542266 research-article2014
POI0010.1177/0309364614542266Prosthetics and Orthotics InternationalRosenberg
INTERNATIONAL SOCIETY FOR PROSTHETICS AND ORTHOTICS
Literature Review
Treatment of painful diabetic peripheral neuropathy
Prosthetics and Orthotics International 2015, Vol. 39(1) 17–28 © The International Society for Prosthetics and Orthotics 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0309364614542266 poi.sagepub.com
Casandra J Rosenberg1 and James C Watson2
Abstract Background: Painful diabetic peripheral neuropathy impairs quality of life and can be difficult to treat. Objective: To discuss current treatment recommendations for painful diabetic peripheral neuropathy. Study design: Literature review. Methods: Systematic review of the literature discussing treatment of painful diabetic peripheral neuropathy. Existing treatment guidelines were studied and compared. Results: Painful diabetic peripheral neuropathy occurs in about one in six people with diabetes. This condition impairs quality of life and increases healthcare costs. Treatment recommendations exist, but individual patient therapy can require a trial-and-error approach. Many treatment options have adjuvant benefits or side effects which should be considered prior to initiating therapy. Often, a combination of treatment modalities with various mechanisms of action is required for adequate pain control. Adequate medication titration and a reasonable trial period should be allowed. Conclusion: The treatment of painful diabetic peripheral neuropathy can be challenging, but effective management can improve patient’s quality of life. Clinical relevance Painful diabetic peripheral neuropathy impairs quality of life and can be difficult to treat. Many treatment options have adjuvant benefits or side effects which should be considered prior to initiating therapy. Often, a combination of treatment modalities with various mechanisms of action is required for adequate pain control. Keywords Diabetes, neuropathy, painful neuropathy, diabetic peripheral neuropathy Date received: 19 May 2014; accepted: 9 June 2014
Background Diabetes affects more than 25 million people, in the United States representing greater than 11% of the adult population.1 Up to two-thirds of people with diabetes develop peripheral neuropathy, with an increasing prevalence with longer disease duration; 15%–25% of diabetic neuropathies are painful.2–6 Patients with painful neuropathies have healthcare costs three times greater than age matched controls.7 Diabetic peripheral neuropathy (DPN) and its sequelae, including ulceration and loss of limbs, cost the United States between 5 and 15 billion US dollars per year.8 Additionally, painful DPN significantly affects multiple measures of quality of life and is highly associated with depression, anxiety, and sleep disturbances.2,9–11 Developing an individualized treatment plan for a person with painful DPN is challenging.12 Choosing a treatment can be difficult because of a lack of comparative
trials of effective treatments13,14 and limited or conflicting evidence for some treatments.13 Once a treatment is initiated, a patient can experience incomplete pain relief13,15 or suffer from the high side-effect profiles seen with many of the effective treatments.13,16 Over the past decade, the treatment of painful peripheral neuropathies has evolved, and several treatment
1Department
of Anesthesiology, Division of Pain Medicine, Mayo Clinic, Rochester, MN, USA 2Department of Neurology, Mayo Clinic, Rochester, MN, USA Corresponding author: Casandra J Rosenberg, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Email: [email protected]
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algorithms have been established (Figure 1).16–20 Each of these guidelines considers treatment efficacy and adverse effects. The Canadian and the International Association for the Study of Pain Neuropathic Pain Special Interest Group (NeuPSIG) guidelines include ease of use and cost-effectiveness, while the NeuPSIG and the American Academy of Neurology (AAN) also consider quality-of-life outcomes. One of the guidelines is strictly for painful DPN,20 and three others include specific subgroup recommendations for DPN.16,18,19
Disease management The first step in the management of painful DPN is treating the cause of neuropathy, the diabetes. There is evidence that tight glucose control, particularly in the early stages of diabetes, can delay progression of painful DPN.21 A recent Cochrane review showed a relative risk of developing DPN of 0.35 for patients who undergo intensive glucose control compared to conventional treatment (95% confidence interval (CI) = 0.23–0.53; p 400 mg/day
Sedation, confusion, dizziness, peripheral edema, euphoria
Sedation, confusion, dizziness, peripheral edema, tremor
Fatigue, nausea, hyperhidrosis
Sedation, dry mouth, orthostatic hypotension, urinary retention, weight gain, confusion, blurred vision, thrombocytopenia
Most common side effects
Nausea, rash, and hypothyroidism
No maximum Constipation, nausea/ dosage vomiting, drowsiness, confusion, dizziness, pruritus
600 mg/day
400 mg/day
600 mg/day
3600 mg/day (divided into three doses)
60 mg twice daily
Maximum dosage
Dosage and titration recommendations
Agent
Table 1. Prescribing recommendations for medications for painful diabetic peripheral neuropathy.
Hypoglycemia
Renal insufficiency (must dose adjust), psychiatric disease (euphoria risk), withdrawal syndromes/seizure with abrupt discontinuation History of substance abuse, sedation, driving impairment, seizure disorder, risk of serotonin syndrome with concomitant use of SSRI, SNRI, and TCAs History of substance abuse, sedation, respiratory depression, driving impairment, seizure disorder, risk of serotonin syndrome with concomitant use of SSRI, SNRI, and TCAs; hepatic dysfunction History of substance abuse, driving impairment, tolerance, abuse, diversion
Small risk of emerging suicidality (boxed warning), caution in patients with cardiac disease (high dosages >100 mg daily associated with sudden cardiac death and dysrhythmias), serotonin syndrome, glaucoma Small risk of emerging suicidality (boxed warning), increased bleeding risk (care with anticoagulants), withdrawal syndromes with abrupt discontinuation, serotonin syndrome, hepatic failure Renal insufficiency (must dose adjust), withdrawal syndromes/seizure with abrupt discontinuation
Precautions
Few toxicities
Rapid onset analgesic benefit
Rapid onset analgesic benefit
Improvement of sleep disturbance, fibromyalgia, and anxiety; no clinically significant drug interactions Rapid onset analgesic benefit
Improvement of sleep disturbance, anxiety, hot flashes; no clinically significant drug interactions
Treats depression and anxiety (at similar dosage used for pain), as well as myofascial pain
Improvement of depression (though typical doses for pain are lower than doses necessary for depression)
Other benefits
22 Prosthetics and Orthotics International 39(1)
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No known systemic toxicities
Not recommended for face or around mucous membranes or over broken skin; apply wearing gloves Not recommended around mucous membranes or over broken skin
Alpha-lipoic acid. A lipophilic antioxidant, alpha-lipoic acid (ALA), has been shown to improve nerve blood flow and distal conduction and to reduce oxidative stress.90 The primary side effect is nausea. Both oral (at a dosage of 600 mg per day) and intravenous supplementation have been shown to improve symptoms of painful DPN.91,92 Acetyl-l-carnitine. Acetyl-l-carnitine (ALC) has shown improved peripheral nerve conduction velocity and nerve regeneration, thought to be due to its antioxidant properties and role in catabolism/anabolism.93 Several studies have shown benefit in patients with painful DPN (at a dosage of 1000 mg three times daily by mouth) (Table 1).94–96
Therapeutic modalities Acupuncture SSRI: selective serotonin reuptake inhibitor; SNRI: serotonin and norepinephrine reuptake inhibitors; TCA: tricyclic antidepressant. Based on information from Dworkin et al.18.
Apply up to three patches for 12 h daily; may cut to shape
Topical capsaicin (0.075%–0.75% cream) Topical lidocaine (5% patch)
May apply up to four patches at one time. Before patch application, use topical anesthetic for 60 min, remove, and confirm anesthesia. Place patch over symptomatic area for 60 min. Should be placed by medical staff trained in its usage using non-latex gloves. May cut patch to shape. Following treatment, wash with provided soap. Apply cream to affected areas four times daily Topical capsaicin (high concentration 8% patch)
Local skin problems such as erythema, burning, or pain Local skin problems such as burning, irritation
Low risk of systemic toxicity
No known systemic toxicities Unknown risk from repeated exposures, not recommended for face or over broken skin
Few toxicities 1000 mg three times per day Acetyl-l-carnitine
Agitation, nausea, vomiting, bloating Local skin problems such as erythema, burning, or pain (patients frequently require prescription analgesics for 1–2 weeks after application)
Maximum dosage Dosage and titration recommendations Agent
Table 1. (Continued)
Most common side effects
Precautions
Other benefits
Other supplements
Acupuncture has been shown to be effective for painful DPN in small trials without placebo control.97–99
Transcutaneous electrical nerve stimulation Transcutaneous electrical nerve stimulation (TENS) delivers an electrical current via electrodes on the skin arranged about the affected area. The intensity, frequency, and pattern of stimulation can be adjusted by the patient or therapist. Several studies including sham treatment arms have demonstrated benefit in painful DPN.100–102
Cognitive behavioral therapy Cognitive behavioral therapy (CBT) replaces dysfunctional thoughts and behaviors with positive ones and has been found effective in multiple pain states.103–105 One randomized pilot study showed benefit for patients with painful DPN as compared to typical management.106
Advanced interventions In addition to medications, several interventions are gaining interest in the treatment of painful neuropathies. Interventional treatments have previously been described as “invasive procedures involving delivery of drugs into targeted areas, or ablation/modulation of targeted nerves.”13 Recently, the NeuPSIG compiled evidence for interventional treatments in the management of neuropathic pain, including a subgroup analysis for painful DPN in combination with other painful peripheral neuropathies.
Neuromodulation Neuromodulation involves the application of electrical current to neural structures to modulate neural transmission.
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The most common method of neuromodulation for pain is dorsal column stimulation, also known as spinal cord stimulation (SCS). Small electrodes are implanted in the epidural space and connected to a battery-operated pulse generator implanted in the flank or abdominal wall. Prior to implantation, a trial of stimulation with temporary percutaneous electrodes is undertaken to ensure effective pain relief. Several non-randomized case series have demonstrated pain relief of peripheral neuropathy even in medically resistant cases.107–109 A single study with a crossover-type design showed benefit compared to sham stimulation.108 For isolated mononeuropathies, placement of a traditional stimulator lead immediately adjacent to the affected nerve has been described.110
Intrathecal drug delivery systems Intrathecal drug delivery systems (IDDS) use a surgically implanted pump attached to a small, flexible catheter tunnelled into the cerebrospinal fluid (CSF). Morphine and ziconotide (a selective N-type voltage-gated calcium channel blocker) are FDA-approved medications for intrathecal infusion.111,112 There are currently no studies showing evidence for intrathecal drug delivery specifically for neuropathic noncancer pain. Given concentrated drug delivery into the CSF, intrathecal systems may be useful when systemic side effects from oral analgesics or adjuvants are limiting. Factors that increase the risk of IDDS implantation in diabetic patients include impaired wound healing, relative immunosuppression increasing the risk of infection, and comorbid cardiovascular or renal disease. If an intrathecal drug delivery system is being considered in a diabetic patient, it is recommended that their glucose control is optimized prior to implantation.113 Patients with an intrathecal system need to be able to maintain regular follow-up for system refills and adjustments.
Managing expectations is vital when starting or changing medications. Most treatments are considered successful if they provide 30%–50% improvement or at least 2 points on a 10-point Likert scale. For some patients, this improvement will be worthwhile, while others may weigh the benefits less favorably relative to the side effects of the medication. Medication side effects can be a barrier to treatment success. A frank conversation discussing common or serious side effects should be had prior to starting a new treatment. Many of these treatment side effects can be improved over time due to progressive tolerance; these can be mitigated at the start of treatment by gradual up-titration of the medication dose. Each medication should be maintained at the lowest effective dose. For patients who have had prior medication trials to treat their painful DPN, it is important to ensure that their trial was adequate in dosage achieved and duration of treatment (several weeks at goal dosage). It is common that a prior trial was inadequate and that a retrial may be appropriate. Finally, an important strategy to the management of painful DPN is multimodal therapy. Many studies show benefit from combination therapies. This strategy is likely effective due to the additive effects of pain relief from multiple mechanisms of action. It is important to carefully consider the individual treatments to avoid unpleasant or life-threatening side effects, such as serotonin syndrome with combinations of high-dose TCAs and tramadol. Topical medications, behavioral strategies, and physical modalities can be particularly beneficial in combination with other treatments due to their negligible side-effect profiles. Author contribution All authors contributed equally in the preparation of this manuscript.
Declaration of conflicting interests
Conclusion While painful DPN can prove difficult to treat, there are a variety of therapeutic options, including behavioral therapies, physical modalities, topical and oral medications, and implantable devices. There are several key concepts for developing a treatment approach. Tight glycemic control is important to delay onset and progression of painful DPN. Consideration of comorbid conditions including sleep disturbance, depression, and other pain states is important both to minimize the pain of DPN itself and when selecting the most appropriate medical therapy. Many painful DPN treatments can also address other comorbid conditions. Furthermore, some medication side effects could exacerbate preexisting problems and should be avoided.
None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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a randomized, double-blind, placebo-controlled trial. Anesthesiology 2005; 103: 140–146. 87. Lynch ME, Clark AJ, Sawynok J, et al. Topical amitriptyline and ketamine in neuropathic pain syndromes: an openlabel study. J Pain 2005; 6: 644–649. 88. Gewandter JS, Mohile SG, Heckler CE, et al. A phase III randomized, placebo-controlled study of topical amitriptyline and ketamine for chemotherapy-induced peripheral neuropathy (CIPN): a University of Rochester CCOP study of 462 cancer survivors. Support Care Cancer. Epub ahead of print 16 February 2014. DOI: 10.1007/s00520-014-2158-7. 89. Barton DL, Wos EJ, Qin R, et al. A double-blind, placebocontrolled trial of a topical treatment for chemotherapyinduced peripheral neuropathy: NCCTG trial N06CA. Support Care Cancer 2011; 19: 833–841. 90. Nagamatsu M, Nickander KK, Schmelzer JD, et al. Lipoic acid improves nerve blood flow, reduces oxidative stress, and improves distal nerve conduction in experimental diabetic neuropathy. Diabetes Care 1995; 18: 1160–1167. 91. Ziegler D, Ametov A, Barinov A, et al. Oral treatment with alpha-lipoic acid improves symptomatic diabetic polyneuropathy: the SYDNEY 2 trial. Diabetes Care 2006; 29: 2365–2370. 92. Ziegler D, Nowak H, Kempler P, et al. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alphalipoic acid: a meta-analysis. Diabet Med 2004; 21: 114–121. 93. Scafidi S, Fiskum G, Lindauer SL, et al. Metabolism of acetyl-l-carnitine for energy and neurotransmitter synthesis in the immature rat brain. J Neurochem 2010; 114: 820–831. 94. Evans JD, Jacobs TF and Evans EW. Role of acetyl-l-carnitine in the treatment of diabetic peripheral neuropathy. Ann Pharmacother 2008; 42: 1686–1691. 95. Sima AA. Acetyl-l-carnitine in diabetic polyneuropathy: experimental and clinical data. CNS Drugs 2007; 21: 13–23. 96. Sima AA, Calvani M, Mehra M, et al. Acetyl-l-carnitine improves pain, nerve regeneration, and vibratory perception in patients with chronic diabetic neuropathy: an analysis of two randomized placebo-controlled trials. Diabetes Care 2005; 28: 89–94. 97. Abuaisha BB, Costanzi JB and Boulton AJ. Acupuncture for the treatment of chronic painful peripheral diabetic neuropathy: a long-term study. Diabetes Res Clin Pract 1998; 39: 115–121. 98. Jiang H, Shi K, Li X, et al. Clinical study on the wrist-ankle acupuncture treatment for 30 cases of diabetic peripheral neuritis. J Tradit Chin Med 2006; 26: 8–12. 99. Tong Y, Guo H and Han B. Fifteen-day acupuncture treatment relieves diabetic peripheral neuropathy. J Acupunct Meridian Stud 2010; 3: 95–103. 100. Dubinsky RM and Miyasaki J. Assessment: efficacy of transcutaneous electric nerve stimulation in the treatment of pain in neurologic disorders (an evidence-based review): report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology. Neurology 2010; 74: 173–176. 101. Kumar D and Marshall HJ. Diabetic peripheral neuropathy: amelioration of pain with transcutaneous electrostimulation. Diabetes Care 1997; 20: 1702–1705. 102. Forst T, Nguyen M, Forst S, et al. Impact of low frequency transcutaneous electrical nerve stimulation on symptomatic diabetic neuropathy using the new Salutaris device. Diabetes Nutr Metab 2004; 17: 163–168.
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103. Glombiewski JA, Hartwich-Tersek J and Rief W. Two psychological interventions are effective in severely disabled, chronic back pain patients: a randomised controlled trial. Int J Behav Med 2010; 17: 97–107. 104. Hoffman BM, Papas RK, Chatkoff DK, et al. Meta-analysis of psychological interventions for chronic low back pain. Health Psychol 2007; 26: 1–9. 105. Holroyd KA, O’Donnell FJ, Stensland M, et al. Management of chronic tension-type headache with tricyclic antidepressant medication, stress management therapy, and their combination: a randomized controlled trial. JAMA 2001; 285: 2208–2215. 106. Otis JD, Sanderson K, Hardway C, et al. A randomized controlled pilot study of a cognitive-behavioral therapy approach for painful diabetic peripheral neuropathy. J Pain 2013; 14: 475–482. 107. Daousi C, Benbow SJ and MacFarlane IA. Electrical spinal cord stimulation in the long-term treatment of chronic painful diabetic neuropathy. Diabet Med 2005; 22: 393–398.
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POI0010.1177/0309364614542266Prosthetics and Orthotics InternationalRosenberg
INTERNATIONAL SOCIETY FOR PROSTHETICS AND ORTHOTICS
Literature Review
Treatment of painful diabetic peripheral neuropathy
Prosthetics and Orthotics International 2015, Vol. 39(1) 17–28 © The International Society for Prosthetics and Orthotics 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0309364614542266 poi.sagepub.com
Casandra J Rosenberg1 and James C Watson2
Abstract Background: Painful diabetic peripheral neuropathy impairs quality of life and can be difficult to treat. Objective: To discuss current treatment recommendations for painful diabetic peripheral neuropathy. Study design: Literature review. Methods: Systematic review of the literature discussing treatment of painful diabetic peripheral neuropathy. Existing treatment guidelines were studied and compared. Results: Painful diabetic peripheral neuropathy occurs in about one in six people with diabetes. This condition impairs quality of life and increases healthcare costs. Treatment recommendations exist, but individual patient therapy can require a trial-and-error approach. Many treatment options have adjuvant benefits or side effects which should be considered prior to initiating therapy. Often, a combination of treatment modalities with various mechanisms of action is required for adequate pain control. Adequate medication titration and a reasonable trial period should be allowed. Conclusion: The treatment of painful diabetic peripheral neuropathy can be challenging, but effective management can improve patient’s quality of life. Clinical relevance Painful diabetic peripheral neuropathy impairs quality of life and can be difficult to treat. Many treatment options have adjuvant benefits or side effects which should be considered prior to initiating therapy. Often, a combination of treatment modalities with various mechanisms of action is required for adequate pain control. Keywords Diabetes, neuropathy, painful neuropathy, diabetic peripheral neuropathy Date received: 19 May 2014; accepted: 9 June 2014
Background Diabetes affects more than 25 million people, in the United States representing greater than 11% of the adult population.1 Up to two-thirds of people with diabetes develop peripheral neuropathy, with an increasing prevalence with longer disease duration; 15%–25% of diabetic neuropathies are painful.2–6 Patients with painful neuropathies have healthcare costs three times greater than age matched controls.7 Diabetic peripheral neuropathy (DPN) and its sequelae, including ulceration and loss of limbs, cost the United States between 5 and 15 billion US dollars per year.8 Additionally, painful DPN significantly affects multiple measures of quality of life and is highly associated with depression, anxiety, and sleep disturbances.2,9–11 Developing an individualized treatment plan for a person with painful DPN is challenging.12 Choosing a treatment can be difficult because of a lack of comparative
trials of effective treatments13,14 and limited or conflicting evidence for some treatments.13 Once a treatment is initiated, a patient can experience incomplete pain relief13,15 or suffer from the high side-effect profiles seen with many of the effective treatments.13,16 Over the past decade, the treatment of painful peripheral neuropathies has evolved, and several treatment
1Department
of Anesthesiology, Division of Pain Medicine, Mayo Clinic, Rochester, MN, USA 2Department of Neurology, Mayo Clinic, Rochester, MN, USA Corresponding author: Casandra J Rosenberg, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA. Email: [email protected]
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algorithms have been established (Figure 1).16–20 Each of these guidelines considers treatment efficacy and adverse effects. The Canadian and the International Association for the Study of Pain Neuropathic Pain Special Interest Group (NeuPSIG) guidelines include ease of use and cost-effectiveness, while the NeuPSIG and the American Academy of Neurology (AAN) also consider quality-of-life outcomes. One of the guidelines is strictly for painful DPN,20 and three others include specific subgroup recommendations for DPN.16,18,19
Disease management The first step in the management of painful DPN is treating the cause of neuropathy, the diabetes. There is evidence that tight glucose control, particularly in the early stages of diabetes, can delay progression of painful DPN.21 A recent Cochrane review showed a relative risk of developing DPN of 0.35 for patients who undergo intensive glucose control compared to conventional treatment (95% confidence interval (CI) = 0.23–0.53; p 400 mg/day
Sedation, confusion, dizziness, peripheral edema, euphoria
Sedation, confusion, dizziness, peripheral edema, tremor
Fatigue, nausea, hyperhidrosis
Sedation, dry mouth, orthostatic hypotension, urinary retention, weight gain, confusion, blurred vision, thrombocytopenia
Most common side effects
Nausea, rash, and hypothyroidism
No maximum Constipation, nausea/ dosage vomiting, drowsiness, confusion, dizziness, pruritus
600 mg/day
400 mg/day
600 mg/day
3600 mg/day (divided into three doses)
60 mg twice daily
Maximum dosage
Dosage and titration recommendations
Agent
Table 1. Prescribing recommendations for medications for painful diabetic peripheral neuropathy.
Hypoglycemia
Renal insufficiency (must dose adjust), psychiatric disease (euphoria risk), withdrawal syndromes/seizure with abrupt discontinuation History of substance abuse, sedation, driving impairment, seizure disorder, risk of serotonin syndrome with concomitant use of SSRI, SNRI, and TCAs History of substance abuse, sedation, respiratory depression, driving impairment, seizure disorder, risk of serotonin syndrome with concomitant use of SSRI, SNRI, and TCAs; hepatic dysfunction History of substance abuse, driving impairment, tolerance, abuse, diversion
Small risk of emerging suicidality (boxed warning), caution in patients with cardiac disease (high dosages >100 mg daily associated with sudden cardiac death and dysrhythmias), serotonin syndrome, glaucoma Small risk of emerging suicidality (boxed warning), increased bleeding risk (care with anticoagulants), withdrawal syndromes with abrupt discontinuation, serotonin syndrome, hepatic failure Renal insufficiency (must dose adjust), withdrawal syndromes/seizure with abrupt discontinuation
Precautions
Few toxicities
Rapid onset analgesic benefit
Rapid onset analgesic benefit
Improvement of sleep disturbance, fibromyalgia, and anxiety; no clinically significant drug interactions Rapid onset analgesic benefit
Improvement of sleep disturbance, anxiety, hot flashes; no clinically significant drug interactions
Treats depression and anxiety (at similar dosage used for pain), as well as myofascial pain
Improvement of depression (though typical doses for pain are lower than doses necessary for depression)
Other benefits
22 Prosthetics and Orthotics International 39(1)
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Rosenberg
No known systemic toxicities
Not recommended for face or around mucous membranes or over broken skin; apply wearing gloves Not recommended around mucous membranes or over broken skin
Alpha-lipoic acid. A lipophilic antioxidant, alpha-lipoic acid (ALA), has been shown to improve nerve blood flow and distal conduction and to reduce oxidative stress.90 The primary side effect is nausea. Both oral (at a dosage of 600 mg per day) and intravenous supplementation have been shown to improve symptoms of painful DPN.91,92 Acetyl-l-carnitine. Acetyl-l-carnitine (ALC) has shown improved peripheral nerve conduction velocity and nerve regeneration, thought to be due to its antioxidant properties and role in catabolism/anabolism.93 Several studies have shown benefit in patients with painful DPN (at a dosage of 1000 mg three times daily by mouth) (Table 1).94–96
Therapeutic modalities Acupuncture SSRI: selective serotonin reuptake inhibitor; SNRI: serotonin and norepinephrine reuptake inhibitors; TCA: tricyclic antidepressant. Based on information from Dworkin et al.18.
Apply up to three patches for 12 h daily; may cut to shape
Topical capsaicin (0.075%–0.75% cream) Topical lidocaine (5% patch)
May apply up to four patches at one time. Before patch application, use topical anesthetic for 60 min, remove, and confirm anesthesia. Place patch over symptomatic area for 60 min. Should be placed by medical staff trained in its usage using non-latex gloves. May cut patch to shape. Following treatment, wash with provided soap. Apply cream to affected areas four times daily Topical capsaicin (high concentration 8% patch)
Local skin problems such as erythema, burning, or pain Local skin problems such as burning, irritation
Low risk of systemic toxicity
No known systemic toxicities Unknown risk from repeated exposures, not recommended for face or over broken skin
Few toxicities 1000 mg three times per day Acetyl-l-carnitine
Agitation, nausea, vomiting, bloating Local skin problems such as erythema, burning, or pain (patients frequently require prescription analgesics for 1–2 weeks after application)
Maximum dosage Dosage and titration recommendations Agent
Table 1. (Continued)
Most common side effects
Precautions
Other benefits
Other supplements
Acupuncture has been shown to be effective for painful DPN in small trials without placebo control.97–99
Transcutaneous electrical nerve stimulation Transcutaneous electrical nerve stimulation (TENS) delivers an electrical current via electrodes on the skin arranged about the affected area. The intensity, frequency, and pattern of stimulation can be adjusted by the patient or therapist. Several studies including sham treatment arms have demonstrated benefit in painful DPN.100–102
Cognitive behavioral therapy Cognitive behavioral therapy (CBT) replaces dysfunctional thoughts and behaviors with positive ones and has been found effective in multiple pain states.103–105 One randomized pilot study showed benefit for patients with painful DPN as compared to typical management.106
Advanced interventions In addition to medications, several interventions are gaining interest in the treatment of painful neuropathies. Interventional treatments have previously been described as “invasive procedures involving delivery of drugs into targeted areas, or ablation/modulation of targeted nerves.”13 Recently, the NeuPSIG compiled evidence for interventional treatments in the management of neuropathic pain, including a subgroup analysis for painful DPN in combination with other painful peripheral neuropathies.
Neuromodulation Neuromodulation involves the application of electrical current to neural structures to modulate neural transmission.
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The most common method of neuromodulation for pain is dorsal column stimulation, also known as spinal cord stimulation (SCS). Small electrodes are implanted in the epidural space and connected to a battery-operated pulse generator implanted in the flank or abdominal wall. Prior to implantation, a trial of stimulation with temporary percutaneous electrodes is undertaken to ensure effective pain relief. Several non-randomized case series have demonstrated pain relief of peripheral neuropathy even in medically resistant cases.107–109 A single study with a crossover-type design showed benefit compared to sham stimulation.108 For isolated mononeuropathies, placement of a traditional stimulator lead immediately adjacent to the affected nerve has been described.110
Intrathecal drug delivery systems Intrathecal drug delivery systems (IDDS) use a surgically implanted pump attached to a small, flexible catheter tunnelled into the cerebrospinal fluid (CSF). Morphine and ziconotide (a selective N-type voltage-gated calcium channel blocker) are FDA-approved medications for intrathecal infusion.111,112 There are currently no studies showing evidence for intrathecal drug delivery specifically for neuropathic noncancer pain. Given concentrated drug delivery into the CSF, intrathecal systems may be useful when systemic side effects from oral analgesics or adjuvants are limiting. Factors that increase the risk of IDDS implantation in diabetic patients include impaired wound healing, relative immunosuppression increasing the risk of infection, and comorbid cardiovascular or renal disease. If an intrathecal drug delivery system is being considered in a diabetic patient, it is recommended that their glucose control is optimized prior to implantation.113 Patients with an intrathecal system need to be able to maintain regular follow-up for system refills and adjustments.
Managing expectations is vital when starting or changing medications. Most treatments are considered successful if they provide 30%–50% improvement or at least 2 points on a 10-point Likert scale. For some patients, this improvement will be worthwhile, while others may weigh the benefits less favorably relative to the side effects of the medication. Medication side effects can be a barrier to treatment success. A frank conversation discussing common or serious side effects should be had prior to starting a new treatment. Many of these treatment side effects can be improved over time due to progressive tolerance; these can be mitigated at the start of treatment by gradual up-titration of the medication dose. Each medication should be maintained at the lowest effective dose. For patients who have had prior medication trials to treat their painful DPN, it is important to ensure that their trial was adequate in dosage achieved and duration of treatment (several weeks at goal dosage). It is common that a prior trial was inadequate and that a retrial may be appropriate. Finally, an important strategy to the management of painful DPN is multimodal therapy. Many studies show benefit from combination therapies. This strategy is likely effective due to the additive effects of pain relief from multiple mechanisms of action. It is important to carefully consider the individual treatments to avoid unpleasant or life-threatening side effects, such as serotonin syndrome with combinations of high-dose TCAs and tramadol. Topical medications, behavioral strategies, and physical modalities can be particularly beneficial in combination with other treatments due to their negligible side-effect profiles. Author contribution All authors contributed equally in the preparation of this manuscript.
Declaration of conflicting interests
Conclusion While painful DPN can prove difficult to treat, there are a variety of therapeutic options, including behavioral therapies, physical modalities, topical and oral medications, and implantable devices. There are several key concepts for developing a treatment approach. Tight glycemic control is important to delay onset and progression of painful DPN. Consideration of comorbid conditions including sleep disturbance, depression, and other pain states is important both to minimize the pain of DPN itself and when selecting the most appropriate medical therapy. Many painful DPN treatments can also address other comorbid conditions. Furthermore, some medication side effects could exacerbate preexisting problems and should be avoided.
None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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