Antidepressant and Anticonvulsant Adjuvant Therapy for Chronic Pain

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LAS VEGAS, NV—Deborah A. Ward, PharmD, BCOP, BCPS, from St. Jude Children's Research Hospital, Memphis, TN, led a symposium on the different adjuvant therapies in pain management, at PAINWeek 2012.

Dr. Ward opened with the statement that pain is a psychosomatic issue, describing it as an “interconnectedness of body and mind in clinical medicine.” Patients with chronic pain frequently present with comorbid psychiatric conditions such as depression, anxiety, personality disorders, and sometimes substance abuse/dependence disorders.

With her pediatric oncology specialty, Dr. Ward noted that 8% of otherwise healthy children and adolescents experience severe chronic pain. This often leads to poor school attendance, reduced participation in activities, and sleep disturbances--all of which can result in higher levels of distress, anxiety, and depression.

In regards to antidepressant use, the FDA issued an advisory in 2004 that children and adolescents have twice the risk of suicidal thoughts and behaviors. After a thorough meta-analysis of all randomized studies of antidepressant use among children and adolescents, the FDA mandated that a boxed warning appear on all antidepressant agents, regardless of class. Similarly, due to the wide range of safety concerns surrounding anticonvulsant use, the FDA mandated warning label changes in 2008 to reflect the increased risk of suicidal thoughts and behaviors. This resulted from the meta-analysis of 199 placebo-controlled trials evaluating 11 anticonvulsants. Because it is a class effect, Dr. Ward noted, “one agent is not safer or better than the other.”

On the opposite spectrum of pediatrics, the elderly population is also at risk for suicide.  More attempts and more successes have been recorded in the elderly than children/adolescents. Five major risk factors have been identified in this psychosocial complexity of pain: psychiatric illness, physical illness, pain, functional impairment, and social disconnectedness.

The definition of an adjuvant analgesic is any drug with a primary indication other than pain, with analgesic properties in some painful conditions. The hope is to enhance pain relief while reducing the amount of analgesics and thus reduce adverse effects. Out of the numerous classes of adjuvant analgesics, Dr. Ward focused on antidepressants and anticonvulsants.

Antidepressants treat psychiatric comorbid conditions by inhibiting ascending  pain pathways, inhibiting prefrontal cortical areas responsible for attention to noxious stimuli, and exhibit direct effects on somatic symptoms. Indications range from nerve injury to postherpetic neuralgia. Dr. Ward emphasized that when it comes to choosing an agent, doctors need to identify the one agent with analgesic properties independent to its effect on mood in order to provide pain relief in patients with or without depression.

Major classes include tricyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and monoamine oxidase inhibitors (MAOIs).  TCAs have the longest track record of safe and effective use among different populations. The major advantages include decades of clinical experience and low cost. The disadvantage includes the often dose-limiting side effect profile, with orthostatic hypotension being a major hindrance for small and frail patients. SSRIs are not too effective for pain control and are instead more established in the treatment of depression. SNRIs are less effective than TCAs, but are generally better tolerated. The major disadvantages lie in the fact that it these drugs are hepatically metabolized and subject to many drug-drug interactions.

In the anticonvulsant class, there are several major agents used as adjuvant analgesics. Carbamazepine is often used to treat trigeminal neuralgia, with modest efficacy in diabetic peripheral neuropathy and postherpetic neuralgia.  Phenytoin has fallen out of favor due to its wide side effect profile and its potential for drug-drug interactions.  Gabapentin, the first anticonvulsant indicated in neuropathic pain, is now used in both nonmalignant and cancer-related neuropathic pain. Gabapentin proves good tolerability among patients with a lack of drug-drug interactions.  Initial doses of gabapentin range from 100–300 mg/day upward to 2,400–3,600 mg/day. Lamotrigine, another anticonvulsant, has modest efficacy in trigeminal neuralgia with inconsistent results in other neuropathies. Its use is limited by its side effect profile. Severe cases have resulted in Stevens-Johnson syndrome and other serious rashes.

Dr. Ward concluded by talking about pregabalin, which provides analgesia by binding to a2-delta subunits in the primary afferent neurons.  There is proven efficacy for this drug in postherpetic neuralgia in multiple randomized controlled trials. The effective daily dose of pregabalin ranges from 300–600mg. Its advantages over other therapies include: twice-daily dosing, rapid titration, early onset of analgesic effect, linear pharmacokinetics, and no reported drug-drug interactions.

In closing, Dr. Ward stated, “Regardless of what clinical trials show, if drugs are not tolerated, they are not efficacious.” There are very few comparative trials for both antidepressant and anticonvulsants in the treatment of pain.  Much of their use is supported by partially controlled and uncontrolled trials, as well as clinical experience. Drug selection ultimately must factor in the patient's comorbidities, applicable contraindications, cost, and side effects of the medication.

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