Diabetic neuropathy

Introduction

Diabetic neuropathy is a common complication of type one and type two diabetics (Vevas et al.2006). An estimated 4% of United Kingdom population suffers from diabetics, and 50% people living with diabetics' mellitus have diabetic peripheral neuropathy (DPN). Diabetic peripheral neuropathy manifests with painful or painless symptoms, approximately 11% of patients with DPN has chronic painful symptoms that diminish quality of life and has significant impact on health care costs (Argoff et al.2006). The total annual cost attributed to DPN is up to 27% of the direct medical cost of diabetes (Gordois et al.2003).

Gabapentin is an anti-epileptic drug and is widely using for the treatment of diabetic neuropathy (Ermis et al.2009). Food and Drug Administration (FDA) in1994 approved Gabapentin to control partial seizures. In 2002 its indication extended to neuropathies and nerve related pain. The common side effects of Gabapetin include, dizziness, ataxia, somnolence and fatigue (>10%). The side-effects occurs infrequently include (<10%) headache, tremor, diplopia, nystagmus, and nausea (Bilgir et al. (2009). Some case studies also reported rare side effects include hypoglycemia, myopathy, and renal impairment (Dogukan et al.2006), (Pierce et al.2008).

In patients seen in clinical practice, diabetic neuropathy has major impact on quality of life for patients. It appears to have negative impact on sleep, the ability to work effectively, mood, mobility and general enjoyment of life. As part of bio psychosocial treatment the author would like to establish the effectiveness of Gabapentin in treatment diabetic neuropathy. Therefore the aim of this assignment will be to critically evaluate the available evidence regarding the efficacy of Gabapentin versus its side effects in diabetic neuropathic pain.

Search Strategies

A literature search was carried out using the Science direct, Pub Med, Medline, Ovid, Cochrane and Google Scholar for relevant studies in the last 5years and then extended into 10 years. The initial search did not yield enough evidence for the assignment aim. The keyword search included: Gabapentin, Gabapentin side effects, Gabapentin toxicity, diabetic neuropathy, neuropathy, anticonvulsants and combination of key word also used. The search was limited to studies published in English and conducted in human beings. The strength of evidence was established using the Sackets' hierarchy of evidence (1997), (Please see appendix 1). Each of the papers were analysed for validity and rigour according to the framework given by (Rees 1997, cited in Taylor 2009), (Please see appendix 2).

Literature Review

Dallocchio et al. (2000) conducted anopen label studyto compare the efficacy of Gabapentin and Amitriptyline in painful diabetic neuropathy. Twenty-five patients were randomly selected for treatment with Gabapentin and Amitriptyline. Gabapentin produced greater improvements than Amitriptyline in pain and paresthesia associated with diabetic neuropathy (see Table.1).

The efficacy of Gabapetin in controlling pain was significantly better than Amitriptyline. In Gabapentin group the mean final pain score was1.9 lower than baseline score (p&lt;0.01) but in the case ofAmitryptyline group, the mean final pain score was 1.3 lower than baseline score (p&gt;0.01).

The efficacy of Gabapentin in treating paresthesia was significantly better than Amitryptyline. The study result showed that Gabapentin group were scoring 1.8 below the base line value but Amitriptyline group was scoring below 0.9 (See Table.2).

The study also reported Amitrypline caused more side effects than Gabapentin(See appendix3). The study showed successful titration of Gabapentin dosage to achieve maximum effect with minimum side effects. This was lacking in other studies where reported higher incidence of Gabapentin side effects. The study showed that effective maximum dose for Gabapentin was 1785+/-351which also agrees with (Gilron et al.2006).

The adjuvant analgesics like other Tri cyclic anti depressants (TCAs) and other anticonvulsants were discontinued one month prior to randomisation. This set criteria promoted the study rigorous as patients werereceiving only Gabapentin and Amitriptyline during experiment period. An inclusion criteria was set to exclude other neuropathic pain in the sample of diabetic patient. The neuropathic pain in diabetic patients may not be only because of diabetics; it may because of any other conditions like hereditary, inflammatory, and metabolic disorders (Vevas et al.2006). There fore the inclusion criteria filtered the other neuropathic pain and thereby the paper has made an attempt to improve the validity of the study.

Even though the study conducted as a randomised trial,the sample size used in this study may not enough to accept the outcome from the study and generalize the study result. The study with small sample size would not add weight and accuracy when it comes to extrapolating results .It is worth mentioning that the study was not blinded which could introduce the chance of performance bias could have affected the rigour of the study. In the light of nature of study and its evidence it can be classified under 1B in hierarchy of evidence.

Nice guideline 2008 (See appendix 4) considered TCAs are the first line of treatment for diabetic neuropathy. Therefore the study result should not generalise to all TCAs, even-though this study showed disadvantages of Amytriptyllin. However the study showed significant results towards the efficacy of Gabapentin for the treatment of diabetic neuropathy, further larger double blind trial might be required to confirm its efficacy, for clinical practise.

Serpell(2002) conducted a randomised placebo-controlled eight weeks study to evaluate the effectiveness and safety of Gabapentin for neuropathic pain. Three hundred and seven, patients with neurotic pain were enrolled for the study. (See fig:1 for results).

Themean daily pain scores on weekly basis showed statistically significant differencebetweenthe Gabapentin treatment and placebo treatment. Even though the pain scores were statistically significantin first, third, fourth, fifth and sixth weeks seventh and eighth weeks did not show any significant difference in pain scores. The study also evaluated effectiveness of Gabapentin in neuropathic pain related symptoms like allodynia, burning pain, hyperalgesia and shooting pain. All four symptoms improved more after Gabapentin treatment compared with placebo treatment. These symptoms are common in all types ofneuropathic pain. So these findings can be applied to all types of neuropathy. (See appendix: 6 for results)

The study identified various effects of pain has on the quality of life by using SF-36 Health Survey to measure and patients scored significantly better than placebo treatment. This evidence gives more strength to support the application of Gabapentin into clinical practise. (See appendix: 5)

The study was conductedin thirty-five hospital outpatient clinics inUK and Republic of Ireland. The geographical setting where the studyhas been conductedmakes the generalisation of findings to UK patients. The level of perceived pain in different country could be based on social conditioning and other cultural influences. The study sample size(307)minimises the chance of type one and two errors and increases the accuracy and reliability of the result .As this was a randomised controlled study it falls under 1B hierarchy of evidence it is worth mentioning that the study excluded the patients who were non-responded to Gabapentin treatment. Also the study filteredthese patients who were not respondedto Gabapentin treatment it might have affected the rigour of the study and reliability of the results. This study also considered statistics of adverse events occurred during the study, which helps in looking in to efficacy verses side effects in Gabapentin treatment for neuropathic pain (See appendix: 7). The study reportedthat the intensity of adverse events was mild to moderate and which resolved laterin the treatment. The study has been able to successfully replicate the results of the previous studies having positive result effect of Gabapentin treatment with maximum effective dose of 2400 mg/day for diabetic neuropathy.

Bilgir et al. (2009) reported a case of Gabapentin induced rhadomyolysis in a 63year old woman with diabetic neuropathy. This woman was treated with Gabapentin (900mg/day) for her diabetic neuropathy .She presented with severe muscle pain in her extremities, fatigue, decreased urine output, discolouration of urine with in three weeks. Laboratory tests and clinical features confirmed the diagnosis rhadomyotysis and the study reported that the discontinuation of Gabapentin resolved the clinical features (See table3).

The table showed that all the parameters investigated was elevated from pre Gabapentin treatment to post Gabapentin treatment. The abnormal lab result improved after 20 days of treatment. The study reported that the Gabapentin treatment discontinued and patient received haemodialysis during her admission period (20days). However it is difficult to analysis the influence of these interventions on lab reports as the study did not mention anything about the details these interventions or lab reports based on the day of these particular intervention, which could introduce the chance performance bias could have affected the rigour of the study. Even though patient was on several medications for her various health conditions, this paper failed to report about possibility of drug interaction with Gabapentin. Guis et al. (2005) reported that exposure to toxic agents, drugs and drug interactions may cause rhadomyotysis.

The patient presented this study was having moderate renal dysfunction (GFR.48m/Lmin/1.73m2) before Gabapentin treatment, (Dogukan et al.2006) reported that in case of patients with renal insufficiency, it is important to reduce dose as Gabapentin is excreted through kidney. The patient was receiving a dose of 900 mg/d for three weeks but the study fail to mention the started dose and its titration .In case of renal impairment treatment should start with lower dose and titrate the dose with careful monitoring of patient response (Zand et al. (2010).

The paper described an important clinical problem addressed via a clearly formulated question .The study presented with evidence of wide reading and systematic literature review. The method of data collection was not described enough in detail and there was no evidence of ethical dimensions considered in this study (Ethics Committee approval or informed consent) which affects the internal validity of the study.

Even though this case study reported about a potential chance of rhadomyotysis after Gabapentin treatment, as it was a case study it is not possible to generalise the result to clinical practise. It is worth mentioning that there were few more studies reported about rhadomyotysis after Gabapentin treatment. (Tuccori et al. 2007) and (Lipson et al.2005). The study is a case study and hence it classified under Class 3d in the hierarchy of evidence. However there are limitations for this study that has important implications for practice. This case report heightened awareness individual assessment before the initiation of Gabapentin treatment and during the treatment for effective treatment and prevent risks.

Ermis et al. (2008) conducted an observational study to evaluate the effect of Gabapentin on autonomic function in patients with diabetic neuropathy through heart rate variability (HRV). Thirty diabetic nephropathy (>5years) patients were recruited for the study .The patients were monitored using the DMS 300-8 Holter recorder. The study reported that the Gabapentin treatment improved the HRV parameters. (See table 4)

The participants were given written and informed consent and the study was a proved by local Ethics Committee. The selected patients confirmed with diabetic neuropathy by using Diabetic Neuropathy Symptom score. The DNS score is a validated symptom score, with high predictive value for screening diabetic neuropathy (Meijer et al 2003).

The dose was titrated up to 2400mg .The effective dose agrees with maximum effective dose of other studies. It is worth mentioning the fact that it closely agrees with the way clinicians titrated the dosage of Gabapentin which is based on patients response in clinical settings, therefore the application of this study findings makes more feasible into clinical practise.

The analysis of HRV was performed according to the recommendation of the European Society of Cardiology Task Force. The data analysis based on ESC recommendation provided rigour to the study. The statistical analysis was performed using SPSS for window version 11.It might promote statistical power that reduces the chances of type II errors and would have increased the internal validity. The titrated dose of Gabapentin was up to 2400 mg/day and 83.3% patients tolerated. The study reported16.7% patients experienced mild to moderate somnolence or dizziness. Considering the nature of the study it can be classified under 2c the hierarchy of evidence. Existence of HRV suggests five fold increments in mortality rate in diabetic patients (Ziegler, 1999) Further studies needed to investigate the effect of Gabapentin in the diabetic neuropathy patients to improve HRV and decrease mortality.

Hanna et al. (2008) conducted a randomised double blind, placebo controlled trial to evaluate the benefit of adding Oxycodone with Gabapentin treatment. Three hundred and thirty-eight patients with diabetic neuropathy were included in the studyThe selected patients were who had moderate to severe neurotic pain despite receiving Gabapentin at its maximum dose. (See fig:2)

The presented graph explains that the group with Oxycodone and Gabapentin demonstrated a mean reduction in BS-11 pain score of 2.1 boxes by the end the study compared to1.5 boxes in placebo group.

Michigan Neuropathy Screening Instrument was used to confirm the diabetic neuropathy, whichexcludes the chance of inclusion of other neuropathy patients. Short form Pain Inventory was used to assess the pain. The use of valid and reliable assessment tool promotes the rigour of the study. The other weakness of the study is the non- steroidal anti-inflammatory drugs; tri cyclic antidepressants and aspirin were started prior to the study and continued during the study. The effects of these analgesics could have distorted the true effects of Gabapentin and Oxycontin.

The study design was a randomised controlled trial, as it included experiments, which might give rigour to the study. Even though the study was mention about the number of patients withdrawn from study for various reasons, it does not present data for attrition which can introduce the chance of bias The study has been done P value calculation to report the study findings helps to increase the reliability of the findings. The statistical adjustment was performed by ANCOVA it would have eliminated confounding factors and might increase the internal validity. In the light of nature the study design this study falls into class 1b of the hierarchy of evidence.

Multi model therapy with low doses of agents may be more effective with lesser side effects than a high dose of single therapy (Solomon Tesfaye and Dinesh Selvarajah 2009)

Backonja et al.(2002) did a systematic review to examine the effectiveness of Gabapentin for neuropathic pain. The reviewed studies were five randomised controlled studies done in neurotic pain from 1996 till date (See table 5 and 6)

TheGabapentin treatment with dose of&gt;/-1800 was statically better (p&lt;0.001) than placebo treatment. The patients who received less than 1800 mg/day did not have a significantly different from placebo patients Even though this paper reviewed only two studies with diabetic neuropathy it reported that glycemic control was maintained during the treatment, which represented the fact that Gabapentin treatment did not affected to the underlying primary disease. It can promote the feasibility of Gabapentin treatment in to clinical practise for the treatment of diabetic neuropathy.

The review identified the research question in a clear manner which was to identified the effectiveness of Gabapentin for the treatment of neuropathic pain

The reviewed studied reported that he treatment started with600mg/day and the dose titrated up to 2400-3600mg/day. However the difference in maximum effective dose did not show any difference in tolerability. The finding reported only one serious adverse event (fainting) apart from common adverse events

The review included five randomised placebo controlled trials. A review of five studies may reduce the credibility of the study findings. It is worth mentioning that the studies included in the review was not blinded or double blinded. The reliability of the study findings would have been stronger if a method of blinding had been used. This review included randomised control studies ofGabapentin for neuropatic pain from 1966.The applicability to current clinical practise would have been better if authors selected recent studies for the review.

Considering the study design it can be classified under1a under the hierarchy of evidence. The sample sizes of thereviewed studies were more than 150 patients, which represented that the reviewed the studies were withgood power. It interested note that the reviewed studies conducted in UK presented with maximum dose of 2400mg/d, which agrees with nice guidelines especially for the treatment diabetic neuropathy.

Conclusion

The evidence from studies led to the conclusion that successful titration of Gabapentin dosage would achieve maximum effect with minimum side effects.

The available evidence from critically evaluated studies, Serpell(2002) ,Ermis et al.(2008), Backonja et al.(2002) and Dallocchio et al. (2000) recommended that the safe dosage of Gabapentin for the treatment of diabetic neuropathy can be 900/2400mg/day.

It is worth mentioning that the maximum dose titrated up to 3600mg/day Backonja et al. (2002) and it did not make any difference in the occurrence of side effects. So the subjects who fail to respond to recommend dose can be given the maximum dose of 3600mg/day with caution, future studies advisable to confirm this finding. Hanna et al. (2008) reported that co-administration of oxycodone with Gabapentin treatment was clinically significant for diabetic neuropathic patients, which agrees with the fact that multi model therapy with low doses of agents may be more effective with lesser side effects than a high dose of single therapy (Solomon Tesfaye and Dinesh Selvarajah 2009). The impact of Gabapentin treatment in patients lifestyle also need to consider in future studies as only one of the reviewed studies, Serpell(2002) considered this aspect.

The side effects that may occurs during the Gabapentin treatment can be avoid to some limit with a successful of dose titration The common adverse events presented in the reviewed studies were dizziness and somnolence which resolved laterin the treatment. Even though the this assignment discussed only one risk rhadomyolysis ( Ermis et al.(2008). The literature there are evidence of adverse events due to Gabapentin treatment like myopathy, irreversible hearing loss, kidney failure (Dogukan et al.2006), (Pierce et al.2008)

The identification of mechanism responsible for pain in eachpatient and tailor the treatment based on appropriate mechanism and laboratory results. This will reduce the occurrence of side effects and will achieve maximum effect. In clinical practise clinicians titrated the dosage of Gabapentin, based on patient's response. Therefore the application of the study findings makes more feasible into clinical practise. Even though the reviewed studies supported the use of Gabapentin, Nice recommentation2010 did not include Gabapentin for the treatment of diabetic neuropathy, Nice recommended Duloxetine as first line of treatment for diabetic neuropathy.

References

  • Argoff, C. E., Cole,B.E., Fishbain,D.A., Irving,G.A 2006 Diabetic peripheral neuropathic pain clinical and quality of life issues. Mayo Clin Proc, 81(4), pp.3-11.
  • Backonja M, Glanzman L. 2002 Gabapentin dosing for Neuropathic Pain: Evidence from Randomized, Placebo-Controlled Clinical Tials. Clinical Therapeutics. 25: 81-104
  • Bilgir, O., Calan,M.,Bilgar,F.,Kebapcilar,L.,Yuksel,A.,Yildiz,Y.,Sari,I. 2009 Gabapetin- Induced rhabdomyolysis in a patient with diabetic neuropathy. Internal Medicine, 48, pp.1085-1087.
  • Dallocchio, C., Buffa,C., Mazzarello,P., Chiroli,S. 2000 Gabapentin vs Amitripytline in painful diabetic neuropathy: An open-label pilot study. Journal of pain and symptom management, 20(4), pp.280-285.
  • Dogukan, A., Aygen, B., Berilgen, M.S. , Dag, S. , Bektas, S., Gunal, A.I. (2006) Gabapentin-induced coma in a patient with renal failure. Hemodial International, 10(2), pp.168-169.
  • Ermis, N., Gullu, H., Caliskan,M., Unsal,A., Kulaksizoglu,M., Muderrisoglu,H. (2009) Gabapentin therapy improves heart rate variability in diabetic patients with peripheral neuropathy. Journal of diabetics and its complications.
  • Gilron, I. Watson, CPN. Cahill, CM. & Moulin, DE. 2006. Neuropathic pain: a practical guide for the clinician. Canadian Medical Association Journal 175(3), pp. 265-75.
  • Gordois, A., Scuffham,P., Shearer, A., Oglesby,A.,Tobian, A. 2003 The Health Care Costs of Diabetic Peripheral Neuropathy in the U.S. American Diabetes Association, 26(6), pp.1790-1795.
  • Guis, S., Mattei, J.P., Cozzone, P.J., Bendahan, D. (2005) Pathophysiology and clinical presentations of rhabdomyolysis. Joint Bone Spine, 72(1), pp.382-391.
  • Hanna, M., O Brien,C., Wilson, M.C. (2008) Prolonged-release oxycodone enhances the effects of existing gabapentin therapy in painful diabetic neuropathy patients. European Journal of Pain, 12(6), pp.804-813.
  • Lipson, J., Lavoie. S., Zimmerman.D. (2005) Gabapentin-induced myopathy in 2 patients on short daily hemodialysis. American journal of kidney diseases, 45(6), pp.100-104.
  • Meijer, J. M. W., Bosma, E., Lefrandt, J.D. , Links, T.P., Smit, A.J., Stewart, R.E. (2003) Clinical diagnosis of diabetic polyneuropathy with the diabetic neuropathy symptom and diabetic neuropathy examination scores. Diabetics Care, 26(3), pp.697-701.
  • Mg, S. (2002) Gabapentin in neuropathic pain syndromes: a randomised, double-blind, placebo-controlled trial. Pain, 99(3), pp.557-566.
  • NICE. 2008. Clinical Guideline 66 (update of NICE clinical guidelines E, F, G and H) Quick Reference Guide Type II Diabetes: The Management of Type II Diabetes Developed by the National Collaborating Centre for Chronic Conditions [Online]. Available at: www.nice.org.uk/CG [Accessed: 15 March 2010].
  • The Pharmacological Management of Neuropathic pain in non-specialist setting. (2010) Directed by Nice.
  • Pierce, D. A., Holt,S.R., Reeves, D.A. 2008 A probable case of gabapentin-related reversible hearing loss in a patient with acute renal failure. Clin Ther, 30(9), pp.1681-1684.
  • Simpson, D. A. (2001) Gabapentin and venlafaxine for the treatment of painful diabetic neuropathy. J Clin Neuromuscul Dis, 3(2), pp.53-62.
  • Tesfa, S., Selvarajah,D. (2010) Recent advances in the pharmacological management of painful diabetic neuropathy. The British Journal of Diabetes and vascular Disease, 9(6), pp.283-287.
  • Tuccori, M., Lombardo, G., Lapi, F., Vannacci, A., Blandizzi, C., Del Tacca, M. (2007) Gabapentin-induced severe myopathy. Annals of Pharmacotherapy, 41(7), pp.1301-1305.
  • Veves, A., Backonja, M., Malik, R.A. 2008 Painful diabetic neuropathy: Epidemiology, natural history, early diagnosis, and treatment options. Pain Medicine, 9(6), pp.660-674.
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Appendix 1:Sackett's hierarchy of evidence (1997)

  1. ASystematic reviews/meta-analyses

    BRCTs

    CExperimental designs

  2. ACohort control studies

    BCase-control studies

  3. AConsensus conference

    BExpert opinion

    CObservational study

    DOther types of study e.g. Interview based, local audit

    EQuasi-experimental, qualitative design
  4. Personal communication

Appendix 2: Framework for critiquing quantitative research (after Rees 1997)

Focus

In broad terms what is the theme of the article? What are the key words you would file this under? Are the key words in the title a clue to the focus? How important is this focus for clinical practice?

Background

What argument or evidence does the researcher provide that suggests this topic is worth exploring? Is there a critical review of previous research on the subject? Are the gaps in the literature or inadequacies with previous methods highlighted? Are local problems or changes that justify the study presented? Is there a trigger that answers the question 'why did they do it then?'

Terms of reference

Does the researcher state terms of reference? This will usually start with the word 'to' e.g. the aim of this research was to examine/determine/compare/establish/etc. In the case of clinical research there may only be a statement of the hypothesis or hypotheses that the researcher(s) wished to test. Is it possible to identify dependent and independent variables Remember level 1 questions will not have both, neither will a correlation study. Are there concept and operational definitions?

Study design

What is the broad research approach? Is it experimental? Descriptive? Action research or audit? Is it quantitative or qualitative? Is the study design appropriate to the terms of reference/hypothesis/research question?

Data collection methods

What tool of data collection has been used? Has a single method been used, or triangulation? Has the author addressed the issues of reliability and validity? Has a pilot study been conducted? Have strengths and limitations been recognised by the author?

Ethical considerations

Were the issues of inf

ormed consent and confidentiality addressed? Was any harm or discomfort to individuals balanced against benefits? Did a local ethics committee consider the study?

Sample

Who or what makes up the sample? Were there clear inclusion and exclusion criteria? What method of sampling was used? Are those in the sample typical and representative or are there any obvious elements of bias? On how many people/things are the results based?

Data presentation

In what form are the results presented? Does the author explain and comment on these? Has the author used correlation to establish whether certain variables are associated with each other? Have tests of significance been used to establish to what extent any differences between groups/variables could have happened by chance? Can sense be made of the way the results have been presented or could the author have provided more explanation?

Main findings

What are the most important results that relate to the term of reference/hypothesis/research question? (Put the results in terms of importance)

Conclusions and recommendations

What is the answer to the terms of reference/research questions? If relevant was the hypothesis accepted or rejected? Are the conclusions made based on and supported by the results? What recommendations are made for practice? Are these relevant, feasible and specific?

Readability

How easy is it to read? Is it written in a clear, interesting or 'heavy' style? Does it assume a great deal of technical knowledge about the subject and/or research procedures?

Practical implications

How could the results be related to practice? Who might find it relevant and in what way? What questions does it raise for practice and further study?

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