Painful Diabetic Neuropathy: Brilliantly reviewed by our esteemed friends, Drs. Casandra Rosenberg and James Watson

Literature Review

Treatment of painful diabetic peripheral neuropathy

Casandra J Rosenberg1 and James C Watson2

Abstract

INTERNATIONAL
SOCIETY FOR PROSTHETICS AND ORTHOTICS

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

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 popula- tion.1 Up to two-thirds of people with diabetes develop peripheral neuropathy, with an increasing prevalence with longer disease duration; 15%–25% of diabetic neuropa- thies 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 mul- tiple 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 per- son with painful DPN is challenging.12 Choosing a treat- ment 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 initi- ated, 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 periph- eral 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-effec- tiveness, while the NeuPSIG and the American Academy of Neurology (AAN) also consider quality-of-life out- comes. One of the guidelines is strictly for painful DPN,20 and three others include specific subgroup recommenda- tions for DPN.16,18,19

Disease management

The first step in the management of painful DPN is treat- ing the cause of neuropathy, the diabetes. There is evi- dence 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 devel- oping DPN of 0.35 for patients who undergo intensive glu- cose control compared to conventional treatment (95% confidence interval (CI) = 0.23–0.53; p < 0.00001; I2 = 0%; 1203 participants; three trials).22 Neuropathic pain symp- toms may improve with tight glycemic control; however, if this occurs, the reversal of symptoms is limited and the primary goal of disease treatment is to prevent or slow pro- gression. Comorbid conditions such as depression, anxi- ety, sleep impairment, and renal dysfunction can affect pain and should also be addressed.11,13,23,24

Medications

Careful consideration of several patient factors can improve success in medical therapy of painful DPN. First, the patient’s medical comorbidities should be considered. Limiting factors such as pulmonary, cardiovascular, renal, or hepatic impairment should be identified as these may influence medication choice. In certain patients, physio- logic testing (such as electrocardiogram (EKG) prior to initiating tricyclic antidepressants (TCAs)) or laboratory testing (such as creatinine or liver function tests) may be required prior to medication initiation. Next, comorbid conditions which might benefit from the same medication used to treat the painful DPN, such as insomnia, depres- sion, fibromyalgia, or headache, should be noted as treat- ing two processes with one medication would be preferable to initiating separate treatments. Finally, the medication side-effect profile should be considered, and the risk-to- benefit ratio weighed.

Neuropathic pain medications rarely resolve pain. However, even a modest to moderate decrease in the patient’s reported pain level can be clinically meaningful and improve a patient’s quality of life. An improvement of 30% or 2 points on a 0–10 Likert scale has been found to be clinically meaningful to patients.25 The practitioner and the patient should discuss expectations and treatment goals to maximize outcomes. When a neuropathic pain medica- tion is tolerated and partially effective, but insufficient to

improve function, a second agent with a distinct mecha- nism of action should be added. Many studies show an additive benefit when combining medications from differ- ent classes.26–28 Most treatment guidelines recommend adding an additional agent rather than transitioning from one agent to another, particularly if some benefit was achieved from the initial medication.18,19

TCAs

Mechanism. TCAs prevent the reuptake of norepinephrine and serotonin; antagonize N-methyl-d-aspartate (NMDA), 5-HT, histamine, muscarinic, and alpha-adrenergic recep- tors; and inhibit sodium and l-type calcium channels.16 Each of these effects may have an impact on pain regulation.

Additional benefits. TCAs are approved for the treatment of depression by the US Food and Drug Administration (FDA), though dosing needed for therapeutic benefit in painful DPN is usually lower than that required for the treatment of depression.29 Additional off-label uses include insomnia, chronic myofascial pain, fibromyalgia, migraine headache, irritable bowel syndrome, and smoking cessation.30–32

Side effects. The most common TCA side effects are dry mouth, decreased gastrointestinal (GI) motility, orthostatic hypotension, weight gain, urinary retention, and cognitive dysfunction.33 Sedation is common and nighttime dosing may improve sleep and limit daytime drowsiness. Toler- ance to side effects develops, and a low starting dose with gradual up-titration is recommended.19 The most severe side effects are cardiac dysrhythmias, and an EKG to screen for conduction system disease in elderly or at-risk patients is recommended prior to initiation of therapy.34,35 As with other antidepressants, there is a slightly increased risk of suicidal thoughts or actions in young adults.36 TCAs confer a risk of serotonin syndrome when used with other medications that affect serotonin (other antidepressants, tramadol, tapentadol, some antiemetics) and should be used with caution at lowered goal dosages when used in combination with other serotonergic agents. TCAs can also lower the seizure threshold.37

DPN evidence. All of the medication treatment guidelines include the TCAs as first-line medications unless contrain- dicated, with one exception.20 TCAs have robust evidence supporting analgesic efficacy in painful neuropathies com- pared to placebo.12 Head-to-head trials have shown equal analgesic efficacy to gabapentin19,26,38

Serotonin–norepinephrine reuptake inhibitors

Mechanism. Serotonin–norepinephrine reuptake inhibitors (SNRIs) affect the balance of these central nervous system neurotransmitters, which is thought to promote

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Figure 1. Treatment algorithm for painful diabetic peripheral. TCA: tricyclic antidepressant.

anti-nociception and reduce pro-nociception.39 While the primary mechanism of action is similar to TCAs, dosing is generally less limited by anticholinergic, antiadrenergic, or muscarinic side effects.

Additional benefits. Duloxetine is a balanced SNRI (block- ing serotonin and norepinephrine equally) that is approved by the FDA for painful DPN, fibromyalgia, chronic mus- culoskeletal pain, depression, and anxiety.40,41 A potential

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advantage of duloxetine is that the therapeutic dosages are similar for each condition such that it can be used to treat two comorbid conditions without dosage adjustment. Other SNRIs, including venlafaxine, may have similar neuropathic pain treatment effects, but have not been as rigorously studied and are only FDA approved for depres- sion and anxiety.

Side effects. Common SNRI side effects include GI upset, headache, and insomnia. Unique side effects with duloxe- tine are hyperhidrosis and a possible increase in bleeding risk.42,43 Side effects are typically less bothersome than those seen with TCAs.41 As with other antidepressants, there is a slightly increased risk of suicidal thoughts or actions in young adults.36 Like TCAs, SNRIs also decrease the seizure threshold, and their serotonergic effect gives a risk of serotonin syndrome.44

Evidence. Two of the above guidelines list SNRIs as first- line treatment options.16,18 Studies have suggested similar efficacy of duloxetine to amitriptyline, with a slightly bet- ter side-effect profile.45

Calcium channel blockers: gabapentin and pregabalin

Mechanism. Gabapentin and pregabalin block the presyn- aptic calcium channel at the α2δ ligand, inhibiting release of excitatory neurotransmitters. Additionally, they may antagonize NMDA receptors associated with pain signaling.46,47

Additional benefits. Pregabalin is FDA approved for the treatment of painful DPN, post-herpetic neuralgia, central neuropathic pain, and fibromyalgia.48 Gabapentin is FDA approved for post-herpetic neuralgia but is also commonly used for other neuropathic pain states.49 Other benefits of the gabapentanoids are improved sleep50 and possibly anxiolysis.51

Side effects. Common gabapentin and pregabalin side effects include cognitive slowing, drowsiness, dizziness, and peripheral edema.17 Pregabalin can cause euphoria in a very small percentage of patients, which may be a con- sideration in patients with psychiatric comorbidities.52 As both gabapentin and pregabalin are renally excreted, dos- age adjustment is required in the setting of renal impair- ment. There are minimal significant medication interactions. As with antidepressants and other antiepilep- tic medications, there is a slightly increased risk of suicidal thoughts or actions in young adults.49

Evidence. Gabapentin has been shown to be as efficacious as the TCA nortriptyline.26 Gabapentin or pregabalin are recommended as first-line medications in the majority of

the above guidelines17–20 with one guideline giving prefer- ence to pregabalin over gabapentin or antidepressants,20 and another as a second choice if TCAs are contraindi- cated.16 One guideline recommends earlier-generation anticonvulsants first; however, gabapentin and pregaba- lin’s minimal drug interactions and reduced requirement for monitoring can be advantages over other anticonvulsants.53

Opioids, including tapentadol and tramadol

Mechanism. Opioid medications bind to μ and other opioid receptors on neuronal cell membranes, modulating descending inhibitory and ascending excitatory pain mechanisms. Their primary analgesic targets are in the spi- nal cord and elsewhere in the central nervous system, but receptors throughout the body are responsible for analge- sia and opioid-related side effects.

Tapentadol is a partial μ agonist with a norepinephrine reuptake inhibitory effect.54 Tramadol is also a partial μ receptor agonist and has both serotonin and norepineph- rine reuptake inhibition.55,56

Additional benefits. The main therapeutic benefit of opioid medications is analgesia. Opioid medications should not be used for insomnia, anxiolysis, or other indications.

Tapentadol is FDA approved for painful DPN.57 It is postulated that the combined μ receptor activation and norepinephrine reuptake inhibition of tramadol and tapen- tadol offers additional benefit compared to the single- mechanism agents.58,59

Side effects. A primary concern in the prescription of opi- oid medications is their potential for misuse. Opioids acti- vate the brain’s mesolimbic reward center, resulting in feelings of pleasure which can lead to craving and compul- sive use.60 Opioids are the most commonly misused pre- scription medication in the United States and are responsible for the majority of prescription drug–related acute hospital admissions and drug treatment center admis- sions.61 Tolerance and physical dependence, resulting in the need for gradually increasing dosage as well as with- drawal symptoms if the medication is decreased or discon- tinued, are an inherent physiologic response to the medication and should not be confused with addiction. Addiction involves craving and compulsive use despite harm.62

The most serious side effect of opioid medications is respiratory depression. The effect can be additive with other substances such as benzodiazepines and alcohol. Other side effects include nausea, vomiting, pruritus, con- stipation, sedation, and dizziness. Overdose or accumula- tion of breakdown products can produce myoclonus and contribute to sedation and respiratory depression. Over time, immune and endocrine dysfunction, including

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hypotestosteronism, occur. Another potential issue with chronic opioid use is opioid-induced hyperalgesia, a state of increased sensitivity to pain and worsening of pain while receiving opioids. This can be particularly problem- atic in patients who already struggle with pain issues.63 Opioids should be used with caution in renal and hepatic impairment, particularly with extended or continuous release formulations.64,65

Tramadol and tapentadol can contribute to serotonin syndrome and can lower the seizure threshold. They should also be used with caution in patients with renal and hepatic impairment and in those receiving other medications with serotonergic effects.66–68

Evidence. There is evidence that opioid medications are effective in painful DPN,69–71 including tramadol55,56 and tapentadol.72 Notably, most studies were carried out with extended or continuous release formulations.55,69,70,72 Opi- oids are included in the treatment algorithms as later-tier choices due to issues with long-term use and risks.20 Their later-tiered position in the treatment algorithms is large part related to the potential adverse effects and chronic use risks inherent with opioids. However, they may be useful in appropriately selected and monitored patients. In a crossover trial for post-herpetic neuralgia, patients pre- ferred extended release morphine to nortriptyline.73

There are multiple established guidelines for opioid pre- scribing risk mitigation.74 Similar to other painful DPN treatments, an opioid trial should include pre-determined goals for pain and functional improvement. A treatment agreement should be agreed upon and maintained, and reg- ular screening for aberrant use, abuse, misuse, and diver- sion should be completed, including urine drug screening to confirm appropriate medication and breakdown products and to screen for other medication or substance use that could increase the patient’s treatment-related risk.74

Topical agents

Topical agents carry the advantage of limited systemic side effects, making them excellent first-line or adjuvant pain medications. Topical creams and gels can cover a wide area. Patches can be less practical given their limited size and the typical distribution of DPN involving the feet.

Topical capsaicin, including high-dose patches (Qutenza)

Mechanism. Capsaicin is an active component of chili pep- pers. It binds to the TRPV1 heat-activated calcium channel and causes it to open at normal body temperature. Pro- longed activation of the receptor results in the depletion of neurotransmitters, particularly substance P, and reduces the ability of neurons to transmit pain signals. Standard capsai- cin creams come in concentrations of 0.025%–0.25%.

They must be applied multiple times per day for several weeks before analgesic effects become significant. Qutenza is a capsaicin patch with an 8% concentration. It is applied after appropriate local analgesia with topical lidocaine and left in place for 60 minutes. A single applica- tion of the Qutenza patch may provide up to 3 months of pain relief.

Side effects. Skin irritation is the most common side effect and many patients do not tolerate capsaicin treatment.75,76 During and after administration of the 8% capsaicin patch, pain can be significant (like a severe sunburn) and may require medical management with opioids for a number of days following application.77 Extreme caution must be used to avoid contact of any concentration of capsaicin with the eyes or mucous membranes.

Evidence. A meta-analysis of studies reported a pooled 2.35 odds ratio in favor of capsaicin over placebo (95% CI = 1.48–3.22).12 High-dose capsaicin was most effective in patients with post-herpetic and human immunodefi- ciency virus–related neuropathies.78 Qutenza is FDA approved for post-herpetic neuralgia.

Lidocaine, including patches

Mechanism. Lidocaine blocks voltage-gated sodium chan- nels, which stops propagation of action potentials in neu- rons.79 A 5% concentration patch is available.

Side effects. With 12 h of continuous wear of the 5% patch, only 3% of the total dose is absorbed, making systemic side effects unlikely.80 Skin irritation is the most common side effect.80

Evidence. The lidocaine 5% patch is FDA approved for post-herpetic neuralgia. The patch has been found to reduce pain and improve quality of life in DPN.81 Lido- caine patches were found to give a similar degree of ben- efit as pregabalin to patients with DPN, as well as additional benefit when used in conjunction with pregabalin.82

Other topical agents

Menthol. Menthol transiently activates TRPM8 ion chan- nels, causing an endogenous cooling-induced analgesia.83 There are no randomized controlled trials for neuropathic pain; case reports and small studies have shown some benefits.84,85

Amitriptyline, ketamine and baclofen. These medications are typically compounded in a cream or pluronic lecithin organogel base for topical application. Studies show no systemic toxicities, but have mixed results, at best, for the treatment of neuropathic pain.86–89

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The most common method of neuromodulation for pain is dorsal column stimulation, also known as spinal cord stimu- lation (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 implanta- tion, 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 tradi- tional 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 tun- nelled into the cerebrospinal fluid (CSF). Morphine and ziconotide (a selective N-type voltage-gated calcium chan- nel blocker) are FDA-approved medications for intrathecal infusion.111,112

There are currently no studies showing evidence for intrathecal drug delivery specifically for neuropathic non- cancer 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 intrath- ecal system need to be able to maintain regular follow-up for system refills and adjustments.

Conclusion

While painful DPN can prove difficult to treat, there are a variety of therapeutic options, including behavioral thera- pies, 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 medi- cal therapy. Many painful DPN treatments can also address other comorbid conditions. Furthermore, some medication side effects could exacerbate preexisting problems and should be avoided.

Managing expectations is vital when starting or chang- ing medications. Most treatments are considered success- ful 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 seri- ous side effects should be had prior to starting a new treat- ment. Many of these treatment side effects can be improved over time due to progressive tolerance; these can be miti- gated 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

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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