PAIN MATTERS Medical Practice Guidelines Hunter Integrated Pain Service Updated July 2007
Use of Oral Antineuropathic Agents
SUMMARY 1. In acute and sub-acute neuropathic pain (≤6 months duration) there is the
potential for intervention to stop progression to a persistent pain state.
2. Once neuropathic pain has become persistent (>6 month duration) the
likelihood of abolition becomes less. A greater emphasis is placed on
helping patients to accept and manage their pain.
3. There is evidence from systematic review of benefit from anticonvulsants
and antidepressants in the treatment of neuropathic pain.
4. There is evidence from randomised controlled trials of benefit from
opioids in treatment of neuropathic pain.
5. Use of oral therapy is generally the initial treatment strategy for
neuropathic pain. Procedural intervention is then considered if response
is inadequate. Optimal therapy may include a combination of oral medication, procedural intervention and self-management approaches.
6. Antidepressants and anticonvulsants (often in combination) are first line
oral agents. Opioids are usually a later option to consider if therapeutic
benefit remains inadequate. Membrane stabilising agents (eg. mexiletine)
7. A 2-4 week trial should be undertaken before considering maintenance
8. Drug adverse effects, including tolerance, are common.
9. Rotation of therapeutic agents can be used to treat tolerance.
What is the current evidence?
1. There is evidence from systematic review of benefit from antidepressants1 and
anticonvulsants2 in the treatment of postherpetic neuralgia (PHN) and painful diabetic neuropathy (DN). Carbamazepine has benefit in trigeminal neuralgia (TN)2.
2. Side effects are common with both antidepressants and anticonvulsants. The NNH
for minor side effects is similar to the NNT for ≥50% pain relief.
3. Pregabalin, the latest anticonvulsant agent, has shown efficacy in the treatment of
both PHN and DN3,4,5,6 in several randomised controlled trials.
4. There is evidence from randomised controlled trials of benefit from opioids in
5. There are no comparative studies to guide the choice between individual
antidepressant and anticonvulsant agents. There is no evidence at this stage that gabapentin and pregabalin are superior in terms of efficacy to the older anticonvulsant agents.
6. Several randomised controlled trials have addressed the role of mexiletine in the
treatment of peripheral and central neuropathic pain11. The NNT ( ≥50% pain relief) for mexiletine in peripheral neuropathy is around 10. Mexiletine was no better than placebo in the treatment of spinal cord injury pain.
Table 1 summarises pooled data for numbers needed to treat (NNT) for ≥50% reduction in pain and also numbers needed to harm (NNH)12. Only small numbers of patients have been studied in selected groups to derive the data for sodium valproate and carbamazepine whereas gabapentin and pregabalin have been more exhaustively studied.
Table 1: Oral Antineuropathic Therapy
1. History of nerve injury or dysfunction 2. Pain in the absence of ongoing tissue damage 3. Pain within (but not necessarily confined to) an area of sensory deficit 4. Character: often burning, shooting, stabbing or pulsing 5. Pattern: paroxysmal or spontaneous pain 6. Allodynia (pain in response to normally non-painful stimuli) 7. Secondary hyperalgesia (hyperalgesia = increased pain in response to normally
painful stimuli; secondary hyperalgesia occurs in a non-inflamed area and is due to central sensitisation)
8. Hyperpathia (increasing pain with repeated stimulation and “after response”) 9. Dysaesthesias (unpleasantly altered sensation) 10. Associated autonomic features (swelling, change in colour, temperature or sweating)
Trial versus Maintenance Therapy
1. A 2-4 week trial is recommended. 2. Analgesic benefit and functional gains need to be weighed against side effects in
determining whether or not to proceed to maintenance therapy.
3. A drug holiday may be worth considering every 6-12 months whilst on maintenance
therapy. If pain increases significantly as the drug is tapered then the agent can be restarted. Otherwise the drug can be withdrawn.
4. Development of tolerance may be an issue with antidepressants and anticonvulsants,
as with opioid therapy. There may be value in rotating antineuropathic agents.
Choice of Agent
a. The reuptake inhibition of noradrenaline is an important contributor to the
b. Tricyclics and venlafaxine which act on both noradrenergic and serotonergic
pathways are therefore preferred to SSRI agents.
c. Although amitriptyline is the “classic” antidepressant for neuropathic pain,
nortriptyline has fewer sedative and anticholinergic side effects.
a. Carbamazepine blocks sodium channel activation in the central nervous
system (CNS) and may have a specific role in trigeminal neuralgia.
b. Sodium valproate blocks sodium channel activation and also increases
GABA inhibitory activity in the CNS. It is often preferred to carbamazepine because it is better tolerated.
c. Gabapentin acts to block the alpha-2-delta subunit of the N-calcium channel.
It is well tolerated with less toxicity and fewer drug interactions than other anticonvulsants. It is often used as a 2nd line agent due to the high cost and lack of PBS listing for pain. Gabapentin is renally eliminated with no hepatic metabolism. Hence it can be useful in hepatic dysfunction. Dose reduction is required in renal impairment.
d. Pregabalin is a new anticonvulsant with similar site of action and efficacy to
gabapentin. It is not PBS listed for neuropathic pain.
e. Other agents such as clonazepam and lamotrigine can also be considered.
a. Opioids are generally reserved for cases of inadequate response to
antidepressant/anticonvulsant combinations.
b. Opioids can be combined with antidepressants and anticonvulsants. c. Oxycodone and methadone may be preferable to morphine in neuropathic
pain due to their specific mechanisms of action (see opioid guidelines).
d. The dual mechanism of tramadol effects both opioid receptors and
descending inhibitory monoamine systems (noradrenergic/serotonergic pathways). Tramadol may have specific benefit in neuropathic pain.
a. Mexiletine has a local anaesthetic like action to block sodium channel
activation. It has a role in the treatment peripheral neuropathic pain refractory to antidepressants and anticonvulsants but is often poorly tolerated with a high incidence of nausea.
Table 2 : Prescribing Recommendations Drug Usual Usual adult Side effects starting regime dose range interactions Amitriptyline Nortriptyline
hypotension, cardiac conduction abn, weight gain
Venlafaxine S. valproate Carbamazepine Gabapentin Pregabalin Mexiletine
1. Lower starting doses and more conservative rates of increase are required in elderly
2. Combination therapy is often helpful.
References
1. Collins SL, Moore RA, McQuay HJ, Wiffen P. Antidepressants and anticonvulsants
for diabetic neuropathy and postherpetic neuralgia: a quantitative systematic review. Journal of Pain and Symptom Management 2000;20:449-458
2. Wiffen P, Collins S, McQuay H et al. Anticonvulsant drugs for acute and chronic pain.
Cochrane Database Systematic Review 2005 Jul 20 (3):CD001133
3. Freynhagen R, Strojek K, Griesing T et al. Efficacy of pregabalin in neuropathic pain
evaluated in a 12-week, randomised, double-blind, multicentre, placebo-controlled trial of flexible and fixed dose regimens. Pain 2005;115(3):254-263
4. Richter RW, Portenoy R, Sharma U et al. Relief of painful diabetic peripheral
neuropathy with pregabalin: a randomised, placebo-controlled trial. J Pain 2005;6(4):253-260
5. Lesser H, Sharma U, LaMoreaux L, Poole RM. Pregabalin relieves symptoms of
painful diabetic neuropathy: a randomised controlled trial. Neurology 2004 14;63(11):2104-2110
6. Sabatowski R, Galvez R, Cherry DA et al. Pregabalin reduces pain and improves
sleep and mood disturbances in patients with post-herpetic neuralgia: results of a randomised, placebo-controlled clinical trial. Pain 2004;109(1-2):26-35
7. Watson CPN, Babul N. Efficacy of oxycodone in neuropathic pain: a randomised trial
in postherpetic neuralgia. Neurology 1998;50(6):1837-1841
8. Huse E, Larbig W, Flor H, Birbaumer N. The effect of opioids on phantom limb pain
and cortical reorganization. Pain 2001;90:47-55
9. Raja SN, Haythornthwaite JA, Pappagallo M, et al. Opioids versus antidepressants in
postherpetic neuralgia: a randomised, placebo-controlled trial. Neurology 2002;59(7):1015-1021
10. Sindrup SH, Anderson G, Madsen C, et al. Tramadol relieves pain and allodynia in
polyneuropathy: a randomised, double-blind, controlled trial. Pain 1999;83:85-90
11. Sindrup SH, Jensen TS. Efficacy of pharmacological treatments of neuropathic pain:
an update and effect related to mechanism of drug action. Pain 1999;83:389-400
12. Finnerup N B, Otto M, McQuay H J, Jensen T S, et al. Algorithm for neuropathic pain
treatment: an evidence based proposal. Pain 2005;118:289-305
Appendix 1
Medication Sheet
Instructions on how to take your medication in increasing doses:
Medication: Sodium Valproate 200mg tablet Afternoon
From day 10 onwards, continue on this maximum dose as
Side effects: The most common side effect is drowsiness. If you experience any troublesome side effects please reduce your medication to a lower level. Please telephone ______________________ during business hours if you have any significant problems whilst taking this medication. Prescribing Information:
Tablets: Appendix 2
Medication Sheet
Instructions on how to take your medication in increasing doses:
Medication: Gabapentin 300mg capsule Afternoon
From day 12 onwards, continue on this maximum dose as tolerated
Side effects: The most common side effects are feeling drowsy or off-balance. If you experience any troublesome side effects please reduce your medication to a lower level. Please telephone ______________________ during business hours if you have any significant problems whilst taking this medication. Prescribing Information: Capsules: Not PBS listed for neuropathic pain Appendix 3
Medication Sheet
Instructions on how to take your medication in increasing doses:
Medication: Pregabalin 75mg capsule
From day 7 onwards, continue on this dose as
directed. Consider increase to 300mg twice
Side effects: The most common side effects are drowsiness and feeling off balance. If you experience any troublesome side effects please reduce your medication to a lower level. Please telephone ______________________ during business hours if you have any significant problems whilst taking this medication. Prescribing Information:
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