A Metabolic Disorder Posing Serious Threat Worldwide - Literature review Example

Introduction Diabetes is a metabolic disorder that affects more that 171 million people around the globe today.51 The prevalence of diabetes is so high that according to the statistics from the Center for Disease Control (CDC), approximately six million people will develop this disease every year.22 This means that by year 2025, more than 300 million individuals will suffer from diabetes and its complications.22 In the United States alone, diabetes ranks as the 6th leading cause of death and places 3rd as the most fatal in some of the ethnic populations.5 This alarming increase in the occurrence of diabetes, according to the World Health Organization (WHO), may be a function of lifestyle and health behavior changes, genetic factors, and diet.16,48,49 The high morbidity of diabetes is due greatly to the chronic complications it brings about.19,27,32 Diabetes, if not properly controlled often causes hyperglycemia, coronary heart disease, stroke, renal failure, atherosclerosis, retinal damage, circulatory ailments, ulcerations, and leg amputation.27,49 Diabetes-associated complication that continues to cause a major concern among clinicians is diabetic neuropathy, a painful problem characterized by a mixture of motor, sensory and autonomic nerve fibre abnormalities which occurs in approximately 60% of diabetic patients.8,29 Over the years, several therapeutic agents and disease-management protocols have been made available for diabetic individuals experiencing painful diabetic neuropathy. These include, among others, the use of antidepressants, topical agents, anticonvulsants, and opioid-based therapies that all have undergone placebo-controlled studies in patients afflicted with diabetic neuropathy.8, 33, 35 Despite this, the use of these pharmacological agents is limited by their debilitating side-effects.8 A comprehensive review conducted by Feldman et al (2008) revealed that tricyclic and tetracyclic agents (TCAs) like amitriptyline, are still considered as the first line of treatment for diabetic neuropathy.8 However, several clinical trials have provided strong evidence that TCAs are actually not well-tolerated in older patients and may pose serious threats in patients with cardiac arrhythmias, congestive heart failure and urinary retention.8 In the early 1990s, a new generation of anti-neuropathic drugs have emerged that were reported to be safer compared to the conventional treatments, but also exhibited high efficacy. Among these drugs, the structurally-related pregabalin and gabapentin compounds have generated considerable clinical interest among health care providers.10,13,41 Both agents were found to be derivatives of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) and selectively bind to a subunit of voltage-gated calcium channels to inhibit release of glutamate and noradrenaline, resulting in analgesic and anticonvulsant actions.4,41 This paper aims to review existing clinical studies and literature involving the use of pregabalin and gabapentin in the treatment of diabetic neuropathy in order to assess their efficacy. Specifically, this paper seeks to determine if pregabalin is a better choice of treatment over gabapentin in the management of diabetic neuropathy. Review of Literature Diabetes, as defined by the World Health Organization (WHO), is a chronic metabolic disease characterized by elevated blood sugar levels which is caused by deficiency in insulin production, insufficiency in insulin uptake, or both.52 Diabetes is classified into two categories: Type I or insulin-dependent diabetes and Type II or non-insulin-dependent diabetes.51,52 In both cases however, patients experience a wide range of complications, such as blindness, kidney failure, coronary heart disease, and diabetic neuropathy.6 Healthcare practitioners acknowledge neuropathy as among the most common and costly complications of both Type I and Type II diabetes.47 Diabetic neuropathy, which is characterized by progressive loss of nerve fibre integrity and function, may be grouped under two general types according to the anatomical distribution of damage: diffused or focal neuropathy.8 Diffused neuropathy, the most common, chronic and progressive type is represented by Diabetic Polyneuropathy (DNP) and Diabetic Autonomic Neuropathy (DAN).8 Focal forms of diabetic neuropathy include mononeuropathy, mononeuropathy complex, plexopathy, radiculopathy, and carinia neuropathy. Although it covers a variety of forms, diabetic neuropathy in general, causes continuous burning and painful sensation, ulcerations, restricted mobility and is associated with abnormal sensory functions such as allodynia (i.e. perception of pain from non-painful stimulus).23,35,47 In fact, according to Rice et al (2001) diabetic neuropathy is the number one cause of non-traumatic leg amputations.35 The anti-convulsant, anti-nociceptive, and anxiolytic drug, gabapentin, originally developed for the treatment of epilepsy, is now a widely used pharmacological agent for the management of painful diabetic neuropathy.1,30 Gabapentin is a structural derivative of the neurotransmitter gamma-aminobutyric acid (GABA).38 Studies have illustrated that gabapentin binds to alpha-2-delta subunits of voltage-dependent calcium ion channels, subsequently blocking central sensitization and occurrence of hyperalgesia.17,25 Specifically, this drug attenuates synaptic transmission by inhibiting the influx of calcium ions in Voltage-Operated Ca2+ Channels (VOCC).18 Many clinical trials and research studies using animal models have demonstrated and confirmed the efficacy of gabapentin in reducing pain.9,38,42 A study conducted by Sist et al (1997) on the effect of gabapentin on neuropathic pain in the head and neck, showed gabapentin to be 80% effective in all the cases being observed.42 Dizziness, sedation and weight gain have been described as the most common side effect of this drug.14,20 Similar to gabapentin, pregabalin is a compound that shares structural similarity to gamma-aminobutyric acid (GABA), and was licensed in mid-2004 for the treatment of seizures and neuropathic pain.41 Pregabalin also acts through inhibition of calcium ion currents by binding on alpha-2-delta subunit of voltage-gated ion channels.41 The use of this drug in pain management has been supported by preclinical and clinical studies.12,36 For instance, Freynhagen et al (2005) reported that pregabalin is superior compared to placebo treatments in reducing pain caused by Post Herpetic Neuralgia (PHN) or painful Diabetic Peripheral Neuropathy (DNP).12 Pregabalin also exhibits minimal adverse effects such as peripheral oedema, weight gain, and dizziness.46 Critical Analysis The popularity of gabapentin as the choice of medication in the management of diabetic neuropathy is mainly due to its high specificity without causing harmful damage to the patients.40,41,42 In a study conducted by Rowbotham et al (1998), 229 patients were randomly assigned to either he gabapentin or placebo group.37 They reported that during the eight-week trial period, patients treated with 3600mg gabapentin showed remarkable daily reduction in pain scores (0–10 scale) from 6.3 to 4.2.37 The reduction in pain experienced by the gabapentin-treated patients was considered significant compared to the placebo group, which only achieved a half point reduction. The researchers also computed for the NNT (number needed to treat) of gabapentin, an epidemiological measure used to evaluate the efficacy of a particular intervention. 37 The higher the NNT, the less effective the intervention is. Based on the data of Rowbotham et al, gabapentin NNT for benefit is 3.2. 37 By using a simple yet effective experimental design and a considerable number of subjects, Rowbotham’s research team clearly demonstrated that gabapentin can significantly reduce neuropathic pain. However, what the study lacked is a comparison between gabapentin and a known anti-pain drug. The results gathered by Rowbotham and his team parallel the findings of other researchers.2,26 In 2002, Serpell conducted a double-blind, placebo-controlled trial to further assess the efficiency of gabapentin at a dose (2400mg/day) lower than what Rowbotham et al used.40 In this study, participants (N=305) with two of the following symptoms: burning pain, allodynia, and shooting pain were randomized to placebo or gabapentin treatments. Results showed that the gabapentin group experienced a 21% reduction in pain scores as compared to the 14% in the placebo group. Although the study further reinforced the findings of Rowbotham et al regarding the anti-pain properties of gabapentin Serpell’s experimental design was quite interesting because its inclusion criteria were according to the presence of specific neuropathic symptoms rather than simply the presence of the syndrome itself. Apart from efficacy-related studies, several research endeavours have also been directed to determine the side-effects of gabapentin use. For instance, Steinhoff et al (1997) looked at 10 medical cases and observed that only two patients (with cerebellar abnormalities) developed ataxia after gabapentin administration.44 Even though the number of subjects involved in the study is very low, nevertheless, gabapentin was still proven to be tolerated by majority of the patients. Mclean et al (1999) also provided evidence that gabapentin evokes mild side reactions.28 Mclean and his team conducted a safety and tolerability study of gabapentin and reported that their subjects (N=312) experienced one of the following side effects: somnolence, dizziness, asthenia, headache, ataxia, and weight gain.28 What is commendable about this particular study is that the researchers were able to monitor the patients for a long period of time and noted the physical changes that cannot be observed at a short observation period. In contrast, to Steinhoff’s research, Mclean and his team used a high number of patients, which increased the reliability of their results. Nonetheless, both studies showed that gabapentin is safe to use as indicated by the mild and tolerable side effects the drug demonstrates. Like gabapentin, many studies have provided clear proof for the effectiveness and tolerability of pregabalin in the treatment of diabetic neuropathy.11,21,47 Baron et al (2008) conducted an open label, flexible-dose study on the efficacy and safety of pregabalin in patients with diabetic peripheral neuropathy.4 A total of 217 outpatients were subjected to pregabalin treatment at a starting dose of 150mg/d increasing to 300 mg/d after one week for 4 weeks.4 The researchers found out that pregabalin improved pain, anxiety and general state of the patients. They also noted that like gabapentin, pregabalin was well tolerated by the patients.4 Baron’s findings were also supported by Freeman et al (2008).11 Freeman’s team conducted a meta-analysis study on the efficacy, safety, and tolerability of pregabalin on Diabetic Peripheral Neuropathy (DPN) using data from seven randomized, placebo-controlled trials.11 Analysis showed that pregabalin significantly reduced pain and pain-related sleep interference associated with DPN (150, 300, and 600 mg/day vs. placebo). Similar to what was observed in gabapentin-treated patients; the most common adverse effects of pregabalin were dizziness, somnolence, and peripheral oedema.11 In addition, Freynhagen et al (2005) computed for the NNT of pregabalin and was found to be 3.6, very close to the NNT value of gabapentin.12 The findings of the these studies clearly support the fact that pregabalin is an effective pharmacological agent for the treatment of neuropathic pain, with only minimal side effects. Also, Baron’s approach on using a flexible dose treatment suggested that pregabalin works over a good range of concentration. However, it might also be informative to compare the efficacy of pregabalin to a known positive control, which both studies did not consider. Although gabapentin and pregabalin both act by inhibiting voltage-gated calcium channels; and both demonstrate high efficiency in reducing pain, several studies have noted a slight difference in their pharmacokinetics.15,20,50 For example, Golembeiwski (2007) tabulated the similarities and differences of the two drugs and found out that their only difference lies in the dosage at which pain reduction is manifested.15,20 It appears that for gabapentin, a higher dose is required (max 3600 mg/day) to elicit the same pain reduction with a lower concentration of pregabalin (max 600 mg/day).15 Vera-Llonch actually observed the same phenomenon.50 In a study on the analgesic outcomes in patients with painful diabetic neuropathy, Vera-Llonch et al compared the effects of gabapentin at 1200 mg and 1800 mg/day to that of the effects of 375 mg/ day pregabalin.50 Results showed that compared with no treatment, pregabalin (375 mg/d) yielded an estimated 37 additional days with no or mild pain while gabapentin treatment (1800 mg/d) resulted to 26 days without pain.50 This study clearly suggests that pregabalin requires a relatively smaller concentration to provide relief from neuropathic pain. Moreover, the study suggests that pregabalin might provide better analgesic effects over a 12-week period.50 Feldman explained that the low dose necessary for pregabalin to reduce pain is because it is absorbed faster in the gastrointestinal tract.8 Furthermore, pregabalin has a linear pharmacokinetics which implies a rapid onset of pain relief.8,13 Taken as a whole, it appears that pregabalin might be a better choice for patients experiencing diabetic neuropathy compared to gabapentin. Conclusion Diabetes is a metabolic disorder that continues to pose serious threat worldwide.27,49, 51, 52 In fact, it has been predicted that over 300 million people across the globe will contract diabetes and suffer from its complications by year 2025.22 If not properly controlled, diabetes often leads to complications like heart disease, blindness, leg amputation, and diabetic neuropathy.6 Diabetic neuropathy occurs in approximately 60% of diabetic patients and is a difficult complication to manage.8 Diabetic neuropathy is characterized by progressive damage of nerve fibres and may either be diffused or focal.8 Both cases however, cause pain, restrict mobility and affect sensory perception.23, 35, 47 Gabapentin and pregabalin are two of the most effective pharmacological agents for the management of diabetic neuropathy. Both drugs are analogues of the neurotransmitter gamma-aminobutyric acid (GABA).38,41 Studies have shown that gabapentin and pregabalin provide pain relief by inhibiting the influx of calcium ions by binding to the alpha-2-delta subunit of voltage-operated calcium ion channels.17,25,41 This binding is very specific and the inhibition of calcium mobility leads to an effective decrease in the perception of pain.17 Preclinical trials and controlled clinical trials provide strong evidence for the efficacy of gabapentin and pregabalin in pain management.4,11,37,40 In fact, both gabapentin and pregabalin appear to influence not only pain perception, but also anxiety levels and sleep patterns.28,40 NNT values for gabapentin and pregabalin are closely related to each other: 3.2 for gabapentin and 3.6 for pregabalin.12,37 Aside from high efficacy, gabapentin and pregabalin also exert minimal side effects to the patients.11,28 The side effects of both drugs include: dizziness, headache, sedation, ataxia, and weight gain.11,28 Both drugs are well tolerated by the patients and in all the literature reviewed for this specific paper, gabapentin and pregabalin are labeled safe for use. Although gabapentin and pregabalin share many properties, there still seems to be a slight yet important difference between the two.15,50 Research has it that pregabalin is more quickly absorbed in the gastrointestinal tract compared to gabapentin.50 In addition, the pharmacokinetics of pregabalin fits to a linear model, indicating that pregabalin’s effect kicks in earlier compared to gabapentin.50 These findings suggest that pregabalin provides faster pain relief to patients suffering from neuropathic pain compared to gabapentin. Hence, pregabalin can be considered as a better choice in the treatment of diabetic neuropathy compared to gabapentin. Future Work One aspect that needs further improvement in the use of gabapentin or pregabalin in the control and management of painful diabetic neuropathy is comparing their effects to other anti-pain drugs. So far, in all the literature included in this review, gabapentin or pregabalin was only compared to placebo treatments.11,15,26, 41 Although results of such studies demonstrated the superiority of both drugs in reducing pain, this does not give us any information on whether gabapentin or pregabalin is comparable to other anti-pain agents.40 Most studies involving the use of gabapentin and pregabalin were focused on adult patients and only a few studies have assessed the effects of these drugs on children.3 Although several preclinical trials have determine that both gabapentin and pregabalin are also effective in controlling neuropathic pain in children, none so far has comprehensively evaluated the side-effects of these drugs on their development.24,34,39 Specifically, it might be necessary to investigate the side effects of these drugs to the height potential of growing children. Next, the therapeutic effect of gabapentin and pregabalin on nursing or lactating mothers and pregnant patients should also be carefully studied. So far, only a small number of trials has looked into the tolerability and safety of these drugs both to mothers and their babies.43, 45 In a comprehensive literature review conducted by Tassone et al (2007) on the pharmacokinetics, tolerability, and efficacy of pregabalin, it has been made evident that many aspects in the drug development of pregabalin has been determined, such as effective range of dose, mechanism of action, kinetics of action, side effects, and even drug-to-drug interaction.45 However, according to Tessone, what needs to be determined next are the effects of pregabalin in pregnant and lactating mothers.45 The same situation applies for gabapentin. Recently, in a review conducted by Stefan and Feuerstein (2007) on the properties of some of the most commonly-used anticonvulsant drugs, it was found out that there is only a limited number of studies that look at the effects of gabapentin on lactating mothers.31,43 The author believes that the studies mentioned above, if carefully conducted will help provide a clear picture of the strengths and limitations of gabapentin and pregabalin as treatment for painful diabetic neuropathy. References 1. Arendt-Nielsen et al. Effects of gabapentin on experimental somatic pain and temporal summation. Regional Anesthesia and Pain Medicine 2007; 32: 382–388 2. Backonja, M. and Glanzman, R. Gabapentin dosing for neuropathic pain: Evidence from randomized, placebo-controlled clinical trials. Clinical Therapeutics. 2003; 25: 81-104 3. Bialer et al. Progress report on new antiepileptic drugs: a summary of the Sixth Eilat Conference (EILAT VI). Epilepsy Research. 2002; 51:31-/71 4. Baron et al. 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