Anti-Epileptics For Neuropathy? An Australian View

Today's post from nps.org.au (see link below) is a very interesting look at the workings of anti-epileptic drugs in the treatment of neuropathy. It's always interesting to look at how different countries approach the treatment of chronic pain and/or neuropathy. In Australia, it's generally recommended that neuropathy patients are treated with a progressive scale of treatments, beginning with non-drug options and moving on, if necessary, via anti-depressants and anti-epilepsy drugs to opiates. This ties into a general world-wide approach to the disease but the article agrees that neuropathy is hard to treat, whatever you use to control the symptoms. Regarding anti-epileptic drugs, it concludes that the only two that are effective (however limited) are gabapentin and pregabalin. However, once again, this ignores Pfizer's own advice that pregabalin (Lyrica) is not suitable for particular groups of neuropathy sufferers (HIV- and diabetic neuropathy patients for instance) and it does seem strange that that advice from the makers is being overlooked across the world. This may partly be due to that fact that doctors see some successes with neuropathy patients being treated with Pregabalin but that doesn't take into account whether the drug is actually good for you or not. Whatever the issues around pregabalin, this is an interesting article for those already on anti-epileptics, or about to begin using them.

Treating neuropathic pain with anticonvulsants — which ones work?
Published in Health News and Evidence Date published: 10 January 2014

Summary
 
Neuropathic pain is a common form of chronic pain, with an array of drugs available for its treatment, including anticonvulsants.

A recent Cochrane review assessed the evidence around efficacy and safety for 10 anticonvulsant drugs used to treat neuropathic pain and found evidence of efficacy for only 2 — gabapentin and pregabalin.
The study provides support for the use of pregabalin and gabapentin in treatment of neuropathic pain, but was not able to distinguish between the 2 drugs in terms of efficacy for the treatment of painful diabetic neuropathy or postherpetic neuralgia. Nor was the study able to identify patients most likely to benefit from treatment with either drug.
Gabapentin and pregabalin are TGA-approved in Australia for the treatment of neuropathic pain. Currently, pregabalin is PBS subsidised when prescribed for neuropathic pain, and gabapentin is subsidised for this indication only under the RPBS. 

Practice points
Use a comprehensive clinical assessment to determine the cause of pain, its nature and severity, and the effect of the pain on the patient.1
Provide each patient with an individual management plan based on this assessment.1
Use a multidisciplinary approach to management that includes patients in decision making, and consider non-drug treatments first.1,2
Consider the TCA amitriptyline as first line if drug treatment is required.3
Consider next an anticonvulsant such as pregabalin or gabapentin if first line is unsuccessful.3
Conduct early and regular clinical reviews of patients on drug treatment.4
Refer patients whose pain relief is inadequate to a pain specialist, a multidisciplinary pain clinic or a palliative care service.3,5
Chronic pain in Australia

Chronic pain affects 1 in 5 Australian adults,6,7 with incidence increasing with age. Much of the burden of patient management falls on general practitioners.1

Chronic pain is Australia's third most costly health condition after cardiovascular diseases and musculoskeletal conditions.8 The total cost of chronic pain to the Australian economy was reported to be $34 billion in 2007, including $7 billion in health system costs.8

Neuropathic pain

Neuropathic pain is a form of chronic pain, and is difficult to treat effectively.3

Neuropathic pain is defined as pain caused by a lesion or disease of the somatosensory system9 and is usually described as burning, painful, cold or electric shocks. These symptoms may occur alongside tingling, pins and needles, numbness or itching.3,10

Causes include nerve damage, which can be followed by changes to the central nervous system.11 This condition can present for months or years, causing significant, disabling, moderate to severe pain.11
Neuropathic pain: Australian guidelines

Australian guidelines recommend that patients with chronic pain, such as neuropathic pain, have an individualised management plan. This plan should be linked to a comprehensive patient assessment to determine the cause of pain, its nature and severity as well as the effect of the pain on the patient.1

There is no generally accepted 'stepwise' approach to treatment of neuropathic pain. Australian guidelines recommend non-drug approaches first.1,5 Many drugs are available for the treatment of neuropathic pain, with TCAs and anticonvulsants the drugs of choice.3,5 However, comparative studies are limited, there is no evidence for differences in the relative efficacies of individual drugs5,11 and these treatments are often associated with adverse events.

Guidelines recommend starting drug therapy for neuropathic pain with a TCA (such as amitriptyline) or an anticonvulsant.3,5 The anticonvulsants gabapentin and pregabalin are recommended by Therapeutic Guidelines as a second-line treatment of neuropathic pain after the TCA amitriptyline.3 The dose of the drugs can be escalated at weekly intervals if tolerated, but it may take several weeks to achieve clinical efficacy.

*TCAs are an established treatment for neuropathic pain but are not approved by the TGA for this indication.
Efficacy and safety of anticonvulsant drugs for neuropathic pain: Cochrane review

The Cochrane Collaboration recently reviewed the efficacy and safety of 10 anticonvulsant drugs for the treatment of neuropathic pain and fibromyalgia.11 This was not a new systematic review of individual studies,11 but compiled data from the 10 previous Cochrane reviews published between 2009 and 201312-21 and comprising 17,955 participants (with at least moderate pain) from 91 studies.11-21

These studies were placebo controlled, double blind, randomised controlled trials. Results were presented for each different drug for 3 different neuropathic pain conditions — painful diabetic neuropathy, postherpetic neuralgia and central neuropathic pain — and for fibromyalgia. This article will focus on the findings related to neuropathic pain.

Evidence of pain reduction for gabapentin and pregabalin only

This Cochrane review reported on efficacy as well as patient impression of improvement, and investigated outcomes including patient-reported pain relief of 50% or more and Patient Global Impression of Change (PGIC).11 Results were reported in terms of whether patients were more likely to achieve the benefit with the treatment than by taking placebo.11

A reduction in pain intensity of 50% or more is considered to be a clinically relevant benefit.3

The Patient Global Impression of Change (PGIC) is a measure of global improvement with treatment where participants rate their improvement from 'very much improved' to 'very much worse' with 'no change' as the mid-point.22

Among the 10 anticonvulsants studied, evidence of pain reduction was only found for gabapentin and pregabalin.11 People taking either of these drugs were more likely to report pain relief of 50% or more for painful diabetic neuropathy and postherpetic neuralgia than those taking placebo†.11 People taking pregabalin for the treatment of central neuropathic pain were also more likely (compared to placebo) to report pain relief of 50% or more†.11

The number of patients who would need to be treated with pregabalin or gabapentin for one patient to see this improvement was estimated to range from 4 to 10 for >=50% reduction in pain.11 Therapeutic Guidelines advises that for pain treatment to be considered to be effective, the number needed to treat for one person to achieve an outcome should be between 2 and 5.3
Further findings

The Cochrane review also found that people taking gabapentin for painful diabetic neuropathy or postherpetic neuralgia were more likely to rate their improvement as 'excellent' or 'very good or excellent' than those people taking placebo*.11

People taking lacosamide or pregabalin for painful diabetic neuropathy were more likely to rate their improvement as 'very good or excellent' than those people taking placebo*.11 The data suggest that the benefit with pregabalin may be dose dependent, as a benefit was seen with the 600mg/day dose but not the 300mg/day dose. Data for other drugs was not presented.11
*These results were statistically significant. The rating of improvement by patients was determined using the PGIC.

Carbamazepine: an accepted treatment for neuropathic pain but insufficient evidence of effect

Carbamazepine is an accepted treatment in Australia for neuropathic pain but is not TGA-approved for this indication.5

This Cochrane review found that evidence of efficacy for carbamazepine was of low quality and consequently likely to be subject to a number of biases that would overestimate efficacy.11 Most studies with carbamazepine were less than 4 weeks' duration, in contrast to studies with other drugs that were of 10-12 weeks or longer.11
Safety

The risk of adverse events in people taking anticonvulsant drugs is high, with CNS adverse events relatively common and often dose dependent, particularly for pregabalin and lacosamide.11 In this Cochrane review, available data showed that only oxcarbazepine statistically significantly increased the risk of a serious adverse event in people taking anticonvulsants for either neuropathic pain or fibromyalgia compared to those taking placebo.11

Limitations of the study

This Cochrane review benefits from, and is also limited by, the fact that the data are taken solely from previous Cochrane reviews. While this ensures that each study included is of a comparative and high standard, it also means that some trials would have been omitted.11 For example, levetiracetam does not feature in a Cochrane review and therefore was not assessed in this study, although it has been tested in other randomised controlled trials.11
Conclusions: pregabalin and gabapentin are the preferred anticonvulsants

While all evidence considered in this Cochrane review was described as 'second tier' or lower due to the potential for biases to overestimate efficacy, the results provide support for current Australian guidelines.3
Treatment best practice and implications for patients
Assess the nature of the pain experience and inform people of realistic outcomes with treatment.23,24
Provide each patient with an individualised management plan based on a comprehensive clinical assessment of their pain.1
The primary treatment goal in most cases is to make the pain tolerable — not usually to eliminate the pain.23
Aim for medium-term drug therapy with a drug holiday after 6 months. Patients who relapse during a drug holiday can resume treatment.
Conduct early and regular clinical reviews.

This Cochrane review supports the use of pregabalin and gabapentin as part of a management plan for neuropathic pain, but is not able to distinguish between their efficacies for treatment of painful diabetic neuropathy or postherpetic neuralgia. Drug therapy is best used as part of a multifaceted, multidisciplinary, active self-management approach to the physical, psychological, social and vocational impacts of neuropathic pain.2

Analgesic failure is common in the treatment of neuropathic pain and there is currently no evidence to inform which patients are most likely to benefit from what drugs and indeed the order in which drugs should be taken to optimise outcomes.11 However, patients who do not respond to one drug may respond to another, even within the same drug class.5 Combination drug therapy may be needed by many patients.24,25 A specific combination of treatments cannot be recommended due to the limited number of studies for any combination therapy, as well as other study factors, such as the limited trial size and duration.25

More information is available from NSW Health.

Refractory, severe neuropathic pain

Assistance from a pain specialist and a multidisciplinary pain service may be required for refractory, severe neuropathic pain, as treatment options are complex.2
Further information
Pregabalin (Lyrica) for neuropathic pain (NPS Medicinewise RADAR: April 2013).26
Information for patients

Patient information leaflet: Key points for patients about chronic pain (Therapeutic Guidelines).

References

1. eTG complete [Internet]. Therapeutic Guidelines: Analgesic. Melbourne: 2012. [Online] (accessed 19 December 2013).
2. Australian Pain Society. Evidence-based recommendations for the pharmacological management of neuropathic pain. Position Statement, June 2008. [Online] (accessed 20 October 2012)
3. eTG complete [Internet]. Therapeutic Guidelines: Neurology. Melbourne: 2011. [Online] (accessed 19 December 2013).
4. National Institute for Clinical Excellence (Nice). Neuropathic Pain: The pharmacological management of neuropathic pain in adults in non-specialist settings. NICE Clinical Guideline 173. Manchester: National Institute for Clinical Excellence, 2013. [Full text]
5. Rossi S e. Australian Medicines Handbook, 2013. Adelaide.
6. Hogg MN, Gibson S, Helou A, et al. Waiting in pain: a systematic investigation into the provision of persistent pain services in Australia. Med J Aust 2012;196:386-90. [PubMed]
7. Blyth FM, March LM, Brnabic AJ, et al. Chronic pain in Australia: a prevalence study. Pain 2001;89:127-34. [PubMed]
8. Access Economics Pty  Ltd. The high price of pain: the economic  impact of persistent pain in Australia. Sydney Deloite Access Economics, 2007 [Full text]
9. Jensen TS, Baron R, Haanpaa M, et al. A new definition of neuropathic pain. Pain 2011;152:2204-5. [PubMed]
10. Votrubec M, Thong I. Neuropathic pain — a management update. Aust Fam Physician 2013;42:92-7. [PubMed]
11. Wiffen PJ, Derry S, Moore RA, et al. Antiepileptic drugs for neuropathic pain and fibromyalgia — an overview of Cochrane reviews. Cochrane Database Syst Rev 2013;11:CD010567. [PubMed]
12. Birse F, Derry S, Moore RA. Phenytoin for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2012;5:CD009485. [PubMed]
13. Corrigan R, Derry S, Wiffen PJ, et al. Clonazepam for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2012;5:CD009486. [PubMed]
14. Gill D, Derry S, Wiffen PJ, et al. Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2011:CD009183. [PubMed]
15. Hearn L, Derry S, Moore RA. Lacosamide for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2012;2:CD009318. [PubMed]
16. Moore RA, Straube S, Wiffen PJ, et al. Pregabalin for acute and chronic pain in adults. Cochrane Database Syst Rev 2009:CD007076. [PubMed]
17. Moore RA, Wiffen PJ, Derry S, et al. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2011:CD007938. [PubMed]
18. Wiffen PJ, Derry S, Lunn MP, et al. Topiramate for neuropathic pain and fibromyalgia in adults. Cochrane Database Syst Rev 2013;8:CD008314. [PubMed]
19. Wiffen PJ, Derry S, Moore RA. Lamotrigine for acute and chronic pain. Cochrane Database Syst Rev 2011:CD006044. [PubMed]
20. Wiffen PJ, Derry S, Moore RA, et al. Carbamazepine for acute and chronic pain in adults. Cochrane Database Syst Rev 2011:CD005451. [PubMed]
21. Zhou M, Chen N, He L, et al. Oxcarbazepine for neuropathic pain. Cochrane Database Syst Rev 2013;3:CD007963. [PubMed]
22. Dworkin RH, Turk DC, Farrar JT, et al. Core outcome measures for chronic pain clinical trials: IMMPACT recommendations. Pain 2005;113:9-19. [PubMed]
23. Moulin DE, Clark AJ, Gilron I, et al. Pharmacological management of chronic neuropathic pain - consensus statement and guidelines from the Canadian Pain Society. Pain Res Manag 2007;12:13-21. [PubMed]
24. Dworkin RH, O'Connor AB, Audette J, et al. Recommendations for the pharmacological management of neuropathic pain: an overview and literature update. Mayo Clin Proc 2010;85:S3-14. [PubMed]
25. Chaparro LE, Wiffen PJ, Moore RA, et al. Combination pharmacotherapy for the treatment of neuropathic pain in adults. Cochrane Database Syst Rev 2012;7:CD008943. [PubMed]
26. National Prescribing Service. Pregabalin (Lyrica) for neuropathic pain. RADAR; April 2013. [Full text]

http://www.nps.org.au/health-professionals/health-news-evidence/latest-issue/treating-neuropathic-pain