Tuesday, January 15, 2013

Suicide Risks of Antiepileptic Drugs for Pain

Drug SuicideAntiepileptic drugs (AEDs, also known as anticonvulsant medications) have a prominent role in the treatment of several types of chronic pain, particularly relating to neuropathy and fibromyalgia. Yet, there have been strong concerns about suicide risks associated with these medications and a new review article examines the relatively weak evidence behind this apprehension.

Writing in an early online edition of the journal PAIN, Anthony Pereira, MD — at the University of Rochester School of Medicine and Dentistry, Rochester, NY — and colleagues review recent research on suicidality and AEDs and discuss implications for the treatment of neuropathic pain and fibromyalgia [Pereira et al. 2013]. According to background information in their article, gabapentin and pregabalin are recommended as first-line treatments for various neuropathic conditions, while carbamazepine and oxcarbazepine are commonly used in trigeminal neuralgia, and other AEDs are considered second- or third-line treatments for neuropathic pain. Additionally, pregabalin is recommended for fibromyalgia, and topiramate and valproic acid are considered first-line treatments for migraine prophylaxis.

Given the major role of AEDs in pain management, it is important to consider findings regarding these medications and suicidality, which includes both suicide ideation and actual suicidal behavior. Furthermore, the researchers note that chronic pain itself is also associated with suicidality, and as many as 50% of patients with chronic pain have comorbid depression, which is a well-established risk factor for suicide.

For their review, the authors searched Medline and PubMed for articles addressing “suicide” and “anticonvulsants” appearing in 2008 or thereafter. Such articles were considered pertinent to the warnings on suicidality in persons taking AEDs that had been issued during that timeframe by the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Three articles were discovered as demonstrating increased suicidality risks of AEDs:

  1. The first article was a large meta-analysis conducted by the FDA that focused on 199 placebo-controlled trials of 11 AEDs and included a total of nearly 44,000 patients. Approximately half of the patients had epilepsy or psychiatric disorders (52%), and the remainder were classified as having “other” conditions, including obesity, insomnia, migraine, and various pain disorders.

    Based on adjusted risk estimates, 0.43% of patients in the AED groups had suicidal ideation or behavior vs. 0.24% in the placebo groups. The FDA concluded that AEDs appeared to increase the risk of suicidality regardless of treatment indication, specific AED, or mechanism of action, and that increased risk was observed as early as one week after treatment initiation and continued for at least 24 weeks.

    The odds ratio for increased suicidality risk in the “other” group in the FDA meta-analysis, which included patients with various pain conditions, was a moderate 1.87 (95% Confidence Interval, 0.81-4.76), but this was not statistically significant. Patients in this group were taking divalproex, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, topiramate, or zonisamide.

  2. A Danish study assessed 6,780 suicides compared with a cohort of 169,725 treatment-naïve patients. The cohort population consisted of patients with epilepsy, psychiatric disorders, and those taking opioids, presumably for chronic pain. The authors concluded that valproate, lamotrigine, clonazepam, and phenobarbital may increase the risk of suicide shortly after treatment initiation.

  3. A third investigation, using a medical claims database, was an observational study of 297,620 patients treated for various neurologic and psychiatric conditions. Suicidal acts and violent death were compared in patients beginning AEDs and those taking topiramate, the reference AED. Various statistical analyses demonstrated that several AEDs, including gabapentin, increased the risk of suicidal acts. Of particular interest, nearly 17% of the gabapentin group was being treated for neuropathic pain; whereas, less than 1% was treated for epilepsy.

Pereira et al. conclude that, considered together, these 3 studies provide evidence consistent with an increased risk of suicidality in patients taking AEDs for pain conditions. However, 2 other studies examining such patients did not find evidence of increased risk:

  • One small study compared suicide-related behaviors in 64 older male patients who received AEDs and 768 matched controls. A high percentage (≈86%) of patients had been previously diagnosed with chronic pain and the association between AED treatment and risk of suicidality was not significant.

  • Another study examined the relationship between gabapentin and suicide attempts in 131,178 patients with epilepsy, pain, or various psychiatric disorders. It was concluded that gabapentin did not increase the risk of suicide attempts in patients with epilepsy or pain.

Several other studies evaluated the association between AEDs and suicidality but did not examine pain patients. Based on their findings, and despite limitations in the data, Pereira et al. conclude that that “the risk of suicidality ─ although small in absolute terms ─ should be considered carefully in the treatment of patients with neuropathic pain, fibromyalgia, and other chronic pain conditions for which treatment with an AED is being considered.

The risk of suicidality can be evaluated in patients initiating AED therapy for pain and periodically thereafter, the authors suggest. This would be especially appropriate in those with evidence of past or current suicidality, past or present mood disorders, and other risk factors for suicidality, including treatment with antidepressant medications in individuals under the age of 25.

COMMENTARY: While news media have been abuzz about an “epidemic” of analgesic overdoses and deaths, a potentially greater threat to public health may be suicide attempts associated with chronic pain. Pereira and colleagues acknowledge this concern in their review article and suicide-pain connections have been discussed in various Pain-Topics UPDATES [see list here].

A survey of pain specialists recently described in an UPDATE article [here] found that anticonvulsants are a preferred first-line therapy for a number of neuropathic pain conditions and fibromyalgia, so concerns about AEDs are important. Yet, the link between AEDs and suicide risk — particularly in persons with pain — seems somewhat tenuous based on the quality and quantity of current evidence. However, erring on the side of caution, both the U.S. FDA and EMA issued warnings in 2008 regarding this potentially serious adverse effect.

The evidence discovered in the limited literature search by Pereira et al. was inconsistent, whether in patients with epilepsy and other neuropsychiatric conditions or in those with chronic pain. The authors acknowledge that the number of available studies was small and the differences between studies were too great to fully understand discrepancies in their outcomes. Additionally, we observed that the absolute suicide risk differences attributable to AEDs were diminutive, making the numbers needed to harm (NNH) extremely large.

As is usual in such cases, from an evidence-based perspective, inconsistent results may be due to the retrospective nature of the studies, variable definitions of suicide ideation and behavior, differences across studies in research designs and control vs comparison groups, and samples sizes. Cause-effect relationships cannot be definitively established by the evidence, and there could be considerable confounding due to the fact that many of the conditions treated with AEDs, including chronic pain, carry suicide risks of their own.

Still, potential suicide risks in patients with pain, and in those treated with AEDs, seem to be important considerations. Pereira and colleagues recommend that “clinicians who evaluate and treat pain must recognize early signals of suicidality and should consider tracking patients’ mental status in relation to suicidal ideation and behavior just as they would pain severity or vital signs.

As an invaluable tool for this purpose, they recommend is the Columbia-Suicide Severity Rating Scale, [available here] from the Center for Suicide Risk Assessment at Columbia University Medical Center. The C-SSRS is a well-validated instrument available in more than 100 languages and has been recommended by the FDA and expert consensus panels. It has been used in multiple states in the U.S. and internationally across numerous healthcare systems.

Pereira et al. urge that, “In deciding whether to initiate or continue AED treatment in chronic pain patients, especially those with risk factors for suicidality (beyond the increased risk conferred by having chronic pain), careful evaluation is necessary to determine whether treatment benefits outweigh risks.” In their benefit-risk assessments, clinicians also need to consider the effectiveness, safety, and tolerability of other pharmacologic and non-pharmacologic therapies that have not been directly associated with increased suicidality. “Although the benefits of AED treatment in epilepsy generally outweigh the risk of treatment-emergent suicidality,” they state, “such an overall evaluation has unfortunately not been conducted for patients with chronic pain.

REFERENCE: Pereira A, Gitlin MJ, Gross RA, et al. Suicidality associated with anti-epileptic drugs: implications for the treatment of neuropathic pain and fibromyalgia. PAIN. 2013; online ahead of print [access here, subscription or purchase required].

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