Painful diabetic neuropathy
BMJ 2014; 348 doi: https://doi.org/10.1136/bmj.g1799 (Published 06 May 2014) Cite this as: BMJ 2014;348:g1799
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Peltier and colleagues have carried out a great review of a common but nevertheless challenging to treat condition - diabetic painful peripheral neuropathy (DPPN) (1). Currently, the pathophysiological mechanisms underlying the development of neuropathic pain remain unclear. Several have been proposed, from peripheral mechanisms such has changes to neuronal sodium and calcium channels, abnormal glycaemic flux related damage to spinal cord related changes and more recently impairment of central pain processing secondary to functional and structural brain changes (2-3). From a clinical perspective, there is no test that currently identifies the site of pain generationnor objectively distinguishes those with painful neuropathy from established neuropathy (to distinguish functional pain in diabetes). Also, there is no test that can predict the development of painful neuropathy in the same way that microalbuminuria does in the development of overt diabetic neuropathy. Such identification, when possible, will lead to more meaningful and targeted pharmacotherapy. At the moment, it is perhaps unsurprising that drugs are therefore not effective to the same degree in affected individuals.
As the authors point out, many patients find Capsaicin cream difficult to tolerate. In the UK, capsaicin 0.075% cream is licensed for diabetic neuropathic pain whilst capsaicin 179mg self-adhesive patch (8%) is not. Whilst prescribing Capsaicin, it is important to warn the patient that they may experience transient burning especially if they apply the cream less than 4 times a day. Cough is another common complaint. In a systematic review for the treatment of chronic neuropathic pain the NNT for capsaicin cream at 4 weeks was 6.4 and at 8 weeks it was 5.7. UK wide experience in Lidocaine 5% patches is lacking outside certain specialist pain clinics. Two other topical treatments not covered by the review have published evidence and are of worthwhile consideration in the appropriate setting. OpSite film has been shown in a placebo-controlled two-period cross-over design to be effective topical treatment in diabetic painful neuropathy (4). Use of topical nitrate builds on the theory that impaired nitric oxide synthesis or release plays a role in the pathogenesis of diabetic neuropathy. Topical isosorbide dinitrate spray and latterly glyceryl trinitrtate patches have been shown to be effective in reducing pain scores (5).
The pain management guidelines, to which the authors refer, are either European or American. It is important to note that whilst Pregabalin has been recommended by the American Association of Neurology as 'effective' (Level A evidence) it was predominantly based on the 3 Class I Pregabalin studies achieving a greater than 80% completion rate (2; 6). Venlafaxine, duloxetine, amitriptyline, gabapentin, valproate, opioids (morphine sulphate, tramadol, and oxycodone controlled-release), and capsaicin were considered 'probably effective' (Level B) (6). More locally for the United Kingdom, National Institute for Health and Care Excellence -NICE - in 2010 published its guidance guidelines on the management of neuropathic pain in nonspecialist settings proposing duloxetine should be the first-line treatment with amitriptyline as alternative (7) . Pregabalin was a second-line treatment option for DPPN. It is understood however that this recommendation of duloxetine as first-line therapy was not based on efficacy but purely on cost-effectiveness (2).
Another challenge when initiating oral pharmacotherapy is to start on the appropriate dose. Under treatment of neuropathic pain is a major problem internationally (8) . In a community setting, our anecdotal experience is that a dose lower than the recommended starting dose if often initiated. Some drugs like Gabapentin requires rapid up titration in neuropathic pain for optimal effect and this entails that the patient is reviewed or contacted regularly by medical practitioners during this period. Whilst great strides are being in the identification of aetiopathogenesis and the developmemt of management algorithms by joint committees (with newer putative pharmacotherapy options around the corner), nevertheless diabetic painful peripheral neuropathy sadly continues to remain hard to treat satisfactorily.
References:
1. Peltier A, Goutman SA, Callaghan BC: Painful diabetic neuropathy. BMJ 2014;348:g1799
2. Tesfaye S, Boulton AJ, Dickenson AH: Mechanisms and management of diabetic painful distal symmetrical polyneuropathy. Diabetes Care 2013;36:2456-2465
3. Selvarajah D, Wilkinson ID, Maxwell M, Davies J, Sankar A, Boland E, Gandhi R, Tracey I, Tesfaye S: Magnetic resonance neuroimaging study of brain structural differences in diabetic peripheral neuropathy. Diabetes Care 2014;37:1681-1688
4. Foster AV, Eaton C, McConville DO, Edmonds ME: Application of OpSite film: a new and effective treatment of painful diabetic neuropathy. Diabet Med 1994;11:768-772
5. Rayman G, Baker NR, Krishnan ST: Glyceryl trinitrate patches as an alternative to isosorbide dinitrate spray in the treatment of chronic painful diabetic neuropathy. Diabetes Care 2003;26:2697-2698
6. Bril V, England J, Franklin GM, Backonja M, Cohen J, Del Toro D, Feldman E, Iverson DJ, Perkins B, Russell JW, Zochodne D: Evidence-based Guideline: Treatment of Painful Diabetic Neuropathy: Report of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation. PM&R 2011;3:345-352.e321
7. Centre for Clinical Practice at NICE (UK) Neuropathic pain: the pharmacological management of neuropathic pain in adults in non-specialist settings. London: National Institute for Health and Clinical Excellence (UK). 2010;
8. Martinez V, Attal N, Vanzo B, Vicaut E, Gautier JM, Bouhassira D, Lanteri-Minet M: Adherence of French GPs to Chronic Neuropathic Pain Clinical Guidelines: Results of a Cross-Sectional, Randomized, "e" Case-Vignette Survey. PLoS ONE 2014;9:e93855
Competing interests: No competing interests
In patients with diabetic neuropathic pain in the lower limbs we believe that decompression at the anatomical tunnels which constitute critical points under of their passage help relieve from the pain and vegetative symptoms 1.
We have already operated tens of the cases referred for drugs resistant neuropathic pain of the lower limbs. Most of them had a positive Tinel sign at the two main tunnel areas: peroneal and tarsal tunnel. Eliciting Tinel sign in these cases used to provoke exacerbation of pain and paresthesia in the area of sensitive distribution of the examined nerve. Even in advanced neuropathic cases with absent Tinel sign decompression proved to be beneficial towards improvement of pain intensity and extension, burning sensation or vegetative skin signs. Wounds over the toes, sole of the foot and heel improve postoperatively.
Under local anaesthesia we cut the superficial and deep fascia of the overlying muscle(s) (peroneals for homonymous nerve and abductor hallucis for plantar nerves) as well as the continuity of the fascia just overlying the trajectory of the nerve(s) to be decompressed. Wound closure was uneventful with stitches removed one week from surgery.
We advocate decompression of peroneal nerve with its crural branch as well as plantar and calcanear branches in tarsal tunnel under local anaesthesia, in case of diabetic painful neuropathy.
1. R Alimehmeti, G. Husi, F. Todi, G. Vyshka, D. Agolli: Entrapment neuropathies in diabetic patients : New trends of surgical treatment. Neuromediterranean 10: 9 May 2009, Durres, Albania. Revue Neurologique;166(2010):353-362.
Competing interests: No competing interests
We apologize for the discrepancy in the statements in the abstract and the summary of the abstract as to the effect of enhanced glucose control in type 1 vs type 2 diabetes. Enhanced glucose control has a greater effect on the prevention of neuropathy in patients with type 1 diabetes (abstract incorrect).
We also want to clarify that calcium channel blockers should be changed to voltage gated calcium channel alpha2-delta ligands throughout the text and in figure 2.
Competing interests: No competing interests
Very interesting article on a very challenging problem.
In the summary you mentioned that glycaemic control prevents neuropathy in type 2 diabetes, but in the summary the opinion is different.Thanks and wait for your reply.
Regards
Dr A Babiker
Competing interests: None
Firstly there is a discrepancy in statements in the abstract and the summary of the abstract as to the effect of enhanced glucose control in type 1 vs type 2 diabetes. Confusing.
Secondly when dealing with treatment options why have first anti-epileptics in the text and suddenly calcium channel blockers in the figure and summary....presumably identifying pregabalin etc as a calcium channel blocker. Most of us think of drugs like amlodipine used in management of hypertension when we talk of calcium channel blockers.
Competing interests: No competing interests
Re: Painful diabetic neuropathy
Jung et al (1) have commendably highlighted the association between vitamin B12 deficiency (B12Def) and long-term use of proton pump inhibitor (PPI) and potential for structural brain changes. However, even more important is the combination of B12 and magnesium deficiencies (MgDef) in patients with diabetes mellitus (DM) and the elderly that has even greater potential to cause serious neurological consequences.
Ting et al (2) have shown that patients with DM who receive metformin are also at risk of B12Def. An additional complication of chronic PPI therapy that needs highlighting is hypomagnesaemia that normalizes once PPI is stopped; remains normal with ranitidine, but re-falls with PPI re-introduction (3). Some patients with IDDM have low magnesium in striated muscles and/or plasma that is dependent on the degree of diabetic control (4). MgDef is also associated with insulin resistance (IR) and increased risk for type 2 DM in adults (5) Chronic Mg depletion in insulin dependent DM has been linked to polyneuropathy (PNP); short term Mg supplementation can decrease the pathological EMG signs typical for PNP. Under stable metabolic control, long-term Mg supplementation can restore normal Mg status and influence favorably the natural evolution of PNP as compared to non-supplemented type1 DM controls (6).
Elderly diabetics receiving PPI for gastro-esophageal reflux and metformin for their diabetes are at serious risk of neurological damage to peripheral nerves and brain, and neuropsychiatric problems from B12 deficiency and hypomagnesaemia; these patients should be monitored and would benefit from routine magnesium and vitamin B12 supplementation.
References
1. Jung SB, Nagaraja V, Kapur A, Eslick GD. Association between vitamin B12 deficiency and long-term use of acid-lowering agents: a systemic review and meta-analysis. IMJ 2015; 43 (4): 409-416.
2. Ting R Zhao-Wei, Szeto CC; Chan M Ho-Ming, Ma KK, Chow KM. Risk Factors of vitamin B12 deficiency in patients receiving metformin. Arch Intern Med. 2006; 166 (18):1975-1979. doi:10.1001/archinte.166.18.1975.
3. Epstein M, McGrath S, Law F. Proton-Pump Inhibitors and Hypomagnesemic Hypoparathyroidism. N Engl J Med 2006; 355:1834-1836 October 26, 2006DOI: 10.1056/NEJMc066308.
4. Sjögren S, Florén Claes-Henrik, Nilsson A. Magnesium deficiency in
IDDM related to level of glycosylated hemoglobin. Diabetes April 1986; 35(4):459-463. doi:10.2337/diab.35.4.459.
5. Huerta MG, Roemmich JN, Kington ML, Bovbjerg BV, Weltman AL, Holmes VF, Patrie JT, Rogol AD, Nadler JL. Magnesium Deficiency Is Associated With Insulin Resistance in Obese Children. doi: 10.2337/diacare.28.5.1175 Diabetes Care May 2005 vol. 28 no. 5 1175-1181
6. Ivo De Leeuw, Wendy Engelen, Christophe De Block, Luc Van Gaal. Long term magnesium supplementation influences favourably the natural evolution of neuropathy in Mg‐depleted type 1 diabetic patients (T1dm). Magnesium Research 2004; 17 (2):109-14.
Competing interests: No competing interests