Friday, August 30, 2013
Cases: Anti-epileptic Medicines for Pain Management

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 It should be withdrawn gradually to avoid precipitating seizures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
Originally posted at the Institute to Enhance Palliative Care,
University of Pittsburgh Medical Center
Original PDF
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.