"Neuropathic pain can be treated with capsaicin, tricyclic antidepressants, anticonvulsants, and local anesthetics."

   Topical amitriptyline 2 to 4% with ketamine 1 to 2% have been compared to placebo. Researchers noted that the higher dose significantly lowered pain intensity, with more subjects attaining 30% reduction in pain and recommended the use of higher doses of amitriptyline coupled with ketamine for longer periods for dull, chronic pain. "In clinical practice, we always recommend starting with the lower dose and slowly titrating upward if needed." Practitioners should exercise caution regarding potential cardiac adverse effects of ketamine and amitriptyline such as QT prolongation, and consider if the patient is concurrently taking other QT-prolonging medications.

   A retrospective study of 51 patients using 2%, 4%, or 6% gabapentin in LipodermŽ cream base 3 times daily for 8 weeks demonstrated a 4 to 5 point reduction in pain scores on a 10-point pain scale. No systemic side effects were reported.

   Topical application of 5% lidocaine gel (without occlusion) relieves post-herpetic neuralgia by a direct drug action on painful skin. In a study of 39 patients, no systemic adverse effects were reported and blood levels measured less than 6 μg/ml. However, extreme caution should be exercised when using topical anesthetics because concentration of each agent and amount applied is critical. If topical anesthetics are over-prescribed and over-applied, patients are prone to serious cardiac side effects, such as deadly arrhythmias.

   Ketamine 5% gel applied 2 to 3 times a day provided pain relief in 16 of 23 patients with post-herpetic neuralgia. Additionally, Gammaitoni et al. demonstrated the efficacy of topical ketamine in managing mixed neuropathic pain 15 minutes after its administration, with no systemic side effects reported.

   Complex regional pain syndrome (CRPS; previously known as Reflex Sympathetic Dystrophy) can be treated with NSAIDs; beta-2 agonists, such as clonidine; tricyclic antidepressants; anticonvulsants; local anesthetics; or NMDA antagonists, such as ketamine. It is critical to consider these medications in patients with CRPS, because there are no drugs approved specifically to treat CRPS. Patients with CRPS might require trials of several medications before adequate pain control is achieved.

   In a case study of a 42-year-old male diagnosed with CRPS, who was previously treated with high-dose gabapentin, pregabalin, tramadol, and NSAIDs without benefit, topical amitriptyline was chosen as the main therapeutic regimen after his clinical response to oral amitriptyline 25 mg. Amitriptyline 5% cream applied three times a day resulted in 30% reduction in pain after one month. Topical ketamine 10% and dimethyl sulfoxide (as a penetration enhancer) were added to the preparation. After eight months of therapy, applying the cream only once daily, his pain almost disappeared, according to the patient.

   Compounded topical creams can play an outstanding role in meeting the needs of patients with diabetic neuropathy-associated pain. In 2015, a study demonstrated good to excellent results in relief of pain associated with diabetic neuropathy and relief of other chronic neuropathic pain with the use of the compounded creams containing ketamine 10%; baclofen 2%; gabapentin 6%; amitriptyline 4%; bupivacaine 2%; and clonidine 0.2%. Nifedipine 2% was added to one cream. Use of the creams resulted in a reduction in the need for oral analgesics and referrals made by physicians to pain specialists. However, these doses were slightly higher than those in other studies that have reported good efficacy. Agents such as nifedipine that increase circulation are beneficial in diabetic neuropathy. As always, start with lower doses and one to two agent combinations as multi-combination creams with five to six ingredients are not needed most of the time.

   Topical treatments have also been used with success to treat vulvodynia. Formulations used include amitriptyline 2%, baclofen 2% and gabapentin 3% to 6%.

For arthritis-transdermal formulation:

• Ketoprofen 10%
• Ketamine 2.5%, ketoprofen 10%, and lidocaine 2%
• Ketoprofen 10%, methylsulfonylmethane 10%

For neuropathic pain:

• CRPS - Amitriptyline 2%, ketoprofen 5%, ketamine 5%, gabapentin 3%, clonidine 0.1%
• Ketoprofen 10%, ketamine 5%, lidocaine 2%
• Intranasal ketamine 10% solution
• Amitriptyline 2%, gabapentin 3%, ketoprofen 10%, lidocaine 2%, and ketamine 10% cream. A case study demonstrated success of this formulation in treating post-herpetic neuralgia in a patient who was nonresponsive to standard treatments.

   Rapid progress is being made to enhance therapeutic action by optimizing delivery of active ingredients in topical formulation administered on the skin and on the buccal mucosa through modifying chemical and physical factors and introducing novel dosage forms, such as vesicles, cyclodextrins, nanoparticles, and other complex systems.