A number of pharmaceutical agents are FDA-approved to treat different types of neuropathic pain. For example, the most recently approved agents include pregabalin (Lyrica, Pfizer) and duloxetine (Cymbalta, Eli Lilly & Company). Additionally Neurontin (gabapentin, Pfizer) and its generics have been available since the 1990s, and have also been used to treat neuropathic pain (it is specifically FDA-approved to treat post-herpetic neuralgia [PHN]).
In June 2005, Lyrica received FDA-approval for treatment of neuropathic pain associated with diabetic peripheral neuropathy (DPN) and PHN as well as for treatment of adults with partial onset seizures. The maximum recommended dose of Lyrica for DPN is 100mg three times daily (TID). When treating patients with a creatinine clearance (CrCL) of < 60 mL/min, initiate at a lower dose (50 mg TID) because it is primarily renally eliminated. When discontinuing Lyrica, it should be gradually tapered over a minimum of one week. The recommended dose for treatment of PHN is 75–150 mg twice daily (BID), or 50–100 mg TID for patients with a CrCL of at least 60mL/min. The dose should be reduced for patients with a CrCL < 60mL/min. If no pain relief is obtained within two to four weeks at this dose, it may be gradually increased to 600 mg/day (200 mg TID or 300 mg BID); however, side effects may be more severe because they are dose-dependent (e.g., ataxia, dizziness, dry mouth, peripheral edema, somnolence, and weight gain).
Other guidelines for dosing in renally impaired patients should be reviewed in the product labeling. Because Lyrica has been reported to cause euphoria, it has been designated as a controlled substance (C-V). There are no specific drug interactions except with the glitazones (weight gain, fluid retention, or congestive heart failure exacerbation may occur) and the possibility of additive central nervous system (CNS) effects if given with other agents that affect the CNS. Lyrica is available in the following strength capsules: 25, 50, 75, 100, 150, 200, 225, and 300mg. Head-to-head comparisons to similar agents are not available.
In August 2004, the FDA approved Cymbalta for treatment of DPN and major depressive disorder (MDD). Dosing for treatment of DPN is 60 mg once daily. A lower starting dose may be used in patients with renal impairment. (It should not be used in patients with a CrCL <30 mL/min.) Common adverse effects include nausea, dizziness, somnolence, constipation, dry mouth, and increased sweating. Serum transaminase elevations have also been reported. Because Cymbalta is metabolized by CYP1A2 and CYP2D6, numerous drug interactions may occur. Drug discontinuation should be performed gradually to avoid withdrawal symptoms. Cymbalta capsules are delayed-release and are available in the following strengths: 20, 30, and 60 mg. (They should not be opened or crushed prior to administration).
Diabetic Peripheral Neuropathic Pain
Earlier this year, a Consensus Guideline on the management of diabetic peripheral neuropathic pain (DPNP) was published, the first of its kind. Treatment of DPNP may mirror other peripheral neuropathic pain syndromes, and, therefore, this guideline may assist in managing other similar patients.
A goal of 100% pain relief is ideal but often unrealistic. Many patients will only experience a 30%-50% reduction in pain relief; however, this may enable the patient to return to social activities or work and improve their quality of life. Hospitalists and other members of the healthcare team must keep in mind that the patients’ treatment goals may significantly differ from their own goals of therapy. In managing these complex patients we must bear in mind that complete pain relief may not be attainable. We must also continue to communicate with our patients and provide them with information on what is known and unknown about the mechanisms and treatment of neuropathic pain. By developing and maintaining these patient relationships, our patients will apt to be more satisfied with their treatment, even if they do not have 100% improvement.
In DPNP (there are many patients who may have this and not know that they are diabetic or may be in denial about the degree of their diabetes), it is important for the patient to play an active role in their care (e.g., glycemic control, foot care, analgesic treatment). If treatment plans are not for FDA-approved uses, obtain patient consent. Remember, patients now have access to approved labeling via the internet. If they feel that their healthcare providers are not being “above aboard,” lack of trust can significantly affect care.
One of the more commonly used agents to treat neuropathic syndromes is Neurontin (gabapentin). Disadvantages to the use of gabapentin include the need for dose titration and multiple daily doses. Gabapentin is a good alternative as a second-line agent for patients with DPNP who don’t respond well to or can’t tolerate first-line agents (approved agents or others with evidence: e.g., oxycodone controlled-release, tricyclic antidepressants, Lyrica, Cymbalta).
It is recommended that treatment is begun using a first-line agent. Then each time you evaluate the patient, ask them whether the pain is worse or whether the nature of the pain has changed. They should also be asked if they are experiencing any adverse effects. The agent should be titrated to the maximum tolerated dose with an expected goal of at least 50% pain reduction from baseline. Some pain improvement should be expected within three weeks of therapy initiation. Therefore ascertain that this is followed upon hospital discharge. If no improvement is noted within three weeks, modification of therapy may be warranted.
If the patient derives some (but not optimal) therapy benefit without adverse effects, consider adding a second agent. The agent can be another first-line agent or a second-line agent. Consider rational pharmacotherapy (e.g., avoid additive side effects, consider synergy of agents, avoid drug interactions), and use an agent with a different mechanism of action.
If the patient is receiving no benefit from the current therapy or they are experiencing intolerable adverse effects, consider changing to another agent with a different mechanism of action. If the current agent is Cymbalta, Lyrica, or Neurontin (and the patient has no risk of seizures), taper the drug off over at least one week. When starting a new treatment, always take into consideration the patient’s medical and psychiatric comorbidities, any potential contraindications, and other factors such as the potential for drug interactions, side effects (e.g., weight gain, edema), and/or cost.
Topical therapies may also provide some benefit to the patient with neuropathic pain syndromes (e.g., capsaicin, lidocaine 5% patch). Remember that a specialist can always be consulted for expert advice or for difficult-to-manage patients. TH
Michele B. Kaufman is a drug information specialist and a medical writer based in New York City.
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