Current approaches to the management of peripheral neuropathic pain

  Dr Jan H Vranken Dr Jan H Vranken is an anaesthesiologist – pain specialist at Slotervaartziekenhuis and Medical Centre Jan van Goyen, Amsterdam, The Netherlands

Published 1 September 2014

Neuropathic pain can be challenging to manage, Dr Jan H Vranken describes the many options for treatment

Key learning points

• Symptoms and signs of neuropathic pain can be both positive and negative.
• Tricyclic antidepressants are the first-line treatment option for neuropathic pain.
• Opioid agonists have demonstrated efficacy in patients with neuropathic pain.
• Combination therapy in the management of neuropathic pain is not well researched.

Introduction

Chronic pain of moderate-to-severe intensity has been shown to occur in 19% of adult Europeans, seriously affecting the quality of their social and working lives.¹ Neuropathic pain is relatively common, occurring in about 3–8% of the general population.² The clinical description of neuropathic pain, as defined by the the Assessment Committee of the Neuropathic Pain Special Interest Group (NeuPSIG) of the International Association for the Study of Pain (IASP), is ‘pain arising as a direct consequence of a lesion or disease affecting the somatosensory system’.³
The symptoms and signs of neuropathic pain include positive signs such as paraesthesia, dysaesthesia, hyperalgesia and allodynia and negative signs due to sensory deficits (hypoesthesia and hypoalgesia), weakness and reflex changes. Clinically, patients may complain of spontaneous ongoing pain (stimulus-independent pain), which is burning with intermittent shooting or electric shock-like (lancinating) sensations and/or of pain hypersensitivity evoked in response to stimuli (stimulus evoked pain) such as hyperalgesia and allodynia.⁴

The first-line treatment for neuropathic pain is a tricyclic antidepressant
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Mechanisms of neuropathic pain

Studies in animal models indicate a number of peripheral and central pathophysiological processes occurring after nerve injury that could be the basis of underlying neuropathic pain mechanisms. Changes in the function, chemistry and structures of neurons (neural plasticity) may underlie the altered sensitivity characteristics of neuropathic pain. Peripheral sensitisation occurs at the peripheral nociceptors and central sensitisation takes place at various levels, ranging from the dorsal horn to the brain. In addition, abnormal interactions between the sympathetic and sensory pathways contribute to mechanisms that mediate neuropathic pain.⁴

Pharmacological treatment of neuropathic pain

Neuropathic pain is challenging to manage. Many patients have pain that is refractory to existing treatments despite the availability of numerous treatment options. Randomised controlled trials (RCTs) that have examined pharmacotherapy have indicated that no more than half of patients experience clinically meaningful pain relief, which is almost always partial not complete relief. In addition, patients frequently experience burdensome adverse effects and as a consequence are often unable to tolerate the treatment.⁵

Antidepressants

There is clear evidence for the effectiveness of antidepressants in the treatment of neuropathic pain.
Tricyclic antidepressants (TCA) including amitriptyline and nortriptyline, interact with pathways running through the spinal cord from serotonergic and noradrenergic structures in the brain stem and midbrain. The predominant mechanism of action is by blocking the reuptake of norepinephrine and serotonin (dual-acting). However, treatment with these analgesics may be compromised (and outweighed) by their side-effects. It is advised that TCAs are used cautiously in patients with a history of cardiovascular disorders, glaucoma and urine retention.⁴
Venlafaxine is a serotonin–norepinephrine reuptake inhibitor and may be considered as an alternative to TCAs in relieving neuropathic pain. Venlafaxine does not have the anticholinergic, antihistaminergic or alpha1- and alpha2-blocking side effects of TCAs and therefore has fewer contraindications to use. Venlafaxine at higher dosages has shown efficacy in painful diabetic peripheral neuropathy and painful polyneuropathies of different origins but not in postherpetic neuralgia.⁴
Duloxetine enhances both serotonin and norepinephrine function in descending modulatory pathways. It has weak affinity for the dopamine transporter and insignificant affinity at several neurotransmitters including muscarinic, histamine, glutamate and GABA receptors. Duloxetine (at dosages of 60mg and 120mg daily) has demonstrated significant pain relieving effect with a generally favourable side-effect profile in painful diabetic neuropathy.⁴
Selective serotonin reuptake inhibitors, SSRIs, may be, at this time, more appropriate for the management of psychological dysfunction associated with severe neuropathic pain.⁴

Calcium channel alpha2-beta ligands

Gabapentin and pregabalin are considered to be first-line treatment options for the treatment of neuropathic pain. The mechanism of action is likely to be mediated via binding to the alpha2-beta subunit of voltage-gated calcium channels and inhibition of glutamate release pre- and postsynaptically in the central nervous system, reducing elements of central sensitisation. Recent studies confirm the effectiveness of pregabalin in peripheral (including postherpetic neuralgia and diabetic polyneuropathy) and central neuropathic pain. The absence of known drug–drug interactions makes pregabalin an important treatment option for older patients with pain of neuropathic origin.⁴

Topical treatment

Neuropathic pain syndromes are typically associated with touch-evoked allodynia and hyperalgesia that impact on patients’ quality of life. Application of topical drugs onto the painful skin area may be effective in treating ongoing pain and allodynia, supporting the idea that peripheral actions are of key importance in the initiation and maintenance of neuropathic pain. Topical treatments for neuropathic pain include lidocaine and capsaicin patches. The lidocaine 5% patch has shown efficacy and tolerability in RCTs involving patients with postherpetic neuralgia and allodynia, and in patients with allodynia due to different types of peripheral neuropathic pain. The fewer systemic adverse effects and drug interactions associated with localised treatment may be particularly advantageous in older patients or patients with complex neuropathic pain.⁴ Capsaicin, either as repeated application of a low dose (0.075%) cream or a single application of a high dose (8%) patch may provide a degree of pain relief to some patients with painful neuropathic conditions. In patients with postherpetic neuralgia, a single 60-minute application of the 8% patch produced significant reduction in pain that was maintained over a 12-week period.⁶

Opioid analgesics, tapentadol and tramadol

Opioids inhibit noxious transmission via pre- and postsynaptically-located opioid receptors in the dorsal horn and at sites in the brain. A review indicated that opioids alleviated nociceptive and neuropathic pain with a mean decrease in pain intensity of at least 30% (comparable to TCAs). Although definitive evidence does not exist, it appears that some opioids may be relatively more effective at providing analgesia for patients with neuropathic pain than others. Based on the literature, oxycodone and methadone have been shown to be particularly effective against neuropathic pain.⁴
Oxycodone is a mu-opioid receptor agonist, although its binding affinity for this receptor appears to be less than that of morphine or methadone. However, some animal studies indicate that the antinociceptive effects of oxycodone may be kappa-opioid receptor-mediated, potentially making it well suited for treating neuropathic pain.⁴
Methadone is a synthetic mu- and delta-opioid receptor agonist with N-methyl-D-aspartate (NMDA) receptor antagonist affinity (similar to that of ketamine). Due to its interaction with the NMDA receptor, methadone may induce an analgesic effect in patients with neuropathic pain.⁴
Tapentadol is a novel, centrally-acting analgesic that acts via a dual mechanism of action, both mu-opioid receptor agonism and norepinephrine reuptake inhibition. Tapentadol has been shown to inhibit hyperalgesia in a neuropathic pain model, most likely due to its inhibition of norepinephrine reuptake; however, it has not been shown to be better than any other opioids or tramadol at alleviating neuropathic pain.⁴
Opioid analgesics have shown efficacy in several high-quality RCTs involving patients with different types of neuropathic pain. In a systematic review on the efficacy of tramadol in treating neuropathic pain, tramadol was found to be effective. Opioids can be considered for first-line use in select clinical circumstances, for example, for patients with acute neuropathic pain, neuropathic pain due to cancer and episodic exacerbations of severe neuropathic pain.⁴

Anticonvulsant medication

The rationale for the use of antiepileptic drugs in treating neuropathic pain is the reduction of neuronal hyperexcitability, one of the key processes in the development and maintenance of neuropathic pain. Carbamazepine has been shown to be effective in chronic neuropathic pain although the side effect and complicated pharmacokinetic profile limit its use. Sodium valproate may reduce pain in diabetic neuropathy and postherpetic neuralgia, but evidence is insufficient to support its use as a first-line treatment for neuropathic pain.⁴
There is limited and conflicting evidence on the effectiveness of lamotrigine in the management of neuropathic pain syndromes. Although increasing evidence suggests that vigabatrin, topiramate, tiagabine, levetiracetam and zonisamide may be useful in treating neuropathic pain, there is a lack of large, published RCTs to determine their role in neuropathic pain.⁴

NMDA receptor antagonists

Several uncompetitive NMDA receptor channel antagonists including dextromethorphan, amantadine, memantine and ketamine have been reported to relieve pain in various neuropathic pain states including phantom limb pain, central neuropathic pain, postherpetic neuralgia and peripheral neuropathic pain. Subanaesthetic doses of ketamine, given parenterally, neuraxially, nasally or orally, have been shown to alleviate pain postoperatively and in a variety of neuropathic pain conditions. However, because of the side effect profile, ketamine has to be considered a third-line option, for use when other standard analgesic treatments are exhausted.⁴

Summary and conclusions

Recent advances in pain research indicate multiple mechanisms underlying the initiation and maintenance of neuropathic pain. Several drug classes are associated with improvements in neuropathic pain and different guidelines on the diagnosis and pharmacological management of neuropathic pain are available; for example, NeuPSIG and European Federation of Neurological Societies (EFNS) guidelines.^2,6 TCAs are often the first drugs selected to alleviate neuropathic pain; however, treatment may be compromised (and outweighed) by their side effects.⁴ Duloxetine and venlafaxine may be considered suitable alternatives for TCAs.
In patients with a history of cardiovascular disorders, glaucoma and urine retention, gabapentin and pregabalin are emerging as first-line treatment options for neuropathic pain.⁴ In patients with postherpetic neuralgia and in patients with diverse peripheral neuropathic pain conditions and allodynia, topical administration of lidocaine may be recommended as first-line treatment.⁵ In addition, opioid agonists have demonstrated comparable efficacy with TCAs and gabapentin or pregabalin. Finally, there are a number of medications, including NMDA receptor antagonists and topical capsaicin, that are generally used as third-line treatments because of weak efficacy, discrepant results or safety concerns.⁴ Although combination treatment is common in clinical practice and potentially may result in greater pain relief, trials of different combinations of analgesics are scarce. If medical treatments have failed, invasive therapies such as intrathecal drug administration and neurosurgical stimulation techniques may be considered.⁴

• Dr Jan H Vranken is an anaesthesiologist – pain specialist at Slotervaartziekenhuis and Medical Centre Jan van Goyen, Amsterdam, The Netherlands

References

1. Breivik H, Collett B, et al. European Journal of Pain 2006;10(4):287–333.
2. Haanpää M, Attal N, et al. Pain 2011;152(1):14–27.
3. Treede RD, Jensen TS, et al. Neurology 2008;70(18):1630–5.
4. Vranken JH. Central Nervous System Agents in Medicinal Chemistry 2012;12(4):304–14.
5. Dworkin RH, O'Connor AB, et al. Mayo Clinic Proceedings 2010;85(3 Suppl):S3–14.
6. Attal N, Cruccu G, et al. European Journal of Neurology 2010;17(9):1113–e88.

• Not all the medications listed are licensed for use in the settings described and physicians should consult the relevant SPCs prior to prescribing