Pain Medicine 2015; 00: 00–00 Wiley Periodicals, Inc.
Brief Research Report Pilot Study of Exercise Therapy on Painful Diabetic Peripheral Neuropathy
Min Yoo, MS,* Linda J. D’Silva, PT,* Katherine Martin, DPT,* Neena K. Sharma, PhD,* Mamatha Pasnoor, MD,† Joseph W. LeMaster, MD,‡ and Patricia M. Kluding, PhD* *Departments of Physical Therapy and Rehabilitation Science; †Neurology, and ‡Family Medicine, 8 University of Kansas Medical Center, 3901 Rainbow Blvd, MS 3051, Kansas City, Kansas, USA Reprint requests to: Patricia M. Kluding, PhD, Departments of Physical Therapy and Rehabilitation Science, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 3051, Kansas City, Kansas, USA. Tel: 913588-6918; Fax: 913-588-9428; E-mail: [email protected] This work was supported by a CTSA grant from NCATS awarded to the University of Kansas Medical Center for Frontiers: The Heartland Institute for Clinical and Translational Research # UL1TR000001 and # TL1TR000120. LD was supported by award number T32HD057850 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or NCATS. There are no conflicts of interest for any authors regarding this manuscript.
Methods. Fourteen sedentary individuals (mean age 57 6 5.11 years) with painful DPN were enrolled in a 16-week, supervised aerobic exercise program. The Brief Pain Inventory-Diabetic Peripheral Neuropathy was used to assess pain intensity (worst, least, average, now) and pain interference with daily life (activity, mood, walk, normal work, relationship, sleep, enjoyment of life) pre intervention and postintervention. Body mass index (BMI), maximum oxygen uptake (VO2max), hemoglobin A1c (HbA1c), and blood pressure were also measured preintervention and postintervention as secondary outcomes of interest. Results. Significant reductions in pain interference were observed with walking (4.93 6 3.03 pre to 3.29 6 2.89 post, P 5 0.016), normal work (5.39 6 3.32 pre to 3.79 6 3.04 post, P 5 0.032), relationship with others (3.96 6 3.53 pre to 1.29 6 1.27 post, P 5 0.006), sleep (5.11 6 3.04 pre to 3.5 6 3.03 post, P 5 0.02), and the overall pain interference (4.65 6 2.70 pre to 2.97 6 2.22 post, P 5 0.013) following the intervention; however, there was no change in pain intensity. VO2max increased significantly postintervention (16.02 6 3.84 ml/kg/min pre to 17.18 6 4.19 ml/kg/min, P 5 0.028), while BMI, HbA1c, and blood pressure remained unchanged. Conclusion. These preliminary results suggest that perceived pain interference may be reduced following an aerobic exercise intervention among people with painful DPN, without a change in pain intensity. Further validation by a RCT is needed. Key Words. Diabetic Peripheral Neuropathy; Exercise; Pain; Pain Interference
Abstract Objective. Painful diabetic peripheral neuropathy (DPN) is a common complication of diabetes. While the beneficial effect of exercise on diabetes is well established, its effect specifically on painful DPN has not been thoroughly explored. The objective of this pilot study was to examine the effect of aerobic exercise on pain in people with DPN.
Introduction As prevalence of diabetes is projected to rise to nearly 10% of the world population and 33% in the United States by 2030, diabetes and its complications pose an enormous burden to global health [1]. Diabetic peripheral neuropathy (DPN) is a frequent complication of diabetes that affects up to 50% diabetic patients in the United States [2,3]. The most common form of DPN is
1
Yoo et al. referred to as “diabetic sensorimotor polyneuropathy (DSPN),” and is predominantly characterized by sensory changes in the “glove-and-stocking” distribution [4]. These symptoms may include significant deficits in tactile and pain sensitivity, vibration sense, lower-limb proprioception, and kinesthesia, caused by promotion neuronal apoptosis and inhibition of nerve regeneration in diabetes [5]. Pain is a common symptom with DPN, affecting 10–26% of the diabetic population [6–8]. Painful DPN (P-DPN) has been shown to have a significantly detrimental impact on anxiety and depression, gait variability, and overall quality of life [7,9,10].
analog scale (VAS) to assess neuropathic pain observed that 6 months of a balanced exercise program demonstrated medium-sized effects without statistical significance, compared to an education group [23]. The purpose of this pilot study was to explore the effect of a supervised, moderate-intensity aerobic exercise training intervention on pain and pain interference in daily life, specifically in people with P-DPN. We hypothesized that our exercise intervention would be associated with reduction of pain in DPN. Materials and Methods
The current standard care for P-DPN focuses on providing symptomatic relief utilizing pharmacological interventions. Commonly used medications for P-DPN include, but are not limited to, tricyclic antidepressants (TCA), anticonvulsants (pregabalin and gabapentin), opioids, and tramadol (a weak opioid agonist) [11,12]. Treatment of P-DPN must be accompanied by proper glycemic control for management of the underlying cause in diabetes [13]. Administration of these regimens can be limited by a number of potential adverse side effects including triggering or worsening of mood disorders, lowered immunity, and development of addiction [13]. Furthermore, these drugs do not alter the progression of DPN. Only a-lipoic acid is a potential option targeting the etiology of P-DPN, although it has not been found to be superior to other drugs in randomized controlled trials [14]. Review of recent literature reveals that finding appropriate pharmacologic therapies for P-DPN remains a frustrated effort even though numerous novel drugs are newly developed and studied each year [11]. Currently, treatment of painful neuropathy continues to pose “enormous challenges” and is considered by clinicians to be “inadequate” [12]. Another therapeutic modality for P-DPN, which remains inadequately explored, is exercise intervention. A strong body of evidences in literature shows that physical exercise and a healthy diet can improve management of diabetes and its complications, including other forms of DSPN [15–17]. A randomized, controlled clinical trial involving diabetic patients without DPN in a long-term, supervised exercise program showed promising results suggesting that exercise may delay or even prevent the onset of DPN in diabetic patients [18]. Randomized studies of weight-bearing exercise in those with DSPN have found such exercise to be well tolerated and not associated with increases in foot ulcers or falls, both common complications of DPN; however, they did not study those with P-DPN [19,20]. A recent streptozotocin (STZ)-induced diabetic mouse model study found that exercise training significantly decreased diabetesassociated neuropathic pain, including thermal hyperalgesia and mechanical allodynia [21]. Despite its’ safety, feasibility, and potential effectiveness discovered in animal models, exercise as a therapeutic option for painful diabetic neuropathy involving human subjects has not been sufficiently addressed in previous intervention studies [22]. A recent controlled study utilizing a visual 2
This study was part of a larger project that investigated the effect of exercise in people with DPN on a variety of outcome measures that will be reported elsewhere, including plasma metabolic and lipid markers, body composition, and intraepidermal nerve fibers (IENF) density from skin biopsy. This study had IRB approval from the University of Kansas Medical Center. The result of exercise on pain and pain interference outcomes for the subset of individuals with painful DPN are reported here. All individuals participated in the intervention in this pre– post test design project. Participants Individuals were recruited for this study through flyers posted in the community and electronically via websites, by phone, and by email. The clinicians involved in the study utilized their databases to identify potential participants, and the University of Kansas Frontiers Research Participant Registry was utilized with approval. Individuals were invited to participate in further screening after signing an institutionally approved informed consent form if they: (1) were between 40 and 70 years of age, (2) reported a diagnosis of type 2 diabetes mellitus, (3) reported either a diagnosis of diabetic neuropathy or signs/symptoms consistent with neuropathy, and (4) were sedentary or under-active, as determined by a score of 5 or lower on the Telephone Assessment of Physical Activity (TAPA) [24]. Following consent, the presence of neuropathy was confirmed with a comprehensive neurological examination by an experienced neurologist (M.P.), nerve conduction studies and quantitative sensory testing, prior to enrolment [25]. Individuals were excluded if they had any of the following conditions: (1) Serious cardiac pathology, such as cardiac autonomic neuropathy, or musculoskeletal problems that would limit ability to exercise; (2) Open wounds on the weight bearing surface of the feet; (3) Inability to ambulate independently; (4) Stroke or other central nervous system pathology; (5) Stage 2 hypertension (resting blood pressure 160 systolic or 100 diastolic); (6) Body weight > 204 kg; (7) Pregnant or planning on becoming pregnant in the 18 weeks following enrollment; and (7) Impaired cognition and communication abilities, defined as
Brief Research Report Pilot Study of Exercise Therapy on Painful Diabetic Peripheral Neuropathy
Min Yoo, MS,* Linda J. D’Silva, PT,* Katherine Martin, DPT,* Neena K. Sharma, PhD,* Mamatha Pasnoor, MD,† Joseph W. LeMaster, MD,‡ and Patricia M. Kluding, PhD* *Departments of Physical Therapy and Rehabilitation Science; †Neurology, and ‡Family Medicine, 8 University of Kansas Medical Center, 3901 Rainbow Blvd, MS 3051, Kansas City, Kansas, USA Reprint requests to: Patricia M. Kluding, PhD, Departments of Physical Therapy and Rehabilitation Science, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 3051, Kansas City, Kansas, USA. Tel: 913588-6918; Fax: 913-588-9428; E-mail: [email protected] This work was supported by a CTSA grant from NCATS awarded to the University of Kansas Medical Center for Frontiers: The Heartland Institute for Clinical and Translational Research # UL1TR000001 and # TL1TR000120. LD was supported by award number T32HD057850 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development. The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or NCATS. There are no conflicts of interest for any authors regarding this manuscript.
Methods. Fourteen sedentary individuals (mean age 57 6 5.11 years) with painful DPN were enrolled in a 16-week, supervised aerobic exercise program. The Brief Pain Inventory-Diabetic Peripheral Neuropathy was used to assess pain intensity (worst, least, average, now) and pain interference with daily life (activity, mood, walk, normal work, relationship, sleep, enjoyment of life) pre intervention and postintervention. Body mass index (BMI), maximum oxygen uptake (VO2max), hemoglobin A1c (HbA1c), and blood pressure were also measured preintervention and postintervention as secondary outcomes of interest. Results. Significant reductions in pain interference were observed with walking (4.93 6 3.03 pre to 3.29 6 2.89 post, P 5 0.016), normal work (5.39 6 3.32 pre to 3.79 6 3.04 post, P 5 0.032), relationship with others (3.96 6 3.53 pre to 1.29 6 1.27 post, P 5 0.006), sleep (5.11 6 3.04 pre to 3.5 6 3.03 post, P 5 0.02), and the overall pain interference (4.65 6 2.70 pre to 2.97 6 2.22 post, P 5 0.013) following the intervention; however, there was no change in pain intensity. VO2max increased significantly postintervention (16.02 6 3.84 ml/kg/min pre to 17.18 6 4.19 ml/kg/min, P 5 0.028), while BMI, HbA1c, and blood pressure remained unchanged. Conclusion. These preliminary results suggest that perceived pain interference may be reduced following an aerobic exercise intervention among people with painful DPN, without a change in pain intensity. Further validation by a RCT is needed. Key Words. Diabetic Peripheral Neuropathy; Exercise; Pain; Pain Interference
Abstract Objective. Painful diabetic peripheral neuropathy (DPN) is a common complication of diabetes. While the beneficial effect of exercise on diabetes is well established, its effect specifically on painful DPN has not been thoroughly explored. The objective of this pilot study was to examine the effect of aerobic exercise on pain in people with DPN.
Introduction As prevalence of diabetes is projected to rise to nearly 10% of the world population and 33% in the United States by 2030, diabetes and its complications pose an enormous burden to global health [1]. Diabetic peripheral neuropathy (DPN) is a frequent complication of diabetes that affects up to 50% diabetic patients in the United States [2,3]. The most common form of DPN is
1
Yoo et al. referred to as “diabetic sensorimotor polyneuropathy (DSPN),” and is predominantly characterized by sensory changes in the “glove-and-stocking” distribution [4]. These symptoms may include significant deficits in tactile and pain sensitivity, vibration sense, lower-limb proprioception, and kinesthesia, caused by promotion neuronal apoptosis and inhibition of nerve regeneration in diabetes [5]. Pain is a common symptom with DPN, affecting 10–26% of the diabetic population [6–8]. Painful DPN (P-DPN) has been shown to have a significantly detrimental impact on anxiety and depression, gait variability, and overall quality of life [7,9,10].
analog scale (VAS) to assess neuropathic pain observed that 6 months of a balanced exercise program demonstrated medium-sized effects without statistical significance, compared to an education group [23]. The purpose of this pilot study was to explore the effect of a supervised, moderate-intensity aerobic exercise training intervention on pain and pain interference in daily life, specifically in people with P-DPN. We hypothesized that our exercise intervention would be associated with reduction of pain in DPN. Materials and Methods
The current standard care for P-DPN focuses on providing symptomatic relief utilizing pharmacological interventions. Commonly used medications for P-DPN include, but are not limited to, tricyclic antidepressants (TCA), anticonvulsants (pregabalin and gabapentin), opioids, and tramadol (a weak opioid agonist) [11,12]. Treatment of P-DPN must be accompanied by proper glycemic control for management of the underlying cause in diabetes [13]. Administration of these regimens can be limited by a number of potential adverse side effects including triggering or worsening of mood disorders, lowered immunity, and development of addiction [13]. Furthermore, these drugs do not alter the progression of DPN. Only a-lipoic acid is a potential option targeting the etiology of P-DPN, although it has not been found to be superior to other drugs in randomized controlled trials [14]. Review of recent literature reveals that finding appropriate pharmacologic therapies for P-DPN remains a frustrated effort even though numerous novel drugs are newly developed and studied each year [11]. Currently, treatment of painful neuropathy continues to pose “enormous challenges” and is considered by clinicians to be “inadequate” [12]. Another therapeutic modality for P-DPN, which remains inadequately explored, is exercise intervention. A strong body of evidences in literature shows that physical exercise and a healthy diet can improve management of diabetes and its complications, including other forms of DSPN [15–17]. A randomized, controlled clinical trial involving diabetic patients without DPN in a long-term, supervised exercise program showed promising results suggesting that exercise may delay or even prevent the onset of DPN in diabetic patients [18]. Randomized studies of weight-bearing exercise in those with DSPN have found such exercise to be well tolerated and not associated with increases in foot ulcers or falls, both common complications of DPN; however, they did not study those with P-DPN [19,20]. A recent streptozotocin (STZ)-induced diabetic mouse model study found that exercise training significantly decreased diabetesassociated neuropathic pain, including thermal hyperalgesia and mechanical allodynia [21]. Despite its’ safety, feasibility, and potential effectiveness discovered in animal models, exercise as a therapeutic option for painful diabetic neuropathy involving human subjects has not been sufficiently addressed in previous intervention studies [22]. A recent controlled study utilizing a visual 2
This study was part of a larger project that investigated the effect of exercise in people with DPN on a variety of outcome measures that will be reported elsewhere, including plasma metabolic and lipid markers, body composition, and intraepidermal nerve fibers (IENF) density from skin biopsy. This study had IRB approval from the University of Kansas Medical Center. The result of exercise on pain and pain interference outcomes for the subset of individuals with painful DPN are reported here. All individuals participated in the intervention in this pre– post test design project. Participants Individuals were recruited for this study through flyers posted in the community and electronically via websites, by phone, and by email. The clinicians involved in the study utilized their databases to identify potential participants, and the University of Kansas Frontiers Research Participant Registry was utilized with approval. Individuals were invited to participate in further screening after signing an institutionally approved informed consent form if they: (1) were between 40 and 70 years of age, (2) reported a diagnosis of type 2 diabetes mellitus, (3) reported either a diagnosis of diabetic neuropathy or signs/symptoms consistent with neuropathy, and (4) were sedentary or under-active, as determined by a score of 5 or lower on the Telephone Assessment of Physical Activity (TAPA) [24]. Following consent, the presence of neuropathy was confirmed with a comprehensive neurological examination by an experienced neurologist (M.P.), nerve conduction studies and quantitative sensory testing, prior to enrolment [25]. Individuals were excluded if they had any of the following conditions: (1) Serious cardiac pathology, such as cardiac autonomic neuropathy, or musculoskeletal problems that would limit ability to exercise; (2) Open wounds on the weight bearing surface of the feet; (3) Inability to ambulate independently; (4) Stroke or other central nervous system pathology; (5) Stage 2 hypertension (resting blood pressure 160 systolic or 100 diastolic); (6) Body weight > 204 kg; (7) Pregnant or planning on becoming pregnant in the 18 weeks following enrollment; and (7) Impaired cognition and communication abilities, defined as
