Ask the Expert May 2013
QUESTION: Is There a Preferred Serum Concentration of Carbamazepine For Trigeminal Neuralgia?
ANSWER: Carbamazepine (CBZ) is considered a first-line option for the pharmacological treatment of trigeminal neuralgia.1,2 It is FDA approved for this indication, with recommended dosing up to 1,200 mg daily. When used as an anticonvulsant, therapeutic drug monitoring to target plasma levels between 4 and 12 mcg/mL in adults is warranted to establish adherence, efficacy, and safety. Steady-state serum concentrations should be achieved within 2 to 5 days for most adult patients. Few studies have examined whether serum CBZ levels should be evaluated when the drug is used for management of trigeminal neuralgia.3 A number of older studies have been published regarding the efficacy of CBZ in treating trigeminal neuralgia, none of which performed or advocated for monitoring serum levels of CBZ.
One study was identified that evaluated serum CBZ levels in patients with trigeminal neuralgia. Seven patients taking CBZ were enrolled with idiopathic trigeminal neuralgia, of constant severity, and they were not taking any other drugs known to affect CBZ metabolism. Patients were given CBZ twice daily, at 3 dose levels for 6 days each. Dosages were blindly adjusted in an attempt to achieve complete pain relief. Plasma levels of CBZ and CBZ-10,11-epoxide were drawn immediately prior to the morning dose on days 4 through 6, as well as 4, 8, and 12 hours after the morning dose on day 6.4
In this study, CBZ doses ranged from 200 to 1,400 mg/day and plasma concentrations were in the range of 3.3 to 10.1 mcg/mL, with a mean of 6.3 mcg/mL. Pain scores were registered by the patient, immediately after paroxysm, and assigned a grade of mild, moderate, or severe. These attacks were given factors of 1, 2, and 3, respectively, and were used to calculate a pain score for each day. Six of the 8 patients reported ≥80% pain relief with increasing CBZ levels. CBZ plasma concentrations of 5.7 to 10.1 mcg/mL were associated with the most prominent reduction in pain scores. Six of 8 patients also recorded adverse reactions; however, all adverse reactions occurred at a plasma concentration >7.9 mcg/mL. Dizziness was the only adverse drug reaction specifically mentioned in the study. Large variability in pain scores was seen, indicating that the plasma-concentration
response curve can vary markedly within each patient.4
A case series of 5 elderly patients with trigeminal neuralgia found that serum levels ranging from 3 to 9 mcg/mL were effective for pain control.5 In one patient, a level of 13 mcg/mL was reached without effective control of pain; the patient was subsequently responsive to a dosage reduction with a lower CBZ plasma level. In this report, serum CBZ levels were measured every 2 to 3 months. As noted in the previous study, the CBZ response curve varied widely from patient to patient, especially in the context of CBZ autoinduction. Overall, it was recommended to periodically monitor levels in the elderly because this patient population may be more predisposed to adverse effects of treatment.5
In summary, routine monitoring of CBZ levels for treating trigeminal neuralgia is not well supported in the literature but may be considered in patients at high risk for toxicity, such as the elderly. Limited studies have found CBZ plasma concentrations of 3 to 10 mcg/mL to be effective in reducing pain scores associated with trigeminal neuralgia, similar to its use as an anticonvulsant. Concentrations ≤8 mcg/mL are safest to avoid adverse reactions and this concentration should be exceeded cautiously and only in patients with inadequate pain response. Careful monitoring is necessary due to the wide variability of interpatient response based upon plasma concentration.
QUESTION: What Is the Evidence That Sustained-Release Opioids Are Better For Persistent Moderate-to-Severe Pain Than Short-Acting Opioids?
ANSWER: A Most widely used opioids (morphine, oxycodone, oxymorphone, fentanyl) have a short duration of action, requiring multiple daily oral or parenteral doses. These agents also are available in sustained-release (SR) formulations that allow for less frequent dosing. A single oral dose of an SR formulation lasts 8 to 24 hours depending on the agent, or every 2 to 3 days for transdermal fentanyl patches. One obvious benefit is the smaller number of units required per prescription. Another benefit is that the patient doesn’t need to be popping pills every few hours or spending his or her days watching the clock until the next dose is due. A third benefit is that a bedtime dose can give continuous pain relief throughout the night, resulting in fewer nocturnal awakenings resulting from renewed pain.
It is widely believed that serum levels are more stable when SR opioids are consumed compared with immediate-release (IR) formulations, and this provides better pain relief and fewer side effects. The thinking is that the ups and downs of IR dosing are more likely to cause increased pain at the trough of the serum level due to end-of-dose failure. "Chasing the pain" by consuming an analgesic when pain resumes is likely to require higher opioid dosing than preventing pain by maintaining a stable blood level. Additionally, it is thought that the peaks temporarily may produce more nausea and sedation than do stable blood levels.
In reality, there have been very few high-quality studies comparing the efficacy of similar total doses of an SR and IR formulation of the same opioid. A review of comparison studies published between 1975 and 20081 concluded the following:
- When dosed according to a fixed schedule, SR and IR opioids confer similar total systemic opioid concentrations and equivalent pain control
- The increased dosing interval with SR formulations may improve treatment adherence
- SR agents may effectively improve sleep in some patients with chronic pain
- SR analgesics, because of their pharmacokinetics, may provide more consistent and prolonged analgesia, which may be vitally important for chronic pain patients who have unremitting levels of daytime pain and for those seeking improved nighttime sleep
- No studies have compared directly the efficacy of SR and IR formulations for treatment of neuropathic pain
The overall incidence of adverse effects in several studies was similar for SR and IR formulations. According to epidemiologic studies, long-term opioid use is not associated with increased car accidents, fatalities, or citations.1 Similar conclusions were reached in another review.2 This review also found that in all of the comparison trials, "functional outcomes were inconsistently examined or measured with heterogeneous scales," so it was impossible to reach consistent conclusions regarding improvement in function. Moreover, the few published trials did not examine other important outcomes such as improved compliance, more consistent pain control, nor likelihood of abuse or addiction.