neuropathic pain can be debilitating and reduces quality of life considerably.1,2 peripheral neuropathic pain has a local inflammatory component , which results in sensitization of peripheral nerve fibers.3 damage and metabolic stress of the nerves result in increased production of pro - inflammatory mediators ( e.g. , cytokines and interleukins ) in both peripheral and central neurons and nonneuronal cells , such as schwann cells , mast cells , and glia cells.3 these pro - inflammatory mediators sensitize nerve fibers and nociceptors , leading to clinical symptoms of neuropathic pain , such as burning , tingling , pins and needles , painful cold , electric shock , itch , hyperalgesia , and allodynia . peripheral nerve damage and increased peripheral input result in enhanced neurotransmitter release within the spinal cord and contribute to the process and maintenance of central sensitization , and thus neuropathic pain.4 peripherally acting drugs , such as lidocaine , formulated in topical creams or as patches , have demonstrated the ability to reduce central sensitization through blocking the peripheral input.4,5 oral antidepressants ( e.g. , amitriptyline and duloxetine ) and anticonvulsants ( e.g. , pregabalin and gabapentin ) are the first - line treatments for neuropathic pain ; tramadol and strong opioids ( e.g. , oxycodon ) are second- and third - line treatments , respectively.6 however , the majority of patients is not compliant , most probably because of the absence of expected effects or the induction of intolerable side effects , including sedation , dizziness , depression , nausea , and constipation.7 furthermore , the chronic use of such analgesics can induce drug despite partial pain relief through standard treatments , neuropathic pain may get worse overtime . new treatments , preferably devoid of troublesome side effects and drug  drug interactions are , therefore , required . topical analgesics might contribute to this field.5 two commonly used topical analgesics are lidocaine ( a voltage - gated sodium channel blocker ) and capsaicin ( a vanilloid receptor agonist ) . lidocaine inhibits voltage - gated sodium channels , and thus stabilizes the neuronal membrane potential of abnormally excitable peripheral nerve fibers . this results in a decrease of allodynia and hyperalgesia.8 lidocaine 5% patch is registered for the treatment of neuropathic pain in several countries and its numbers needed to treat ( nnt ) is ~4.9 the patch needs to be replaced every 12 hours , with patch - free intervals of at least 12 hours and can not be used on wounds , ulcers , damaged , or inflamed skin , commonly seen in patients with diabetic neuropathy . guidelines recommend lidocaine patch in elderly as a first - line treatment , especially if there are concerns about the cns side effects of oral medications.10 one study shows that topical lidocaine gives no rise to cognitive impairment in elderly , whereas oral analgesics do.11 capsaicin is thought to cause desensitization and denervation , the latter through reversible retraction of the nerve endings induced by trpv1 receptor activation , leading to an overall long - term reduction of pain.12 capsaicin 8% patch , however , has the disadvantage that it can provoke or increase burning pain and often needs to be combined with a local anesthetic . its nnt is disappointingly low , between 6 and 12.13,14 topical capsaicin 0.025%0.075% cream has the disadvantage that it has to be applied 34 times daily during 56 weeks , its nnt is ~7 , and considerable side effects , such as burning , stinging , or erythema , complicate its use.15 because capsaicin is lipophilic and usually is emulsified in a cream , thorough hand washing or the use of hand gloves is necessary to avoid irritation of eyes and/or mucous membranes , all leading to decrease in patient compliance . the main disadvantage of patches is that its application on certain parts of the body can be complicated due to the shape , such as feet . the handling , therefore , can be complex , especially for elderly and thus the compliance is suboptimal . analgesics , such as ketamine , amitriptyline , clonidine , baclofen , and gabapentin , have been used as standalone topical formulations and in various combinations , compounded in creams , gels , or ointments.1618 we have been working with such compounding creams in our clinic for neuropathic pain since 2009.19 our experience is that it is unpredictable whether a topical analgesic in an individual patient will lead to sufficient pain reduction . to optimally select a cream leading to a higher chance of a positive response , we mostly test two creams on two selected areas of neuropathic pain , while patients sit in the waiting room . responders will usually detect a clear pain reduction within 2030 minutes and are able to point out which analgesic cream has superior effects . in our endeavor to find new , more effective and safe topical creams , we discovered that the classical compound phenytoin , also known as diphenylhydantoin or 5,5-diphenyl-2,4-imidazolidinedione , administered as a topical cream of 5% or 10% , could reduce neuropathic pain in a clinically meaningful way without causing side effects . phenytoin is known in the clinic since 80 years , and new indications are emerging on a continuous base.20 topical treatment of neuropathic pain might be such a new indication for this old drug . we tested this cream in a number of patients who all were refractory for other analgesic therapies with good results . the stability of the cream was also excellent , and prototypes have been stable now for 12 months . we describe the clinical effects of this new compounded phenytoin cream in three patients , who presented themselves in our clinic for neuropathic pain , and who were treatment resistant for other analgesic treatments . antiepileptics are effective systemic analgesics for neuropathic pain , and pregabalin and gabapentin are most well known in this class . however , in our hands , topical gabapentin 10% cream was not very effective . therefore , we selected one of the most senior of all antiepileptics , phenytoin , which targets , among others , the voltage - gated sodium channels as the active pharmaceutical ingredient for a new compounded topical cream.21 topical phenytoin had an impressive analgesic effect as described in the following cases . all patients signed an informed consent for approval to publish their cases on topical phenytoin anonymously . a 69-year - old male suffered since 2007 from peripheral neuropathic pain in both fore feet due to diabetes mellitus type ii . he scored his average pain as 9 on the 11-point numerical rating scale ( nrs ) . his pain was characterized by burning , electric shocks , tingling , pins and needles , allodynia when soft stroking , and hand in hand , there was a numbness ( anesthesia dolorosa in the pain area ) . especially , his allodynia on his left foot was bothering him in the night , and he scored this annoying symptom with 10 on the nrs . we prescribed compounded ketamine 10% cream.22 this resulted in a reduction of allodynia to 3 on the nrs , within 25 minutes after application . the reduction of pain lasted 6 hours , after which he woke up and had to apply the cream again . phenytoin 5% cream reduced the allodynia and other pain symptoms to 3 on the nrs with an onset of action of 5 minutes with the duration of effect of 8 hours . after application of phenytoin 10% cream , he did not experience allodynia or other pain symptoms during the night anymore ( 0 on the nrs ) . the pain reduction appeared within 5 minutes after application and was maintained for at least 12 hours . the patient applied the phenytoin 10% cream two times daily during a period of 3 months . a 71-year - old male suffered since 2008 from ciap , which worsened after chemotherapy vincristine for the treatment of a non - hodgkin lymphoma in 2010 . the characterization of the pain was tingling , pins and needles , electric shocks , burning and cramps within the legs , as well as anesthesia dolorosa . we tested our compounded creams : baclofen 5% , amitriptyline 5% , and clonidine 0.2%.16,17,23,24 however , none of these creams could reduce the pain totally , though he experienced adequate analgesia ( 24 on the nrs ) the following 2 years . in 2013 , prostate cancer was diagnosed for which he underwent local radiation therapy , and he also received the antitestosterone agent leuprorelin ( eligard ) . his neuropathic pain in his right foot recurred and the prescribed analgesic creams lost most of their analgesic effects . phenytoin 5% cream , however , could reduce the tingling , pins and needles , and burning pain within 20 minutes , and the effect was scored as a reduction of pain from 8 to 3 on the nrs . he also perceived a cooling effect of phenytoin 5% cream , and the duration of the effect was longer than the other analgesic creams , at least 5 hours . his sleep quality improved considerably . before the use of phenytoin 5% cream , he scored 6 on the nrs with regard to interference of his pain on his sleep ( 0 no interference and 10 complete interference ) . after application the patient applied the cream three times daily during a period of 2 months . in may 2016 , a 54-year - old female received chemotherapy treatment ( bortezomib ) because of immunoglobulin light chain amyloidosis . due to neuropathic pain in both hands , the treatment had to be stopped after five injections . the neuropathic pain in the hands diminished ; however , the patient developed neuropathic pain in both feet in may 2016 . she described her pain as burning , painful cold , tingling , and pins and needles . the patient received gabapentin 2000 mg daily , oxycodone 20 to 30 mg daily to reduce the pain , though she scored still 8 on the nrs in august 2016 . other medications , such as amitriptyline and tramadol , did not have any analgesic effect . the sensation of warm and cold was disrupted in her feet up to her ankles . test applications with analgesic creams revealed that baclofen 5% cream had a more profound pain reducing effect compared with two other compounded analgesic formulations : clonidine 0.2% cream and lidocaine 3% combined with isosorbide dinitrate 0.4% cream . the pain could be reduced to 3 on the nrs , although allodynia was still present . following ketamine 10% cream application , the patient received phenytoin 5% cream and was asked to compare the pain reduction of this new cream with baclofen 5% cream . before application of both creams the time of onset for baclofen 5% cream was 20 minutes and for phenytoin 5% cream was 30 minutes . the patient scored her pain reduction for baclofen 5% cream from 7 to 3 on the nrs and for phenytoin 5% cream from 7 to 0 on the nrs . this effect resulted in a reduction of oxycodone from 20 to 10 mg daily , and gabapentin from 2000 to 1600 mg daily . she applied the phenytoin 5% cream three times daily during 1 month . in october 2016 , she received phenytoin 10% cream to test whether a higher concentration of phenytoin resulted in a more profound effect . after application of the phenytoin 10% cream , the time of onset for analgesia decreased , and within 1015 minutes she experienced a reduction of pain from 7 to 0 on the nrs . furthermore , duration of the effect was increased to 6 hours after the new phenytoin 10% cream application . antiepileptics are effective systemic analgesics for neuropathic pain , and pregabalin and gabapentin are most well known in this class . however , in our hands , topical gabapentin 10% cream was not very effective . therefore , we selected one of the most senior of all antiepileptics , phenytoin , which targets , among others , the voltage - gated sodium channels as the active pharmaceutical ingredient for a new compounded topical cream.21 topical phenytoin had an impressive analgesic effect as described in the following cases . all patients signed an informed consent for approval to publish their cases on topical phenytoin anonymously . a 69-year - old male suffered since 2007 from peripheral neuropathic pain in both fore feet due to diabetes mellitus type ii . he scored his average pain as 9 on the 11-point numerical rating scale ( nrs ) . his pain was characterized by burning , electric shocks , tingling , pins and needles , allodynia when soft stroking , and hand in hand , there was a numbness ( anesthesia dolorosa in the pain area ) . especially , his allodynia on his left foot was bothering him in the night , and he scored this annoying symptom with 10 on the nrs . we prescribed compounded ketamine 10% cream.22 this resulted in a reduction of allodynia to 3 on the nrs , within 25 minutes after application . the reduction of pain lasted 6 hours , after which he woke up and had to apply the cream again . phenytoin 5% cream reduced the allodynia and other pain symptoms to 3 on the nrs with an onset of action of 5 minutes with the duration of effect of 8 hours . after application of phenytoin 10% cream , he did not experience allodynia or other pain symptoms during the night anymore ( 0 on the nrs ) . the pain reduction appeared within 5 minutes after application and was maintained for at least 12 hours . the patient applied the phenytoin 10% cream two times daily during a period of 3 months . a 71-year - old male suffered since 2008 from ciap , which worsened after chemotherapy vincristine for the treatment of a non - hodgkin lymphoma in 2010 . the characterization of the pain was tingling , pins and needles , electric shocks , burning and cramps within the legs , as well as anesthesia dolorosa . we tested our compounded creams : baclofen 5% , amitriptyline 5% , and clonidine 0.2%.16,17,23,24 however , none of these creams could reduce the pain totally , though he experienced adequate analgesia ( 24 on the nrs ) the following 2 years . in 2013 , prostate cancer was diagnosed for which he underwent local radiation therapy , and he also received the antitestosterone agent leuprorelin ( eligard ) . his neuropathic pain in his right foot recurred and the prescribed analgesic creams lost most of their analgesic effects . phenytoin 5% cream , however , could reduce the tingling , pins and needles , and burning pain within 20 minutes , and the effect was scored as a reduction of pain from 8 to 3 on the nrs . he also perceived a cooling effect of phenytoin 5% cream , and the duration of the effect was longer than the other analgesic creams , at least 5 hours . his sleep quality improved considerably . before the use of phenytoin 5% cream , he scored 6 on the nrs with regard to interference of his pain on his sleep ( 0 no interference and 10 complete interference ) . after application in may 2016 , a 54-year - old female received chemotherapy treatment ( bortezomib ) because of immunoglobulin light chain amyloidosis . due to neuropathic pain in both hands , the treatment had to be stopped after five injections . the neuropathic pain in the hands diminished ; however , the patient developed neuropathic pain in both feet in may 2016 . she described her pain as burning , painful cold , tingling , and pins and needles . the patient received gabapentin 2000 mg daily , oxycodone 20 to 30 mg daily to reduce the pain , though she scored still 8 on the nrs in august 2016 . other medications , such as amitriptyline and tramadol , did not have any analgesic effect . the sensation of warm and cold was disrupted in her feet up to her ankles . test applications with analgesic creams revealed that baclofen 5% cream had a more profound pain reducing effect compared with two other compounded analgesic formulations : clonidine 0.2% cream and lidocaine 3% combined with isosorbide dinitrate 0.4% cream . the pain could be reduced to 3 on the nrs , although allodynia was still present . following ketamine 10% cream application , allodynia disappeared . in september 2016 , the patient received phenytoin 5% cream and was asked to compare the pain reduction of this new cream with baclofen 5% cream . before application of both creams , she scored her pain 7 on the nrs . the time of onset for baclofen 5% cream was 20 minutes and for phenytoin 5% cream was 30 minutes . the patient scored her pain reduction for baclofen 5% cream from 7 to 3 on the nrs and for phenytoin 5% cream from 7 to 0 on the nrs . this effect resulted in a reduction of oxycodone from 20 to 10 mg daily , and gabapentin from 2000 to 1600 mg daily . she applied the phenytoin 5% cream three times daily during 1 month . in october 2016 , she received phenytoin 10% cream to test whether a higher concentration of phenytoin resulted in a more profound effect . after application of the phenytoin 10% cream , the time of onset for analgesia decreased , and within 1015 minutes she experienced a reduction of pain from 7 to 0 on the nrs . furthermore , duration of the effect was increased to 6 hours after the new phenytoin 10% cream application . to our knowledge , this is the first report of the efficacy and safety of topical 5% and 10% phenytoin cream in reducing neuropathic pain . oral use of phenytoin for patients with facial neuralgia was first described in 1942 by bergouignan.25 low - quality small randomized controlled trials ( rcts ) ( n=40 and n=12 ) of oral phenytoin for diabetic neuropathic pain had mixed results.26,27 an interesting double - blind crossover rct with intravenous infusion of 15 mg / kg phenytoin over a 2-hour period showed significant reduction in neuropathic pain.28 this reduction in overall pain persisted for 1 day after infusion , whereas 4 days after infusion , shooting pain was still reduced . pain relief with phenytoin in this study was significantly longer than both the infusion period and the plasma half - life of phenytoin . other topical analgesic creams gave overall good pain reduction , though sometimes patients had to apply the analgesic cream every other hour to maintain the analgesic effect . the use of topical phenytoin is known for the reduction of pain due to superficial burns and chronic leg ulcers.29 topical phenytoin is also known to accelerate wound healing.30,31 however , the analgesic effect of topical phenytoin in neuropathic pain has never been reported , and thus seems to be totally overlooked . the basis of the topical phenytoin formulation is a nongreasy moisturizer and does not contain any perfumes . to date , one of phenytoin s side effects , the gingival overgrowth , resulted in the focus on wound healing.32 wounds ( in rat models ) treated with topical phenytoin , tissue edema , and inflammatory cell infiltration were significantly decreased ; epidermal growth factor , vascular endothelial growth factor , and transforming growth factor- were significantly increased.33,34 as phenytoin is an established anticonvulsant since 80 years , most mechanistic studies have been conducted in the 60s , 70s , and 80s of last century.20 its mechanism of action is not yet completely understood , and most authors focus only on the inhibitory effects of phenytoin in voltage - activated sodium channels , leading to reduction of firing of depolarized neurons.21 it is thought that phenytoin blocks sodium channels poorly at slow firing rates allowing normal activity , but suppresses the high - frequency repetitive firing.21 phenytoin ( ic50=40 m ) has six times stronger sodium channel binding activity than lidocaine ( ic50=240 m).35 voltage - dependent l - type calcium channels are also inhibited by phenytoin.36 furthermore , phenytoin potentiates gamma - aminobutyric acid ( gaba)-induced current through modulation of the gabaa receptor in the nanomolar range.37 our cases demonstrate that topical applied phenytoin cream can reduce neuropathic pain considerably , sometimes even better than other topical analgesics and in this case series in nonresponders to various other analgesics . the analgesic potential of topical phenytoin cream 5%10% in neuropathic pain should be evaluated in well - controlled randomized clinical trials .
we developed and tested a new putative analgesic cream , based on the anticonvulsant phenytoin in patients suffering from treatment refractory neuropathic pain . 
 the use of commercial topical analgesics is not widespread due to the facts that capsaicin creams or patches can give rise to side effects , such as burning , and analgesic patches ( e.g. , lidocaine 5% patches ) have complex handling , especially for geriatric patients . only in a few countries , compounded creams based on tricyclic antidepressants or other ( co-)analgesics are available . such topical analgesic creams , however , are easy to administer and have a low propensity for inducing side effects . 
 we , therefore , developed a new topical cream based on 5% and 10% phenytoin and described three successfully treated patients suffering from neuropathic pain . 
 all patients were refractory to a number of other analgesics . in all patients , 
 phenytoin cream was effective in reducing pain completely , without any side effects , and the tolerability was excellent . 
 the onset of action of the phenytoin creams was within 30 minutes . 
 phenytoin cream might become a new treatment modality of the treatment of neuropathic pain .