Pain is a strikingly prevalent symptom in our society. It has been estimated that 20.4% of American adults have chronic pain of various etiologies [1
]. Approximately half of these people have neuropathic pain secondary to small fiber neuropathy (SFN) caused by damage of small diameter somatic nerve fibers, which carry pain and temperature information, and small autonomic fibers involved in regulating sympathetic and parasympathetic nervous system functions (e.g., cardiovascular and sweat functions) [2
]. This disorder is associated with many different types of neuropathy including metabolic, autoimmune, inflammatory, infectious and toxic etiologies, as well as with fibromyalgia [3
]. One of the most common causes of peripheral neuropathy associated with SFN is diabetes mellitus. About half of the patients with diabetes mellitus develop peripheral neuropathy, and about one in three of these patients experience neuropathic pain [1
]. Diagnosis in these patients is often missed as the neuropathy may precede clinical evidence of diabetes [4
]. The mechanisms of diabetic neuropathic pain are still not fully clear, with both genetic and environmental factors involved [5
Painful SFN is difficult to treat. Currently, the first line of treatment for neuropathic pain involves antidepressants such as serotonin norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs) and anticonvulsants (such as gabapentin and pregabalin) [5
]. However, overall, only about 50% pain relief is achieved in less than half of the patients treated with one of these agents, and many discontinue treatment within a few months due to poor tolerability [9
], indicating the need for more effective treatments.
Topical therapies have had mixed results, but lidocaine, capsaicin and amitriptyline show promise [13
]. Opioids have been used, but their use is controversial and may not be effective [14
]. Because monotherapy in general is unsatisfactory, attempts were made to utilize combination therapies. Treatment with an anticonvulsant combined with an antidepressant, both at lower doses, may be more efficacious than either alone [15
]. This also indicates that the combination treatment targets more mechanisms that may underlie the complex disease pathology [16
There clearly is an urgent unmet need to develop safer and more effective therapies for neuropathies and neuropathic pain. To this end, we sought to assess the effectiveness of the neuroprotective dietary ingredient agmatine [17
] in treating neuropathies associated with painful small fiber neuropathy.
Substantial preclinical evidence suggests the utility of agmatine in treating a wide spectrum of complex nervous system diseases [20
]. Previous clinical trials showed that oral agmatine sulfate treatment is safe and effective in reducing neuropathic pain and improving health-related quality of life in lumbar disc-associated radiculopathy (sciatica) [22
]. These clinical studies served as a proof-of-concept for using dietary agmatine as a nutraceutical for neuropathies.
Agmatine, decarboxylated arginine [(NH2
C(NH= )NH], is a ubiquitous molecule found in low amounts in a wide variety of plant-, fish- and animal-derived foodstuffs [24
]. Additionally, gastrointestinal (GI) bacteria produce agmatine and the significant concentrations of agmatine found in the GI tract implicate microbial production as the main source of systemic agmatine [25
]. Animal studies demonstrated that exogenous agmatine sulfate, the commonly used salt form of agmatine, is absorbed in the GI tract and then rapidly (within minutes) distributed throughout the body, including the brain [20
]. In humans, ingested agmatine is readily absorbed and eliminated unmetabolized by the kidneys, with an apparent blood half-life of about 2 h [27
Agmatine is principally metabolized into urea and putrescine, the diamine precursor of polyamines, which are essential for the viability of nerve cells [28
]. Additionally, agmatine can also be oxidized, resulting in the formation of agmatine-aldehyde, which may be toxic and secreted by the kidneys [29
]. This latter route is tissue specific, being significant in some tissues [26
], but minor in others [30
], and apparently negligible in the central nervous system [25
It is postulated that, like a ‘molecular shotgun’, agmatine exerts its salutary effects by modulating multiple molecular targets including: several neurotransmitter receptors and receptor ionophores; key ionic channels and membrane transporters; nitric oxide (NO) formation; polyamine metabolism; protein ADP-ribosylation and hence signaling pathways; matrix metalloproteases (MMPs); enzymes implicated in nerve cell death and neuropathic pain; and advanced glycation end (AGE)-product formation, a process involved in the pathology of diabetes and neurodegenerative diseases [20
]. Conceivably, agmatine may modulate its molecular targets both at the peripheral and the central nervous system levels.
A concerning caveat of the previous clinical trials was that after the short two-week treatment period, the effectiveness of agmatine treatment gradually dissipated [23
]. This suggested that treatment should continue for as long as symptoms persist. Reports from hundreds of people who use agmatine sulfate treatment on their own cognizance (unpublished observations), support the implications of these clinical trials. Namely, the treatment is effective in alleviating symptoms in several types of neuropathy, including diabetic neuropathy and idiopathic neuropathy—which are known to involve small fiber pathology [3
]—and that in order to maintain effectiveness, agmatine treatment must continue for as long as symptoms persist.
Therefore, in the present study, we set up a study to assess the effectiveness of a two-month long oral agmatine sulfate treatment for patients diagnosed with neuropathies associated with painful SFN.
The results of the present study provide evidence that a two-month treatment with the neuroprotective dietary ingredient agmatine sulfate is effective in alleviating neuropathic pain in patients suffering from neuropathies associated with painful SFN. The results indicate that agmatine treatment should continue for as long as symptoms persist and corroborate previous observations [22
] showing that dietary agmatine sulfate treatment lacks any significant side effects. The findings also lend support to unpublished observations of hundreds of people who are, on their own cognizance, using long-term (years) agmatine sulfate treatment for various types of neuropathy involving SFN.
All participants who entered this open-label consecutive case series study had neuropathy associated with SFN as adjudged by reduced numbers of nerve fibers in skin biopsies and by abnormal autonomic nerve functions using the ANSAR and QSART [7
]. The painful symptoms in all patients were confirmed to be neuropathic using accepted criteria of the 12-item questionnaire (NPQ) and calculated changes in pain descriptors (TDF), which distinguish neuropathic pain from other types of pain according to Krause and Backonja [36
The symptoms most clinically associated with neuropathic pain numbness, tingling and burning [36
] showed the greatest response to treatment with agmatine, suggesting that these neuropathic pain descriptors are associated with SFN involving autonomic nerves. Reductions in the categories least considered characteristic of neuropathic pain—electric, squeezing and increased pain due to touch [36
]—did not reach statistical significance after agmatine treatment.
Ample evidence indicates that agmatine sulfate can modulate multiple molecular targets implicated in neuroprotection and in mitigating neuropathic pain [20
]. These include modulation of key neurotransmitter receptors [including nicotine, N-methyl-D-aspartate (NMDA), imidazoline and α2-adrenoceptors], ionic channels (including potassium and calcium channels), cell signaling pathways (by inhibiting ADP-ribosylation of proteins), nitric oxide (NO) synthesis, polyamine metabolism and extracellular protein modifications (by inhibiting matrix metalloproteases and advanced glycation end (AGE)-product formation) [20
]. The spectrum of molecular mechanisms underlying painful SFN may be even broader [38
]. With this body of evidence taken together with the fact that anti-inflammatory drugs are ineffective [4
], the results of the present study further validate the notion that agmatine exerts its salutary action on nervous system-associated processes, rather than by acting on inflammatory mechanisms [20
Peripheral neuropathies associated with painful SFN are complex, difficult to treat conditions, which often require a drug combination treatment. The first line of treatment involves antidepressants such as SNRIs (serotonin norepinephrine reuptake inhibitors), or TCAs (tricyclic antidepressants) and anticonvulsants (such as gabapentin and pregabalin) [4
]. Interestingly, substantial preclinical evidence indicates that agmatine treatment exerts antidepressant and anti-seizure effects in animal models of depression and epilepsy, respectively [20
]. Additionally, one clinical case study reported the antidepressant effects of oral agmatine sulfate in three patients [39
]. Based on the cumulative evidence, it is postulated that ingested agmatine sulfate exerts its beneficial effects by interacting simultaneously like a ‘molecular shotgun’ with multiple molecular mechanisms critical for neuropathic pain [23
]. Agmatine is readily absorbed [26
] and may modulate these molecular targets in both the central and peripheral nervous systems [41
While the results of this study are encouraging, there are several major limitations, as follows. (1) It was an open-label uncontrolled study. For example, a randomized placebo-controlled study would account for the possible effects of concomitant treatments. (2) It consisted of a small sample size. For example, a larger sample would enable the assessment of gender, age or BMI differences. (3) It did not employ objective follow-up measures such as skin biopsies, ANSAR and QSART measures to assess whether neuropathic pain improvement measures are associated with the structure and function recovery of small nerve fibers; in this regard, longer follow-up periods than the two-month period used in the present study will be required.
In summary, this pilot study suggests that agmatine sulfate has a significant effect in reducing overall pain intensity in patients with SFN resistant to treatment with conventional neuropathic pain medications. The inadequate effectiveness of current pharmacotherapy underscores the importance of the continued research and development into agmatine as a novel treatment for neuropathies. Further randomized placebo-controlled studies, conducted over properly extended periods with adequate numbers of participants, are required to establish agmatine sulfate as a preferred treatment.