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  • • Ketamine is an anesthetic that exerts its analgesic properties at lower doses. Mechanistically, it works via non-competitive NMDA receptor blockade. This leads to the blocking of glutamate production, and thus ameliorating analgesic effects.
  • • Finch et al.16 studied the use of topical ketamine 10% cream on 20 patients with complex regional pain syndrome (CRPS). Sensory tests on both symptomatic and non-symptomatic limbs w'ere performed, both before and 30 minutes after ketamine cream was applied, to evaluate pain response. Ketamine inhibited allodynia to light brushing and hyperalgesia to punctate stimulation when applied to the symptomatic limb. Systemic ketamine levels w'ere below detectable limits. Topical ketamine can be used to reduce allodynia in patients with CRPS.
  • • Rabi et al.17 looked at the use of topical ketamine 10% for neuropathic pain in spinal cord injury. An open-label trial was conducted in five subjects at an outpatient rehabilitation hospital with spinal cord injury. Ketamine 10% was applied three times a day for 2 weeks. Numerical pain scores (NPS) were recorded from 0 to 10. At the end of 2 weeks, all five subjects had a decrease in their NPS ranging from 14 to 63%. The duration of effect varied, ranging from 1 hour in one subject to the next application in other subjects w'ith no adverse effects. Four of the five patients reported satisfaction with their treatment. Topical ketamine 10% should be considered for patients w'ith neuropathic pain in spinal cord injury.
  • • A retrospective review was conducted in patients from a specialty pain clinic suffering from complex regional pain syndrome. Sixteen patients were included in the review and were treated from May of 2006 to April of 2013. The patients were prescribed one of nine different ketamine combination topical formulations containing ketamine in either 6% or 10%. Eight of the patients reported a reduction in pain, seven reported a worsening of pain, and one reported no benefit. The researchers concluded that the use of topical ketamine should be considered as it shows promise and there are limited treatment options for CRPS. They highlighted that additional efficacy trials with topical ketamine are needed before it can be implemented as a first-line therapy.18


  • • Clonidine is an alpha 2 adrenergic receptor agonist. Topical use targets alpha 2 receptors located in the brain, spinal cord, the dorsal root ganglia on sensory neurons, and nociceptors. When these G protein-coupled receptors are activated, downregulation of adenylate cyclase and other secondary messengers that support abnormal excitability of nociceptors occurs.
  • • Campbell et al.19 conducted a randomized, double-blind, placebo-controlled, parallel- group, multicenter trial of topical clonidine 0.1% gel for the treatment of painful diabetic neuropathy. A total of 179 subjects applied clonidine 0.1% gel three times daily or placebo for 12 weeks on their feet. Outcomes were measured using a 0-10 NPS. The clonidine- treated group had decreased foot pain by an average of 2.6 points compared to 1.4 for placebo. This study showed that topical clonidine significantly reduced foot pain in patients with diabetic neuropathy.
  • • Kiani et al.20 compared the safety and efficacy of topical clonidine gel and capsaicin cream in the treatment of painful diabetic neuropathy. A 12-week randomized double-blind and parallel-group trial of 139 patients with type 2 DM and a VAS of at least 4 were treated for up to 3 months. Outcomes were assessed via the VAS to measure a reduction in the median pain score from baseline. Both drugs proved to be efficacious, with an average of a 4-point reduction in VAS scores. There was no difference in efficacy between the two drugs; however capsaicin had a higher discontinuation rate due to dermatologic side effects. This study shows that both topical preparations may be used to treat diabetic neuropathies, and selection should be done on a patient-specific basis to minimize side effects.


  • • Phenytoin acts by blocking voltage gated sodium channels. Kopsky and Keppel-Hesselink21 examined the usefulness of topical phenytoin in patients suffering from refractory neuropathic pain. Three patients were given a topical cream based on phenytoin 5% or 10% after experiencing no analgesia from gabapentin 10% cream. Case 1 was a 69-year-old male with diabetic neuropathy who first received phenytoin 5% cream for allodynia at night. Phenytoin 5% cream reduced the allodynia and other pain symptoms to 3 on the NRS with an onset of action of 5 minutes and duration of effect of 8 hours. After increasing to phenytoin 10% cream twice daily for 3 months, the patient did not experience any allodynia symptoms at night (0 on NRS). Pain reduction appeared within 5 minutes after application and was maintained for at least 12 hours. Case 2 was a 71-year-old male suffering from combined chronic idiopathic axonal polyneuropathy (CIAP) and chemotherapy-induced polyneuropathy (CIPN). He was given phenytoin 5% cream, leading to a reduction in tingling, pins and needles, and burning pain within 20 minutes. His pain score reduced from 8 to 3 on the NRS and the duration of effect was at least 5 hours. His sleep quality also improved. The patient applied the cream three times daily during a period of 2 months. Case 3 was a 53-year-old female who suffered from CIPN in both hands. She was given phenytoin 5% cream and asked to compare it to baclofen 5% cream (previous use reduced her pain to 3 on the NRS, although allodynia was still present). Before application of both creams, her pain was 7 on the NRS. The patient’s pain was reduced with baclofen 5% cream from 7 to 3 with a time of onset of 20 minutes. With phenytoin 5% cream, her pain went from 7 to 0 on the NRS with a time of onset of 30 minutes. The duration of effect of phenytoin 5% cream was 4 hours. With phenytoin 10% cream, the time of onset for analgesia decreased, and within 10-15 minutes she experienced a reduction in pain from 7 to 0 on the NRS. The duration of effect was increased to 6 hours.
  • • Kopsky et al.22 looked at a cohort of 70 patients who were treated with either 5% or 10% phenytoin cream for neuropathic pain. The onset of pain relief, duration of effect, and reduction in pain intensity were measured on the 11-point NRS. Nine patients applied phenytoin 5%, and 61 patients applied phenytoin 10%. After grouping the effects of all of the patients, the mean onset of pain relief was 16.3 minutes and the mean duration of effect was 8.1 hours. The mean pain reduction on the NRS was 61.2%, which was statistically significant. No systemic phenytoin side effects were reported. Phenytoin cream reduced neuropathic pain considerably, while providing a quick onset of relief.
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