What should you add to prevent a loss of limb?

Amputations can be a major potential complication of diabetes. Only a small percentage of people diagnosed with diabetes require amputations, diabetic patients still account for approximately 60% of non-traumatic lower-limb amputations performed in people over the age of 20. Since diabetes is a major risk factor for peripheral arterial disease (PAD), it is important to properly manage PAD in order to reduce complications down the rode in diabetes patients. Although statins are recommended for PAD patients, there is little research as to whether statins are an effective option to aid the prevention of amputations in type 2 diabetes patients.

Researchers used data from Taiwan’s National Health Insurance Research Database (NHIRD) to “investigate whether the use of statins is associated with a lower extremity amputation rate in a high risk population with known PAD as compared to two propensity score-matched cohorts without statin use while taking into consideration the competing risk of death.” The study population included patients who were age 20 or older with a diagnosis of both diabetes mellitus and peripheral arterial disease during the search period and had 5 years of data before inclusion in the study.  Patients were then divided into three groups based on current PAD treatment: statin-user, non-statin lipid-lowering agent, or non-user. Patients who were excluded from the study were those who were on a combination of statins and other lipid-lowering agents. A propensity score was calculated for patients to determine the probability of a patient receiving a lipid-lowering agent and control patients were matched to both statin and non-statin users with a similar propensity. The primary outcome of the study was new lower extremity amputation and secondary outcomes were in-hospital cardiovascular death and all-cause mortality.

The study included a total of 69,332 diabetes patients with a mean age of 62.6 years who were diagnosed with PAD during the study period.  The majority of the patients, approximately 77%, were non-users of lipid-lowering agents, 17% of the patients were statin users, and 6% used non-statin lipid-lowering agents. Over approximately 5.7 years of follow up, patients in the statin user group had less incidence of any lower extremity amputation, less total lower extremity amputation, and less in-hospital cardiovascular death and all-cause mortality compared to non-users. After adjusting for relevant factors, statin users had significantly lower risk of lower extremity amputation events (adjusted HR [aHR] 0.75, 95% CI 0.62-0.90) and significantly lower risk of total lower extremity amputations (aHR 0.58, 95% CU 0.36-0.93) when compared to non-users. In comparison, non-statin lipid-lowering agents were not associated with any significant decrease in lower extremity amputation events (aHR 0.95, 95% CI 0.73-1.23) and both the statin user group and non-statin lipid-lowering agent group. For the propensity score-matched analysis, 11,373 patients from both the statin user group and non-user group were matched and 4,428 patients from both the non-statin lipid-lowering agent group and the non-user group were matched. In the propensity score-match analysis, the statin user group had a 25% lower risk of any lower extremity amputation (HR 0.75, 95% CI 0.60-0.94), 52% lower total extremity amputation (HR 0.48, 95% CI 0.28-0.83), lower in-hospital cardiovascular death (HR 0.75, 95% CI 0.66-0.87), and lower all-cause mortality (HR 0.72, 95% CI 0.67-0.77) when compared to matched non-users, while non-statin lipid-lowering agents had a neutral effect on all outcomes compared to matched non-users. Other factors, such as gender, age> 65, hypertension, heart failure, CAD, use of antiplatelet drugs, and use of a high potency statin showed no significant effects on the outcome of the study.

Statins have known pleiotropic effects that aid in its protective effects for lowering risk of amputations in diabetes mellitus patients. While this study had a very large sample size, further studies may be needed in varying populations to determine relative effect and real world practice application.

Practice Pearls:

• Statins can decrease the risk of lower limb amputation in diabetes mellitus patients with peripheral arterial disease.
• Non-statin lipid lowering agents are not as beneficial as statins in decreasing the risk for lower limb amputations.
• Statins should be combined with diet, exercise, and regular foot checks for the best outcome.

References:

“Statistics About Diabetes.” American Diabetes Association. Web.

Hsu, Chien-Yi, Yung-Tai Chen, Yu-Wen Su, Chun-Chin Chang, Po-Hsun Huang, and Shing-Jong Lin. “Statin therapy reduces future risk of lower limb amputation in patient with diabetes and peripheral artery disease.” The Journal of Clinical Endocrinology & Metabolism (2017). Web.

Priscilla Rettman, BS, PharmD Candidate 2017, Philadelphia College of Osteopathic Medicine – GA Campus

What treatments can improve pain and quality of life?

Diabetic neuropathy is a nerve disorder that the National Institute of Diabetes and Digestive and Kidney disease estimates affects about 60 to 70% of diabetic patients in some form, with the highest rates of neuropathy occurring in patients who have had diabetes for over 25 years. Although diabetic neuropathy can affect almost any organ in the body, the most common type of diabetic neuropathy is peripheral neuropathy. Peripheral neuropathy, which is often worse at night, results in tingling, numbness, and pain occurring in the hands, arms, fingers, legs, feet, and toes. The best way to prevent diabetic neuropathy is keeping glucose under control and maintaining a healthy weight, but for those who experience this painful condition, finding the best relief can often be difficult and confusing.

Previous meta-analysis studies have been published on effectiveness of different diabetic neuropathy treatments, but they do not include newer treatment options or show how treatments improve quality of life. They are also missing review data with how the meta-analysis was conducted. Building upon a previously published study from 2014, a new systemic review was conducted to “systemically assess the effect of pharmacological treatments of diabetic peripheral neuropathy (DPN) on pain and quality of life” plus a search of PubMed and Cochrane Database of systemic reviews (reviews from 2011 – March 2016),  After the literature search, investigators identified the trial types, assessed the risk for bias, and pooled data on outcomes of pain intensity, health-related QOL, adverse effects, and dropouts due to adverse effects.

A total of 106 randomized controlled trials were used in the final systemic review, including trials analyzed by the previously published study. Only two medications, duloxetine and venlafaxine, had a moderate strength of evidence (SOE) compared to the low strength of evidence found with the remaining 12 study medications. As a class, serotonin-norepinephrine reuptake inhibitors (SNRIs) was found to be an effective treatment for diabetic neuropathy with the most commonly reported adverse effects of dizziness, nausea, and somnolence. Focusing on specific SNRIs, duloxetine was found to be effective for pain relief based on data from 2 new trials in addition to 5 trials from the previously published systemic review (Standardized mean difference (SMD) 21.33 [ Credible Interval (CrI) 21.82 to 20.86]). Venlafaxine and tricyclic antidepressants were also determine to be effective at relieving pain compared to placebo using the previous analysis’ data ((SMD 21.53 [CrI 22.41 to 20.65]; (SMD 20.78 [CrI 21.24 to 20.33])), but there was insufficient SOE to make any determination on the effectiveness of desvenlafaxine. Using 15 trials with a calculable SMD, pregabalin was determined to be effective at reducing pain compared to placebo (SMD 20.34; 95% Confidence Interval (CI) 20.50 to 20.18), but found to have a low SOE due to the inclusion of four unpublished studies causing potential bias. Pregabalin, as well as the other anticonvulsants included, had adverse effects of dizziness, nausea, and somnolence. Oxcarbazepine was also found to be an effective neuropathy pain reliever compared to placebo based on the previously published analysis (SMD 20.45 [CrI 20.68 to 20.21]).

Atypical opioids have a dual mechanism of action, norepinephrine reuptake inhibition and mu antagonism, which aids in a class wide effective pain relief compared to placebo, and more specifically tramadol and tapentadol were found to be effective vs placebo using new pooled data and data from the previously published analysis (SMD -0.68 [95% CI -0.80 to -0.56). The most common adverse effects reported for opioids were constipation, somnolence, and nausea. The last medication that was determined to be an effective pain reliever of diabetic neuropathy compared to placebo was botulinum toxin (SMD ranging from -0.96 to -0.79). Gabapentin, using five randomized controlled trials, was determined at two different doses to be ineffective at treating pain when compared to placebo (SMD 20.65, 95% CI 21.1 to 20.23; SMD 20.27, 95% CI 20.67 to 0.14; and SMD 20.20, 95% CI 20.46 to 0.06). Other agents that were determined to be ineffective treatments for diabetic neuropathy were typical opioids (oxycodone), topical capsaicin 0.075%, dextromethorphan, and mexiletine. Quality of life (QOL) could not be assessed due to incomplete reporting and insufficient SOE.

Limitations of this systemic analysis include lack of drug-drug comparison data, short duration of many of the included RCTs, and possible exclusion of relevant data due to exclusion of studies involving mixed origins of neuropathic pain. This analysis opens up the need for new trials comparing relative effectiveness of drug vs drug treatment for diabetic neuropathy.

Practice Pearls:

• Pregabalin, oxcarbazepine, and tapentadol have shown to be effective vs placebo at relieving pain due to diabetic neuropathy and are also FDA approved for this indication.
• Serotonin-norepinephrine reuptake inhibitors may be a good choice for relief of diabetic neuropathy pain and have the additional benefit of relieving depression that is commonly associated with diabetic neuropathy
• Additional studies are needed to assess long-term pain relief effectiveness.

References:

“Nerve Damage (Diabetic Neuropathies) | NIDDK.” National Institutes of Health. U.S. Department of Health and Human Services. Web 05 April 2017

Julie M. Waldfogel, Suzanne Amato Nesbit, Sydney M. Dy, Ritu Sharma, Allen Zhang, Lisa M. Wilson, Wendy L. Bennett, Hsin-Chieh Yeh, Yohalakshmi Chelladurai, Dorianne Feldman, Karen A. Robinson. “Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life”. Neurology, 2017; 10.1212/WNL.0000000000003882 DOI: 10.1212/WNL.0000000000003882

Mark T. Lawrence, RPh, PharmD Candidate, University of Colorado-Denver, School of Pharmacy NTPD

Study finds improvement in pain relief and sleep patterns

Effective management of peripheral neuropathy can be challenging in patients with uncontrolled diabetes. At least 47% of type 1 and type 2 diabetes patients who have both experience peripheral neuropathy and at least 35% of these patients experience painful diabetic neuropathy. Adequate pharmacotherapeutic management of painful peripheral neuropathy relies on utilizing antiepileptic and antidepressant through a decrease in neurotransmission leading to nociception. Agents like pregabalin, gabapentin, amitriptyline, and duloxetine are widely prescribed for management of diabetic neuropathy. However, pregabalin and duloxetine are the agents that the FDA approved for this indication. Recently, more evidence is supporting the use of buprenorphine in diabetic neuropathy due to its pharmacological actions. It has been postulated that the activity of pertussis toxin-sensitive G-protein is reduced in neuropathic pain. Buprenorphine is not affected by levels of activity of this G-protein. Other analgesics acting on the mu opioid receptors depend on this G-protein activity to exert analgesic action. The amount of research on this topic is limited and clinical trials looking into these effects are not widely conducted.

However, Richard W. Simpson and John H. Wlodarcyzk from the Eastern Clinical Research Unit in Box Hill Hospital, Australia conducted a clinical trial where they sought to evaluate the safety and efficacy of transdermal buprenorphine in patients with diabetic peripheral neuropathic pain. This study was a multicenter, randomized, placebo-controlled, parallel-group trial where 186 patients were enrolled to receive buprenorphine patch or placebo patch, however, 61 patients completed the study. Patients were included in this study if they had well-controlled type 1 diabetes and type 2 diabetes for the preceding six months. Additionally, they were included if they experienced diabetic neuropathic pain for a minimum of 6 months on non-opioid analgesic therapy. In addition to the buprenorphine patch, patients were allowed to continue on stable doses of any antidepressants, antiepileptics, or other medications indicated for neuropathic pain that did not entail using weak opioid analgesics, NSAIDs, or any other topical drug and non-drug therapies. The primary endpoint of the study was a 30% reduction in average pain intensity at the end of week 12. Therapy with buprenorphine was started at 5 mcg/hour and titrated to effect on a weekly basis during the first 6 weeks, followed by every 2 weeks from weeks 7-12; max dose of 40 mcg/hour.

Results from this study showed that 51.7% of patients in the buprenorphine group achieved 30% reduction compared to 41.3% in the placebo group (OR 1.56; 95% CI 0.82, 2.97; p=0.175). The most common reported adverse events were nausea, vomiting, and constipation. All of which led some participants to withdraw from the study. One thing to take into consideration in this study is the use of other medications while in the study. Simpson and Wlodarcyzk analyzed the effects of these medications on buprenorphine. The odds ratio for these effects show no meaningful alterations to the efficacy of buprenorphine (antidepressants 0.77; 95% CI 0.39, 1.52 vs antiepileptics 1.48; 95% CI 0.58, 3.81). Furthermore, there was significant change in pain scale scores from baseline (average pain: 5.7) in the buprenorphine group (-1.20 (95% CI 21.83, 20.57; P< 0.001). There was also a significant improvement in sleep in patients receiving buprenorphine when compared to placebo (p<0.05).

In conclusion, the use of the buprenorphine patch in patients with diabetic peripheral neuropathy was able to provide adequate pain relief. This pain relief was determined by significant changes in pain scales and improvements in sleep patterns. The efficacy of buprenorphine does not seem to be affected by the use of other diabetic neuropathy pain medications. Its use is well tolerated and the anticipated adverse effects, associated with opioid use, can be managed through lifestyle and diet changes. Additionally, over-the-counter medication use aids as well in the management of these side effects. Proper patient education and close pain monitoring is needed to ensure optimal pain control and tolerability.

Practice Pearls:

• Use of buprenorphine should be used as an adjuvant to manage neuropathic pain.
• Treatment failures are commonly due to adverse effects, such as vomiting, nausea, and constipation, which is also associated with the inability to achieve pain control.
• Buprenorphine, when used in diabetic neuropathy pain, is associated with improved sleep, which is usually affected by uncontrolled pain.

References:

Simpson, Richard W., Wlodarcyzk, John H. “Transdermal Buprenorphine Relieves Neuropathic Pain: A Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Trial in Diabetic Peripheral Neuropathic Pain” Diabetes Care 39(9) (2016):1-8. Web.

Wiffen, Philip J., Derry, Sheena, Moore, R Andrew, Stannard, Cathy, Aldington, Dominic, Cole Peter, and Knaggs, Roger. “ Buprenorphine for neuropathic pain”. Cochrane Database of Systematic Reviews. 9 (2015): n. pag. Web.

Researched and prepared by Christian Gill, Pharm.D. Candidate, Class of 2017. Reviewed by Michelle Caetano, Pharm.D., BCPS, BCACP, CDOE, CVDOE

People who have diabetes are usually taught to purchase protective soft leather shoes with a wide toe box. That doesn’t mean everybody who has diabetes follows those recommendations.

A woman, type 2 diabetes, who is knowledgeable about diabetes and foot complications was wearing cloth shoes with a “corded” bottom and manmade rubber sole. She was caught in the rain. Her shoes were soaked. When she got home she let them dry out. Later when she put them back on they were tight. At first she thought she may have some lower extremity edema, but then realized her shoes must have shrunk from being wet and drying out. She started to wear them, thinking they would stretch out. She then felt pressure on the sole of her left foot. She remembered all the stories she had heard about people with diabetes who have peripheral neuropathy, can’t feel when shoes don’t fit right, and ultimately develop a sore which can get infected and for too many end up needing an amputation. She realized how lucky she was to have sensation and even pain to protect her from this happening…that is, if she listened to those signs. Although it would make her late, she immediately went home and changed her shoes. Disaster Averted.

Lessons Learned:

• Teach diabetes foot care, which includes prevention, to all patients who have diabetes.
• Teach that just because shoes once fit well does not mean they always will.
• Teach that if you feel something, you should listen to what that feeling is telling you. It could be saying, “Change your shoes.”
• Teach that if you can’t feel…see podiatrist!

Early diagnosis of Diabetic Peripheral Neuropathy can be critical;

 Detect Loss of Protective Sensation (LOPS) earlier with 

MEDIPIN – the single use protected neurological pin designed to optimize pinprick perception without piercing delicate skin

The pinprick or sharp sensation test is acknowledged and recommended by the ADA as a useful and sensitive method of testing for Loss Of Protective Sensation and predicting serious complications associated with diabetes.(1,2)

Medipin is a unique single use cutaneous pinprick testing device. Its patented precision technology has been designed to enhance patient pinprick sensation response. Each Medipin has a short pyramid shaped point with highly defined edges and a flattened top intended to stretch rather than penetrate the skin surface. The point is surrounded by an annular ring to provide a contrasting perimeter of dull stimulation that further augments the sharp sensation created by the point and helps prevent skin puncture. The tab, which protects the point integrity until it is ready to be used, is designed to break away and can be used to conduct a two-point discrimination (6mm) test. The blunt end head of the Medipin is for comparison testing.  An FDA listed instrument, Medipin has been in regular use by US Doctors for many years, as well has having been employed successfully in quite a number of international medical studies.  For Medical Professionals the cost is less than 18 cents each.  Use it then provide it to your patient.  Also available in a convenient 12 pack with a year’s supply for one person. Discount code for a box of 100 units is Medipin25.

TESTING FOR EARLIER DETECTION OF LOSS OF PROTECTIVE SENSATION IN YOUR OWN PRACTICE: The professional examination procedure utilising an advanced pinprick technique and dedicated device for improved diagnosis of loss of protective sensation – Medipin 100 Count Box for clinical use –

TESTING AT HOME: Educate your patients with diabetes about home testing for peripheral neuropathy – Box of 12 for Home Use – the monthly Diabetic Toes Test by Medipin – why wait? Medipin 12 Count Box for a full year of home testing.

1) Boulton et al, Comprehensive Foot Examination And Risk Assessment, Diabetes Care, Vol 31, No 8, Aug 2008.

2) Abbott CA, Carrington AL, Ashe H, for the North-West Diabetes Foot Care Study. The North-West diabetes foot care study: incidence of, and risk factors for, new diabetic foot ulceration in a community- based patient cohort. Diabet Med. 2002;19:377-384.