Challenges in the management of painful diabetic peripheral neuropathy

Diabetic neuropathy (DN) comprises a group of disorders that damage the nervous system and affect up to 50% of people with diabetes¹. The most common form of DN is diabetic peripheral neuropathy (DPN), which may progress to neuropathic pain and is a leading risk factor for foot ulceration and amputation^2-4.

Painful DPN (PDPN) affects 20–24% of people with diabetes and significantly impairs quality of life, mental health and sleep⁵. PDPN pain is described as 'burning', 'tingling' or 'electric shock-like', and is accompanied by numbness, paraesthesia or hyperalgesia⁶.

Challenges in PDPN management include guideline inconsistencies, PDPN that is refractory to treatment, and few mechanistic-based therapies^6-12

Challenges in managing painful diabetic peripheral neuropathy

Guideline inconsistencies

• Sodium channel blockers (carbamazepine, oxcarbazepine, lamotrigine, lacosamide): not considered in all guidelines^6-12
• Serotonin and norepinephrine reuptake inhibitors (SNRI)/opioid dual mechanism (tramadol, tapentadol): several guidelines support tramadol and tapentadol for second- or third-line treatment^6,8,9; however, the American Association of Clinical Endocrinology (AACE) and the American Academy of Neurology (AAN) do not support these medications for PDPN^11,12
• Opioids: several guidelines recommend opioids for second- or third-line^6,8-10
• Capsaicin 8% patch: recommended first-line therapy by the AACE, AAN, and German Diabetes Association (DDG)^9,11,12; third-line by the International Diabetes Federation (IDF) recommendations¹⁰, but not considered by ADA and Diabetes Canada guidelines^6,8
• Lidocaine 5% infusion: not considered in many guidelines^6,8-12
• α-Lipoic acid: not considered or not recommended by many guidelines^6,8,10-12

An overview of pain management in PDPN is captured in Table 1^6,8-12.

Table 1. Guideline pharmacotherapy recommendations for painful diabetic peripheral neuropathy^6,8-12.

1: first line; 2: second line; 3: third line; NR: not recommended; UR: unclear recommendation; –: not considered. *γ-linolenic acid is no more likely than α-lipoic acid to improve pain for PDPN¹¹. Abbreviations: AACE, American Association of Clinical Endocrinology; AAN, American Academy of Neurology; ADA, American Diabetes Association; DC, Diabetes Canada; DDG, German Diabetes Association; IDF, International Diabetes Federation; SNRIs, serotonin and norepinephrine reuptake inhibitors.

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Management options for refractory PDPN

Patients who do not respond to first-line treatments for PDPN are at risk of progressing to refractory PDPN. The patient with suspected refractory PDPN should be referred to a pain management specialist, neurologist, or endocrinologist with pain expertise.

As medications prescribed for PDPN can impose a significant side-effect burden, clinical consideration of patient comorbidities and contraindications is necessary^6-12

Treatment options for refractory PDPN in the specialist setting include off-label botulinum toxin, spinal cord stimulation and lidocaine infusions¹³. Infusing lidocaine can be analgesic for chronic neuropathic pain. For example, a randomised controlled trial (RCT) of patients with refractory neuropathic pain found that infusing 3 mg/kg lidocaine provided analgesia, which was maintained after repeated infusions¹⁴.

Few mechanism-based treatments for PDPN

Explaining the neurobiology of PDPN is important for the development of mechanism-based therapies^6-12. Several current treatments show efficacy for PDPN based on the irritable versus non-irritable nociceptor phenotype^15,16, intraepidermal nerve fibre density^17,18, or the Hoffman reflex rate-dependent depression (HRDD)^19,20.

Irritable versus non-irritable nociceptor phenotype

An RCT investigating oxcarbazepine (sodium channel antagonist) for peripheral neuropathic pain found greater efficacy in people with the irritable versus non-irritable nociceptor phenotype¹⁵. Similar findings have been published for use of intravenous lidocaine¹⁶ and the lidocaine 5% patch²¹.

Intraepidermal nerve fibre density

Topical clonidine can benefit individuals with PDPN and functional nociceptors, with the level of nociceptor functionality positively associated with the density of intraepidermal nerve fibres¹⁸. Thus, investigation of cutaneous nociceptor function could identify patients with PDPN for topical treatment¹⁸. In a trial of pregabalin for prediabetic neuropathic pain, non-responders had lower intraepidermal nerve fibre density¹⁷. Small nerve fibres could therefore be a factor for explaining the beneficial effects of medications for PDPN.

Hoffman’s reflex rate-dependent depression

A mechanism of treatment response for PDPN could be the HRDD. Preclinical models of diabetes and patients with PDPN versus DPN demonstrate impaired HRDD¹⁹. Gabapentin modified diabetes-induced loss of RDD has been observed, suggesting that HRDD could predict efficacy of gabapentin for PDPN²⁰.

Conclusion

Painful diabetic peripheral neuropathy affects roughly over 100 million people worldwide. The disorder significantly impairs quality of life, mental health and sleep quality. Most guidelines consistently recommend gabapentinoids, tricyclic antidepressants and SNRIs as first- or second-line treatment for PDPN. However, inconsistencies exist for second- and third-line treatments, complicating treatment selection for refractory PDPN. Investigations should evaluate the reasons for guideline inconsistency, the consequences for developing recommendations, and the role of evidence synthesis across recommendations for effective management of PDPN. Further studies are needed for developing mechanistic-based treatments for PDPN. Such treatments could make personalised treatment of PDPN an option for patients.

References

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