McQuay HJ, Jensen TS, Sindrup SH. Algorithm for neuropathic pain treatment:
an evidence based proposal. Pain, 2005; 118: 289-305.

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