Anti Epileptic Drugs For Neuropathic Pain

Today's post from pallimed.org (see link below) will be of interest for those neuropathy patients being treated with anti-convulsion, anti-epileptic or seizure medications. The information using case studies, is meant for student or colleague doctors and nurses and as such is slightly more technical in nature but is nevertheless quite easy to follow. It's always interesting to know how your doctor is thinking when he or she prescribes a certain type of drug for your complaint. It also helps you understand why that particular drug has been chosen. Remember too, anti-epilepsy drugs are on the treatment list for neuropathy and if you aren't taking them now, they may well be prescribed for you in the future - it's worthwhile knowing what you may be dealing with.

Cases: Anti-epileptic Medicines for Pain Management
Posted by Christian Sinclair on Friday, August 30, 2013

 
Personal details in the case have been altered to protect patient privacy. These cases may reflect a composite image of many different cases to illustrate a teaching point.

Case: Mr. LF is a 58 year-old gentleman with a history of metastatic lung cancer with metastases to the bone including the sacrum. He is seen in a palliative care clinic for severe right lower extremity burning pain lasting several months. Noting LF’s pain appeared to be neuropathic in nature, LF’s primary care physician prescribed, in succession, duloxetine and then amitriptyline. Unfortunately, neither of these interventions decreased his pain. His oncologist prescribed a fentanyl patch and oxycodone 5-10mg as needed. LF reports the opioid pain medications make him tired but do not relieve his pain. He wonders if there is anything else to try for his pain.

Discussion: Tri-cyclic antidepressants (TCAs), serotonin-norepinephrine reuptake inhibitors (SNRIs) and anti-epileptic drugs (AEDs) are the mainstays of adjuvant therapy for neuropathic pain. This Case of the Month will focus on oral anti-epileptic neuropathic pain analgesics. Due to lack of head-to-head data, evidence is presented as numbers needed to treat (NNT) and numbers needed to harm (NNH). For instance, an NNT of 5 for 50% pain reduction means for every 5 patients treated with a drug, only 1 of them would achieve a 50% reduction in pain. Gabapentin (Neurontin) and pregabalin (Lyrica) are considered first-line anti-epileptics for the treatment of neuropathic pain.

Gabapentin is effective in treating central and peripheral neuropathic pain. According to a 2011 Cochrane review of the effect of gabapentin on chronic neuropathic conditions (including post-herpetic neuralgia, painful diabetic neuropathy, mixed neuropathic pain), the NNT is 5.8 (4.8-7.2) to achieve at least moderate benefit. This NNT is more conservative than those previously published due to better definitions of efficacy outcomes and an increased number of participants and studies evaluated.

Adverse effects are frequent and include drowsiness, dizziness and edema. Typically, if the dose is increased slowly these side effects are tolerable (1). Gabapentin should be dose adjusted for renal dysfunction. It should be withdrawn gradually to avoid precipitating seizures (2).

Pregabalin is effective in treating peripheral and central neuropathic pain. Since both gabapentin and pregabalin are chemical analogs of GABA, they are not used simultaneously in clinical practice. There are no comparison studies of gabapentin versus pregabalin. Pregabalin’s effectiveness increases as the dose approaches 600 mg/day. Based on a recent meta-analysis, at a dose of 600 mg/day the NNT to decrease pain by 50% for the following conditions is: 3.9 (range 3.1-5.1) for post-herpetic neuralgia; 5.0 (range 4.0-6.6) for diabetic neuropathy; and 5.6 (range 3.5-14) for central neuropathic pain. There was no difference in incidence of side effects among participants taking pregabalin vs. placebo and no indication of a dose response to side effects (3 - Open Access (OA)).

Carbamazepine is effective in treating neuropathic pain, specifically trigeminal neuralgia, but is not considered first-line therapy due to its adverse effects. A 2011 meta-analysis focused on the use of carbamazepine for chronic neuropathic pain reported carbamazepine reduced pain compared to placebo (NNT of 1.7, range 1.5-2.0). However, adverse events occur frequently: NNH = 2.6, range 2.1-3.5 (4). Common side effects include leukocytosis, thrombocytopenia, dizziness, drowsiness, ataxia, nausea/vomiting and blurred vision. Additionally, there is a risk of agranulocytosis, aplastic anemia, and Stevens Johnson syndrome. Laboratory tests (BUN, complete blood count, sodium, liver function tests, urinalysis) and serum drug levels should be checked at baseline and during treatment. Oxcarbazepine is an analogue of carbemazepine which is equally effective at treating trigeminal neuralgia as carbemazepine (5) but with fewer side effects (6 - OA).

Valproic acid was evaluated in a 2011 meta-analysis for the treatment of neuropathic pain. There were insufficient data for reliable pooled analysis, and the authors recommend against its use as first-line therapy (7).

Several small studies (n less than 60) showed benefit of the use of valproic acid (maximum of 1200 mg/day in divided doses) over placebo in the treatment of diabetic neuropathy (8 - OA). However, this data is not convincing. Other studies of valproic acid have failed to find an effect (9). Adverse effects include liver function test abnormalities, dizziness, drowsiness and nausea (2).

Topiramate was evaluated in a 2010 systematic review for the treatment of neuropathic pain. Of four randomized placebo-controlled trials, three were negative and one positive for the treatment of painful polyneuropathy. No studies were found to evaluate its efficacy in the treatment of post-herpetic neuralgia, peripheral nerve injury or central pain (9). Serious adverse events thought to be related to topiramate included convulsion and bradycardia plus syncope. Additional adverse effects include sedation, nausea, diarrhea and metabolic acidosis (2).

Summary: Neuropathic pain remains best treated with TCAs, SNRIs, and the AEDs gabapentin and pregabalin. For patients who are intolerant to or who experience pain unresponsive to those medications, one can consider therapy with other anti-epileptics. However, these agents are associated with more side effects and lower rates of efficacy.

Resolution of the case: LF was started on gabapentin and titrated up to a dose of 900mg three times a day with moderate pain relief. His opioids were tapered and discontinued.

References:
Moore RA, Wiffen PJ, Derry S, McQuay HJ. Gabapentin for chronic neuropathic pain and fibromyalgia in adults. Cochrane Database of Systematic Reviews. 2011, Issue3, Art No.: CD007938. DOI: 10.1002/14651858.CD007938.pub2
Micromedex® Healthcare Series [Internet database]. Greenwood Village, Colo: Thomson Reuters (Healthcare) Inc. Updated periodically.
Moore RA, Straube S, Wiffen PJ, Derry S, McQuay HJ. Pregabalin for acute and chronic pain in adults. Cochrane Database of Systematic Reviews. 2009, Issue 3. Art. No.: CD007076. DOI: 10.1002/14651858.CD007076.pub2. Open Access PDF
Wiffen PJ, Derry S, Moore RA, McQuay HJ. Carbamazepine for acute and chronic pain in adults. Cochrane Database of Systematic Reviews. 2011, Issue 1. Art. No.: CD005451. DOI: 10.1002/14651858.CD005451.pub2.
Zakrzewska J, Linskey M. Trigeminal Neuralgia. Clinical Evidence. 2009; 3(1207). Retrieved Nov 15, 2011 from http://clinicalevidence.bmj.com/ceweb/conditions/nud/1207/1207.jsp
Finnerup NB, et al. Algorithm for neuropathic pain treatment: An evidence based proposal. Pain. 12005; 18:289-305.PMID: 16213659. Open Access PDF
Gill D, Derry S, Wiffen PJ, Moore RA. Valproic acid and sodium valproate for neuropathic pain and fibromyalgia in adults.Cochrane Database of Systematic Reviews. 2011, Issue 10. Art. No.: CD009183. DOI: 10.1002/14651858.CD009183.pub2.
Kochar DK, et al. Sodium valproate for painful diabetic neuropathy: A randomized double-blind placebo-controlled study. Quarterly J Med. 2004; 97:33-8. PMID: 14702509 Open Access PDF
Finnerup NB, et al. The evidence for pharmacological treatment of neuropathic pain. Pain. 2010; 150: 573-581. PMID: 20705215

Original Case by Rene Claxton, MD, Edited by Christian Sinclair, MD
Originally posted at the Institute to Enhance Palliative Care,
University of Pittsburgh Medical Center
Original PDF

Pallimed Case Conference Disclaimer: This post is not intended to substitute good individualized clinical judgement or replace a physician-patient relationship. It is published as a means to illustrate important teaching points in health care.

http://www.pallimed.org/2013/08/cases-anti-epileptic-medicines-for-pain.html

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Two Anti Depressants For Nerve Pain How Did They Do

Today's short post from alert.psychnews.org (see link below) reports that a new study has shown both Duloxetine (Cymbalta and others) and Venlafaxine ( ‎Effexor, Trevilor, Lanvexin, others) to be reasonably effective treatments for nerve pain. Well reasonable in the sense that they performed better than other pills...when compared to placebos. These two serotonin-norepinephrine reuptake inhibitors (anti-depressants) are already widely prescribed for neuropathic pain but as we know, what works for one patient, doesn't necessarily work for others, which leads to patient frustration and difficulties for researchers and studies to come to definitive conclusions. The article also states that pregabalin is FDA approved for neuropathic pain - it's not! The FDA goes as far as to demand that warnings about the side effects be placed on boxes. It's a minefield for patients wondering whether what their doctor has prescribed is a)going to work and b) going to be safe. It is safe to say that almost all drugs prescribed to limit neuropathic pain can have side effects and therefore it's vitally important that you have a serious discussion with your doctor before embarking on a course of drugs. Together you need to weigh up the benefits and risks and even then there's no guarantee that your symptoms will diminish. However, maybe that shouldn't stop you trying - anything is better than that relentless pain...right! But your doctor should monitor your progress on any given drug, with great care and if necessary change the treatment.
 

Duloxetine, Venlafaxine May Be Most Effective at Reducing Diabetic Nerve Pain
Posted by Psychiatric News Monday, March 27, 2017

The serotonin-norepinephrine reuptake inhibitors duloxetine and venlafaxine appear to have the best evidence for being effective at reducing nerve pain in people with diabetes, according to a meta-analysis published in Neurology. Duloxetine is FDA-approved for treating pain in diabetic neuropathy, though venlafaxine is not.

The researchers pooled together data from 106 clinical studies published between 2011 and 2015 examining the effectiveness of pharmacologic approaches to improving pain in patients with diabetic peripheral neuropathy. The analysis compared outcomes in patients taking 21 different medications, though the authors were unable to draw conclusions for any head-to-head drug comparisons due to insufficient evidence.

The researchers found moderate evidence to suggest that duloxetine and venlafaxine were more effective at reducing neuropathy-related pain than placebo. Tricyclic antidepressants, botulinum toxin, the opioids tramadol and tapentadol, and the anticonvulsants pregabalin and oxcarbazepine were also found to be more effective than placebo, but the evidence base for these medications was weak.

In contrast, the anticonvulsant gabapentin, mood stabilizer valproate, and capsaicin cream were all found to be no more effective than placebo; these findings run contrary to guidelines for treating diabetic peripheral neuropathy published by the American Academy of Neurology in 2011, which listed all three agents as probably effective.

“Our findings generally support the effectiveness of the three drugs approved by the Food and Drug Administration (FDA) for the treatment of pain in diabetic peripheral neuropathy: duloxetine, pregabalin, and tapentadol,” wrote Julie Waldfogel, Pharm.D., of the Johns Hopkins Hospital and her colleagues. “Additional studies evaluating longer term outcomes are needed to better inform clinical decision-making, patient choice, and clinical practice guidelines.”

http://alert.psychnews.org/2017/03/duloxetine-venlafaxine-may-be-most.html

Anti Epileptic Drugs For Neuropathy Review

Today's post from sacfs.asn.au (see link below) is an Australian review of anti-epileptic drugs used to treat neuropathic symptoms, with particular attention to gabapentin and pregabalin (Lyrica). It's interesting that most of these reviews conclude that if they work, anti-epileptic drugs can be efficient in controlling neuropathic symptoms but in general, these drugs are by no means top-notch solutions to the problem. HIV and diabetic patients especially have been put off Lyrica (pregabalin) by the fact that the makers (Pfizer) have withdrawn their own recommendation for treatment of HIV and diabetes related neuropathies. There is little evidence that the other common anti-epileptics used for neuropathy (lamotrigine and carbamazepine) are effective either. You sometimes get the feeling that drugs are promoted by drugs company salesmen on very little evidence and with the, wet-finger-in-the-wind theory that something has got to work, especially if the scientific theory suggests it could. If your doctor is prescribing you anti-epileptic drugs for your neuropathy and they don't seem to be working, you should maybe have a serious talk with him or her as to whether an alternative may not be more appropriate in your case.

A Review of Antiepileptic Drugs for Neuropathic Pain and Fibromyalgia
www.ProHealth.com • December 2, 2013 

Editor's comment: Antiepileptic drugs – also called anticonvulsants or antiseizure medications – are frequently used to treat neuropathic pain and fibromyalgia. Lyrica (pregabalin) – the first drug to be approved for fibromyalgia – is an antiepileptic. This study reviews available research assessing the effectiveness of antiepileptic drugs for neuropathic pain and FM. They concluded that the evidence from clinical trials only supported the use of two antiepileptics – gabapentin and pregabalin – for neuropathic pain and FM. What's interesting is that although the drugs only worked for a minority of patients, when it worked, it worked really well – providing at least a 50% reduction in pain intensity.

Antiepileptic drugs for neuropathic pain and fibromyalgia - an overview of Cochrane reviews.

By Philip J. Wiffen, et al.

Plain Language Summary: (abstract follows)

Neuropathic pain is pain coming from damaged nerves. It is different from pain messages carried along healthy nerves from damaged tissue (e.g., a fall, cut, or arthritic knee). Neuropathic pain is treated by different medicines than pain from damaged tissue. Medicines such as paracetamol or ibuprofen are probably not effective in neuropathic pain, while medicines that are sometimes used to treat depression or epilepsy can be very effective in some people with neuropathic pain. Our understanding of fibromyalgia (a condition of persistent, widespread pain and tenderness, sleep problems, and fatigue) is lacking, but fibromyalgia can respond to the same medicines as neuropathic pain.

Antiepileptic drugs (previously called anticonvulsants) are used for treating epilepsy, but have also been used for treating neuropathic pain and fibromyalgia. Many of the drugs have been the subject of individual Cochrane reviews. In August 2013 we collected all these Cochrane reviews on antiepileptic drugs together to provide an overview. Individual antiepileptic drugs work in different ways, and there is no expectation that they are equally effective.

We found that only for gabapentin and pregabalin was there some evidence that they worked in long-term nerve pain with diabetes (painful diabetic neuropathy) and pain after shingles (postherpetic neuralgia). Pregabalin also had evidence of efficacy in central neuropathic pain (typically pain after stroke) and in fibromyalgia. The drugs work very well in some people with these painful conditions, with pain reduced by half. However, only between 1 in 10 and 1 in 4 people will get this level of benefit, depending on the pain condition and the drug. Most people will get no pain relief.

The antiepileptic drugs produced side effects in most people taking them, and for about 1 in 4 these could not be tolerated so they stopped taking the drug. Serious side effects were no more common with antiepileptic drugs than with a harmless placebo.

The evidence we found did not meet current best standards, and as a result it may overestimate benefit. The biggest concern is a lack of any evidence for most drugs in most types of neuropathic pain and fibromyalgia. For lacosamide and lamotrigine there is evidence of a lack of effect; for other antiepileptic drugs (including carbamazepine, clonazepam, phenytoin, valproate) there is no evidence of effect or insufficient evidence of effect.

Abstract:

BACKGROUND: Antiepileptic drugs have been used for treating different types of neuropathic pain, and sometimes fibromyalgia. Our understanding of quality standards in chronic pain trials has improved to include new sources of potential bias. Individual Cochrane reviews using these new standards have assessed individual antiepileptic drugs. An early review from this group, originally published in 1998, was titled 'Anticonvulsants for acute and chronic pain'. This overview now covers the neuropathic pain aspect of that original review, which was withdrawn in 2009.

OBJECTIVES: To provide an overview of the relative analgesic efficacy of antiepileptic drugs that have been compared with placebo in neuropathic pain and fibromyalgia, and to report on adverse events associated with their use.

METHODS: We included reviews published in the Cochrane Database of Systematic Reviews up to August 2013 (Issue 7). We extracted information from each review on measures of efficacy and harm, and methodological details concerning the number of participants, the duration of studies, and the imputation methods used, in order to judge potential biases in available data. We analysed efficacy data for each painful condition in three tiers, according to outcome and freedom from known sources of bias. The first tier met current best standards - at least 50% pain intensity reduction over baseline (or its equivalent), without the use of last observation carried forward (LOCF) for dropouts, an intention-to-treat (ITT) analysis, in parallel group studies with at least 200 participants lasting eight weeks or more. The second tier used data from at least 200 participants where one or more of the above conditions were not met. The third tier of evidence related to data from fewer than 200 participants, or with several important methodological problems that limited interpretation.

MAIN RESULTS: No studies reported top tier results. For gabapentin and pregabalin only we found reasonably good second tier evidence for efficacy in painful diabetic neuropathy and postherpetic neuralgia. In addition, for pregabalin, we found evidence of efficacy in central neuropathic pain and fibromyalgia. Point estimates of numbers needed to treat for an additional beneficial effect (NNTs) were in the range of 4 to 10 for the important outcome of pain intensity reduction over baseline of 50% or more. For other antiepileptic drugs there was no evidence (clonazepam, phenytoin), so little evidence that no sensible judgement could be made about efficacy (valproic acid), low quality evidence likely to be subject to a number of biases overestimating efficacy (carbamazepine), or reasonable quality evidence indicating little or no effect (lamotrigine, oxcarbazepine, topiramate). Lacosamide recorded such a trivial statistical superiority over placebo that it was unreliable to conclude that it had any efficacy where there was possible substantial bias. Any benefits of treatment came with a high risk of adverse events and withdrawal because of adverse events, but serious adverse events were not significantly raised, except with oxcarbazepine.

AUTHORS' CONCLUSIONS: Clinical trial evidence supported the use of only gabapentin and pregabalin in some neuropathic pain conditions (painful diabetic neuropathy, postherpetic neuralgia, and central neuropathic pain) and fibromyalgia. Only a minority of people achieved acceptably good pain relief with either drug, but it is known that quality of life and function improved markedly with the outcome of at least 50% pain intensity reduction. For other antiepileptic drugs there was no evidence, insufficient evidence, or evidence of a lack of effect; this included carbamazepine. Evidence from clinical practice and experience is that some patients can achieve good results with antiepileptics other than gabapentin or pregabalin. There is no firm evidence to answer the important pragmatic questions about which patients should have which drug, and in which order the drugs should be used. There is a clinical effectiveness research agenda to provide evidence about strategies rather than interventions, to produce the overall best results in a population, in the shortest time, and at the lowest cost to healthcare providers.

Source: The Cochrane Database of Systematic Reviews, November 11, 2013. By Philip J Wiffen, Sheena Derry, R Andrew Moore, Dominic Aldington, Peter Cole, Andrew S C Rice, Michael PT Lunn, Katri Hamunen, Maija Haanpaa, Eija A Kalso. Pain Research and Nuffield Department of Clinical Neurosciences, University of Oxford, Pain Research Unit, Churchill Hospital, Oxford, Oxfordshire, UK, OX3 7LE.

http://sacfs.asn.au/news/2013/12/12_22_a_review_of_antiepileptic_drugs_for_neuropathic_pain_and_
fibromyalgia.htm