Think Combination Therapies
Anticonvulsant medications (ACMs) are usually considered the first-line treatment for the management of neuropathic pain. A course of antidepressants would typically follow. While titrating to optimal dosages, which may take as long as 2 months, immediate-release opioids may be helpful. However, the use of extended-release opioids is not usually initially recommended.
Polypharmacy (combination therapy) is commonly used, which means the physician must understand the pharmacology of the various drugs. Both older (conventional) and newer ACMs may be used in patients with neuropathic pain, migraine, fibromyalgia, essential tremor, spasticity, restless leg syndrome, and low back pain, as well as several psychiatric disorders, including bipolar disorder and schizophrenia (Table 1).1-5
When using ACMs, here are some clinical pearls to improve their effectiveness:
- Always start low and go slow when titrating an ACM.
- Understand the pharmacokinetics as well as mechanistic differences between the ACMs.
- In treatment-resistant patients (those with poor effectiveness), it is useful to combine 2 ACMs, if necessary, but be certain to use drugs with different mechanisms of action.
- All too often a patient will state that he or she has tried and failed on an ACM, or more than 1 ACM. Be certain to find out exactly what happened. Most commonly, the patient took a very low dose of an ACM for a very short period of time (less than what would be necessary to develop a steady state with clinical efficacy) and claimed lack of effectiveness. At that point, instead of the physician insisting that the titration be continued appropriately, a different ACM is used, and the same problems persist. If an ACM is not titrated appropriately, the drug was really not used, and there would have been no clinical effectiveness. Stopping a drug due to adverse effects is absolutely appropriate.
- Push the ACM dosages until you see clinical effectiveness or have to stop it due to adverse effects.
- In many patients, maximal effectiveness (in the treatment of neuropathic pain) is found with ACMs given at 50% to 100% of their anti-epileptic dosages. This does not hold true for ACMs approved by the US Food and Drug Administration (FDA), which were approved at specific dosages for the treatment of neuropathic pain.
ACMs are FDA approved for the treatment of trigeminal neuralgia, postherpetic neuralgia (PHN), diabetic neuropathy, as well as central pain.6,7 These agents may also relieve burning dysesthesias. Chemically, ACMs are a diverse group of drugs, typically highly protein bound, and undergo extensive hepatic metabolism.
Almost immediately after it was approved by the FDA in 1993 for use as an adjunctive treatment in adults with partial epilepsy, physicians also began to use gabapentin for various neuropathic pain disorders, such as diabetic peripheral neuropathy (DPN) and PHN.8-10 Gabapentin's benign side effect profile, especially in comparison to tricyclic antidepressants (TCAs), quickly made it very popular among physicians. It is now the most commonly prescribed ACM.
Over time, a growing consensus concerning the usefulness of gabapentin in reducing pain has emerged, supported by well-controlled clinical trials.11 Gabapentin appears to act primarily at the alpha 2 delta (α2δ) subunit sites on the calcium channels, and has been shown to be effective in reducing pain behavior in a model of central sensitization and neuropathic pain, as well as in lessening spinally mediated hyperalgesia seen after sustained nociceptive afferent input caused by peripheral tissue injury.12,13 Gabapentin also appeared to enhance spinal morphine analgesia in a laboratory model of nociceptive pain.13
Further research suggests gabapentin is effective in reducing painful dysesthesias and improving quality-of-life scores in patients with painful DPN.14 Research comparing gabapentin with amitriptyline for diabetic neuropathy found both to be equally effective.15 However, the number needed to treat (NNT) for the TCAs is 2.5, compared to 4.2 for gabapentin.16-18
Gabapentin is now FDA approved and considered a first-line therapy for PHN, another difficult neuropathic pain syndrome that affects approximately 10% to 15% of patients who develop herpes zoster. Only about half of patients obtain adequate relief with antidepressants. Research has found a modest but statistically significant pain reduction for patients treated with gabapentin compared with controls.19 Gabapentin also appears to improve sleep and quality-of-life scores. Adverse reactions include somnolence, dizziness, and infection.
Overall, gabapentin is generally well tolerated, even in the geriatric population, and has a safer side effect profile than TCAs. In the PHN study, the majority of patients were titrated to 3600 mg daily, and the median patient age was 73. Because the kidneys excrete gabapentin, the dosage must be reduced for patients with renal insufficiency.20 Also critical to note, the bioavailability of gabapentin is inversely proportional to dose, secondary to saturable absorption.21
Behind gabapentin, pregabalin (Lyrica) is the next most commonly used ACM. The agent reduces the release of excitatory neurotransmitters (e.g., glutamate, norepinephrine, serotonin, dopamine, and substance P) and has been FDA approved for the treatment of neuropathic pain associated with DPN, PHN, and fibromyalgia, and as adjunctive treatment of partial seizures.21-26 Several randomized clinical trials show pregabalin to be superior to placebo in the treatment of PHN and DPN at doses of 300 to 600 mg daily.27-30 Improvements in sleep have also been seen. The most common adverse effects include dizziness, somnolence, peripheral edema, infection, and dry mouth.22-23
Pregabalin was the first drug approved for use in fibromyalgia, based on two initial randomized clinical trials of approximately 1800 patients.31 Researchers found patients treated with pregabalin compared to placebo had lasting improvement on the patient global impression of change.32 At 600 mg daily, it appeared no more effective than the lower doses, and there was evidence of dose-related side effects.31 Again, the agent should be used at lower doses in patients with renal insufficiency.22,23
Carbamazepine also has a long history of use for lancinating neuropathic pain, including trigeminal neuralgia, and is the most appropriate ACM to use for lancinating pain. It is chemically related to the TCA imipramine, has a slow and erratic absorption, and may produce numerous side effects, including sedation, nausea, vomiting, and hepatic enzyme induction.