Role of Different Pain Killers in Control of Diabetic Neuropathy Pain-A Review

fifty percent in subjects suffering from this disease, depending on the technique utilized for diagnosis. Additionally, DM has remained the top causative factor of polyneuropathy in the modern world. As much as fifty percent of the polyneuropathies are related to DM. It is more common in chronic DM: it negatively impacts the quality of life (QOL) in those suffering from it. Polyneuropathies cause chronic neuropathic pain, resulting in depression, anxiety, and insomnia among sufferers. Diabetic neuropathy is a painful and disabling condition that has enormous incurring costs in terms of disrupted quality of life and financial implication while treating its complications. Various pain killers have been tried in this regard with varying results. Aim of this review was to delve into various drugs outcomes in this regard.


Introduction
Diabetic neuropathy (DN) is a frequent complication of diabetes mellitus (DM). It has an approximate prevalence ranging from thirty to fifty percent in subjects suffering from this disease, depending on the technique utilized for diagnosis [1]. Additionally, DM has remained the top causative factor of polyneuropathy in the modern world. As much as fifty percent of the polyneuropathies are related to DM [2]. It is more common in chronic DM: it negatively impacts cause chronic neuropathic pain, resulting in depression, anxiety, and insomnia among sufferers [1,2]. Diabetic polyneuropathy is defined as "phenomenon of symmetrical, distal and progressive degeneration of the sensorimotor and autonomic peripheral fibers, due to metabolic and microvascular changes in as a result of chronic hyperglycemia (DM) and other cardiovascular risk factors" [1].
More than four hundred million people are suffering from diabetes mellitus globally (3). Out of them, up to one-quarter fall prey to chronic painful diabetic neuropathy (PDN). Wherein they present with symptoms of neuropathic pain, continuous or intermittent more than three months [2,4]. Generally, the pain starts distally, is remarkably unpleasant at night, and follows a proximal and symmetrical progression: discomfort initially starts the toes, feet, then follows ankles. Patients' description of this pain is a "burning" sensation accompanying by a feeling of tingling. Uncommonly, it may manifest as allodynia (sensitive to touch such as combing hair), wherein normal activities lead to pain [4][5][6]. Hitherto, its diagnosis and treatment are a troublesome task. It is challenging and is still a debatable issue. It is of note here that up to more than one-third of subjects who have PDN did not receive a suitable treatment strategy for their pain, while every eight patients did not even go to a doctor for seeking help in this regard [4]. The effectiveness of different regimens for this disease has shown mixed results. More work is required in this regard.

Methods
We did search on PubMed, Medline database publications using: Painful diabetic neuropathy, Pain control, painkillers, chronic pain, Management. The publications included were special communications, reviews, conferences papers, books, and research studies regarding the subject matter over last twenty-five years.

Discussion
Diabetic neuropathy is a painful and disabling ailment that has enormous incurring costs in terms of disrupted quality of life and financial implication while treating its complications.
Its prevalence is unalike in different parts of the world ascribable to the heterogeneity of population and differences in healthcare systems, financial restraints, and social cognizance. Gabapentin monotherapy has established itself to be effectual and nicely tolerated when used for the care of pain and sleep disturbance in patients with diabetic polyneuropathy (DPN). Various studies have supported the role of gabapentin in this regard. In one RCT, gabapentin and amitriptyline were compared as monotherapies and deduced that both were equally efficacious in pain control in diabetic PN [13]. While another study showed that neither gabapentin nor nortriptyline was more effective as monotherapy when compared to combination therapy of both [14]. Pregabalin has been frequently studied as a monotherapy for the management of painful Polyneuropathy [15,16]. A study compared the effects of pregabalin and amitriptyline in patients with painful DPN, and both therapies were found safe and efficacious as monotherapies [17].
It is noteworthy that side effects were observed less frequently Regarding the potential role of pregabalin as monotherapy in prediabetic small-fiber neuropathic pain, when compared to placebo [19].
Other anticonvulsants drugs such as topiramate provided pain control in a better way as compared to the placebo in patients who had moderate intensity of diabetic neuropathic pain [32].
Lacosamide is another safe drug that can be effective monotherapy for the treatment of DPN either as a monotherapy or as an add-on [21,22]. The role of Lamotrigine, as monotherapy, has not been much of a success in the management of painful DPN (23,24 Oxcarbazepine, Levetiracetam, perampanel, and other experimental anticonvulsants, such as ABT-639 and PF-05089771, did not show much of a value in the treatment of Polyneuropathic pain [27,28].

Antidepressants such as Serotonin-Norepinephrine Reuptake
Inhibitors, Tricyclic, and Tetracyclic Antidepressants Tricyclic (TCAs), and tetracyclic antidepressants (TeCAs) have also been tried in this regard. In one RCT [29], venlafaxine manifested its effectuality in controlling painful Diabetic Polyneuropathy pain at high doses as compared to low doses (150-225 mg daily vs 75 mg daily). In yet another study venlafaxine was found to be inferior to pregabalin in this regard [30]. Duloxetine monotherapy was found to be an equally potent agent as gabapentin for the treatment of Diabetic Polyneuropathy pain, however with much better tolerability [31]. Likewise, duloxetine showed efficacy comparable to pregabalin for the treatment of such pain [32]. Tricyclic and Tetracyclic Antidepressants Tricyclic (TCAs) and tetracyclic antidepressants (TeCAs) have shown mixed results in studies relating to the management of painful DPN [33]. Opioids such as tramadol are efficacious as monotherapy or in combination therapy with paracetamol or acetaminophen in ameliorating poly neuropathic pain [34]. The beneficial effects of oxycodone/naloxone have not been much confirmed. In a study, dextromethorphan/quinidine as monotherapy resulted in amelioration of pain due to DPN [35].
Topical application of Capsaicin has been utilized either in form of a patch or a lotion in varying strengths. Studies have depicted the effectuality of topical application of capsaicin in pain reduction due to diabetic neuropathy. On the other hand, few studies were of the view that capsaicin lotion did not attain a statistically significant pain control in patients having Diabetic neuropathy [36]. Utilization of glyceryl-trinitrate spray [37] and isosorbide dinitrate spray has shown a statistically significant, but momentary, pain-relieving effect and amelioration in the burning sensation when used in subjects who from painful Diabetic neuropathy pain. Ketamine/ amitriptyline cream and Topical clonidine as add-on drugs, did not attain significant amelioration of pain [38]. Utilization of Botulinum Toxin Type A as intradermal injection (on dorsum of foot) resulted in attaining adequate pain control, when used in subjects with diabetic neuropathy pain [39,40]. Few other therapies without strong evidence include use of herbal therapies such as topical application of nutmeg extract oil in controlling of pain due to diabetic neuropathy pain. Great caution must be observed when prescribing chronic guideline medications since they may cause significant side effects in patients with pre-existing disease. These

Conclusion
Various pharmacological agents are effective in treating diabetic polyneuropathy pain. There has been a moderate decrease in pain after using these drugs. More RCTs are required to explore safer and optimum options in this regard.