Local Therapies for Localised Neuropathic Pain

Local Therapies for Localised Neuropathic Pain

This paper presents a man in his 70’s with non-small cell lung cancer (cT3N2M0, Stage III A) after chemoradiation therapy during follow-up visits. The stimulation causes sodium to enter the nerve ending, which causes an electrical signal to build up in the nerve. Phytomedicine. This paper will address local treatment options that are effective for localised neuropathic pain whilst avoiding the long-term systemic side effects of medications; it should be mentioned that there are well known complications that could arise after invasive therapies, but these are minimised in the hands of experienced clinicians and by using advanced imaging techniques and other precautionary measures. Pain 80:533-538. Pain in thoracic or lumbar regions for a minimum of 90 days after crusting of Herpes Zoster (HZ) lesions. The mechanisms for topical relief of pain seem to differ from their central effects, and the mechanism of action is unknown.

2012;28(2):101-107. Lidoderm is made from an adhesive material that contains 5% lidocaine. The agency cautioned that because many medications are available in combination with acetaminophen, the risk of accidentally taking too much acetaminophen exists. CALL YOUR HEALTHCARE PROVIDER IMMEDIATELY IF YOU THINK YOU MAY HAVE A MEDICAL EMERGENCY. Always seek the advice of your physician or other qualified health provider prior to starting any new treatment or with any questions you may have regarding a medical condition. Steroids (prednisone) and tricyclic antidepressants (amitriptyline) are also prescribed to lessen shingles symptoms, and the former might help prevent PHN. Ketamine is used as a systemic agent in the management of neuropathic pain, but its use as a topical gel has also been explored11.

In severe cases, nerve blocks might be used. The most-studied proteolytic enzymes include papain (from papaya), bromelain (from pineapple), and trypsin and chymotrypsin (extracted from the pancreas of various animals). A double-blind study of 190 people with shingles compared proteolytic enzymes to the standard antiviral drug acyclovir. 1 Participants were treated for 14 days and their pain was assessed at intervals. Although both groups had similar pain relief, the enzyme-treated group experienced fewer side effects. Combination of doxepin and capsaicin cream was found to produce faster results in another study20. Some patients find it difficult to be compliant with the treatment due to the burning nature of the cream and it needs to be applied 3–4 times a day for several weeks before producing pain relief.

This is followed by pain relief thought to be mediated by a reduction in TRPV 1expressing nociceptive nerve endings. Driving and consumption of alcohol should be avoided before and after the patch has been administered. Methods and compositions are provided for safely reducing nerve injury pain from shingles (herpes zoster and post herpetic neuralgia) and analogous neuropathies. Cutaneous sensory neurons expressing nociceptive receptors such as transient receptor potential vanilloid 1 [TRPV1] channels and voltage-gated sodium [Na+ (V)] channels are critical for pain transmission [1]. There are also a number of contraindications and potential drug-drug interactions to take into account with systemic neuropathic pain treatments, especially in the often elderly population of patients with PHN [6,9]. The mechanism of action is still unclear, but the local analgesic effect is by stabilising neuronal membranes, and from animal studies it is thought to down-regulate the sodium channels present in the peripheral nerve endings, reducing ectopic nociceptive pain signal transmission25. Do this even if there are no signs of discomfort or poisoning.

Lidocaine induces a TRPV1 dependent release of CGRP, which is a key component of neurogenic inflammation and long-term topical application of lidocaine reduces nerve fibre density in the epidermis26,27; this degeneration may explain the observed loss of pain28. Additionally, the plaster acts as a barrier protecting the skin from mechanical stimuli, which can trigger pain sensations due to allodynia and hyperpathia. The plasters should be worn for 12 hours and then removed. Various studies evaluating the long-term efficacy, safety and tolerability of the lidocaine plaster show consistent and sustained long-term pain relief for up to 24 months and longer29 The data further confirms that in newly diagnosed patients, pain relief was achieved at 1 week of treatment and subsequent reductions occurred in the weeks thereafter. 5% lidocaine plasters have also been successfully used in patients with other types of neuropathic pain states, either as a single agent30 or in combination31. (2009) Grading quality of evidence and strength of recommendations in clinical practice guidelines.An overview of the GRADE approach and grading quality of evidence about interventions. It was found that the plaster was well tolerated by the patients who also reported a low side effect profile.

5% lidocaine plasters are also used in treating other pain conditions including myofascial pain syndrome (MPS), caused by trigger points in muscle or muscle fascia. The existing standard treatment for this is infiltration of the trigger points with local anaesthetic +/− steroids; however this intervention normally can produce some discomfort in the patients. This study suggests that there is minimal absorption of lidocaine from the patch in dogs. Tricyclic antidepressants (including desipramine, nortriptyline, and amitriptyline) are considered first-line drugs for treating neuropathic pain by the International Association for the Study of Pain. It has also been shown that 5% lidocaine plaster can be used as an additional therapeutic option in chronic back pain” and also showed no statistically significant difference between using the 5% lidocaine plaster versus COX-2 inhibitors in treating osteoarthritis pain36. In summary, 5% lidocaine plaster is an effective means of treating ongoing pain and allodynia due to localised neuropathic pain and diverse peripheral neuropathies. The sustained efficacy, combined with its safety and tolerability profile results in a favourable benefitrisk ratio, suggesting its safety for long-term use.

However, it is to be noted that, being licensed for post-herpetic neuralgia, the predominant use is still in neuropathic pain and not for musculoskeletal pain. Capsaicin (8-methy-N-vanillyl-6-nonenamide) is the active component of the chilli pepper and is an agonist of the transient receptor potential vanilloid-1 receptor (TRPV1)37. Topical capsaicin creams, 0.025% and 0.075%, have been used over twenty years in the management of peripheral neuropathic pains38, but tend to have limited analgesic effect, as it needs to be applied up to four times daily for several weeks, which could lead to reduced compliance rates. Some patients also complain of experiencing a burning sensation when using the cream39. The low dose topical capsaicin cream may reduce neuropathic pain in PHN but in one trial it failed show efficacy in HIV-associated distal sensory polyneuropathy40. A high concentration capsaicin (8%w/w) patch was approved in the UK in 2010 for the treatment of PHN and other peripheral neuropathic states other than diabetic neuropathy. Each 14 cm x 20 cm patch, with a total of 179 mg of capsaicin (640 mcg/cm2) in the silicone-adhesive mixture, is designed to deliver a therapeutic dose of capsaicin during a single application of 30–60 minutes.

Capsaicin causes an initial enhanced stimulation of TRPV1-expressing cutaneous nociceptors that may be associated with painful sensations, followed by a reduction in the TRPV1-expressing nociceptors, leading to prolonged analgesia41. Over a period of months, there may be a gradual re-emergence of the neuropathy due to nerve fibre reinnervation of the treated area. The mechanism of action is thought to be selective and reversible defunctioning of cutaneous sensory nerve endings expressing TRPV1. Conventional gelling or thickening agents may be employed to provide for a formulation which can be conveniently applied to the skin. Additional autonomic dysfunction (mediated by skin cholinergic and vasomotor fibers) leads to frequent vascular deregulation in lower limbs [12, 20]. Safety and tolerability analyses were performed on all enrolled patients who received study drug. The studies also confirmed that it could be effective as a monotherapy or in conjunction with other pain analgesia40,42,43 and more importantly, the pain relief was maintained for up to at least 12 weeks43–46.

The patch showed greater improvement in mean pain scores at all assessment times42–46. A randomised double blind controlled study in patients with PHN for at least three months showed that following treatment with the 8% capsaicin patch, pain scores began declining as early as the end of day 1 and were on average reduced by 36% during the first week46–47. Studies have also shown that the 8% capsaicin patch is effective in HIV-associated distal sensory polyneuropathy, a painful condition with limited effective treatments40,48,49. A multicentric double blind controlled dose-finding study, which evaluated the safety and efficacy of the 8% patch but studied with different durations of application – 30, 60 or 90 minutes in treating PHN46. In summary the authors found that a single topical application of the patch provided pain reduction for up to 3 months46. Treatment duration of 60 minutes was found to be the lowest effective dose time and generally well tolerated, but for the treatment of painful HIV neuropathy of the feet, it was found that a 30 minutes application gave similar analgesic effect for a similar duration48–49. Side effects of 8% capsaicin are predominantly localised, such as application site pain, pruritus and papules; these responded to localised cooling and analgesics, and lasted only for a few days45,50.

A transient, but clinically insignificant rise in blood pressure has also been noted during the duration of the patch application and was self-limiting45. Exposure to capsaicin may result in nasopharyngitis and this can be avoided by careful removal, rolling the patch inwards to avoid contact, for safe disposal. In summary, high dose capsaicin patch is generally well tolerated by patients and appears to have some potential advantages over some of the current first line agents in term of side effect profile. Patients that have undergone abdominal surgery, including ovariohysterectomy or laparot­omy, can benefit from lidocaine patch application at the ventral abdominal midline. Teach patients taking a combination product to include the acetaminophen dosage when calculating the total daily amount of acetaminophen they’re taking. Since the advent of the “Gate Control Theory” of pain51, electrical stimulation has been used to provide analgesia. Pain due to nociceptive stimuli is carried via C-fibres to the dorsal horn at laminar 1 & 2 and then onwards via the spinothalamic tract to terminate in the sensory cortex.

Local Therapies for Localised Neuropathic Pain
Transcutaneous Electrical Nerve Stimulation (TENS) causes a reduction of pain by stimulating peripheral inhibitory fibres. This may not always be effective in some neuropathic pain states, as C-fibre termination at laminae 1 & 2 ceases as a result of peripheral nerve damage and is replaced by Aβ-fibres at the lamina52. The Aβ-fibres projecting into the lamina can cause an exaggerated nociceptive response to what are normally innocuous stimuli53 and hence these patients may not tolerate TENS, but may be more likely to benefit from PENS therapy. PENS uses a frequency-dependent electrical current (usually 2 Hz and 100 Hz alternating every 3 seconds), to modulate the activity of peripheral nerves and can be used to stimulate a single peripheral nerve54 or the most peripheral branches of a peripheral nerve as field stimulation55 The electrical current is delivered through a 21 gauge disposable probe of varying lengths of 20 mm to 200 mm inserted percutaneously to target the affected area for a period of 25 minutes. PENS therapy offers patients the potential for intermediate relief and ongoing management of chronic peripheral neuropathic pain conditions like scar pain including post-thoracotomy, post-mastectomy and post-hernia repair pains56. It has also been used with success in intractable cluster headaches57 and occipital neuralgias58. PENS gives good analgesic results in patients with post-irradiation allodynia and following trigeminal field neuropathy following head and neck cancer surgery and radiotherapy59.

These patients reported improved quality of life and could make a significant reduction in opioid analgesia and also systemic neuropathic pain agents60. PENS therapy is contraindicated in the presence of demand type cardiac pacemakers and patient refusal. Caution is to be exercised in patients known to have heart disease, epilepsy, on anticoagulants and in pregnancy. PENS therapy is best deferred when there is local or systemic infection or coagulopathy. C. The availability of commercial tests for SFN has enabled clinicians to easily measure IENF density. The number of patients receiving medication for treatment-related discomfort decreased rapidly after the day of NGX-4010 treatment, with only 4 patients receiving medication on Day 1, 2 patients on Day 3, 1 patient on Days 5 and 6 and no patients on Day 7.

It has also been used with success in patients with focal neuropathic pain in patients with cancer who require frequent MRI scans which make an implantable neurostimulator contraindicated60. PENS offers the option of a minimally invasive neuromodulation therapy that can be carried out in a procedure room, either as a diagnostic tool prior to implantable stimulators or a continuing treatment option for localised neuropathic pain states. It is associated with a low risk profile and is a cost-effective option when pharmacological options are either ineffective or when the effective dose causes unacceptable side effects to the patient that could significantly impact on their quality of life. The evidence base for PENS treatment is growing, but are currently limited to case series and case reports; there needs to be carefully conducted randomised controlled clinical trials (RCTs) to further validate and provide hard evidence of therapeutic efficacy. Radiofrequency techniques have been in use for more than 30 years in the management of chronic pain conditions62, particularly back63 and neck pain and also neuropathic conditions like trigeminal neuralgia and other refractory neuropathic pain states64. There is a wealth of clinical experience and success in the use of both conventional (thermal) and pulsed radiofrequency techniques, including several large case series, but there are only a few high quality randomised controlled trials to validate these results65. However, it is widely used in clinical practice in the management of focal neuropathic pain66.

The principles and procedure of radiofrequency have been well established and both conventional and pulsed lesioning are used in common practice67,68. Conventional radiofrequency using a thermal lesion at temperatures higher than 65 degrees Celsius can produce significant damage to neural tissue; pulsed lesioning is done at lower temperatures around 42 degrees Celsius and thus gives rise to minimal damage and hence a lower incidence of complications69. Experimental studies have shown that though no gross change is seen on both treatments, electron microscopic examination has revealed minimal disruption of the myelin envelope of the axon70, indicating that the analgesic effect of radiofrequency technique is not just by causing a thermal lesion. Pulsed radiofrequency defines an electromagnetic field in the vicinity of a lesion, modifying neuro-cellular function with minimal cellular destruction71. The mechanisms of the analgesic action by pulsed radiofrequency by the enhancement of descending nor-adrenergic and serotonergic systems72 have also been described in animal studies. It’s approximately 100 times more potent than morphine. The use of radiofrequency lesioning for trigeminal neuralgia has been in practice for nearly forty years74; the technique is well described75 and studies have shown that conventional radiofrequency is far more effective in sustaining analgesia than pulsed lesioning76.

Percutaneous radiofrequency rhizotomy has been effective in idiopathic trigeminal neuralgia, symptomatic facial pain and herpes zoster of the fifth cranial nerve, but not effective in atypical fecial pain77. It has been the recommended option for treating trigeminal pain in the elderly, but microvascular decompression remains the first line choice for younger patients78. The procedure is not without complications and apart from pain and bruising, major complications such as other cranial nerve palsies79, subarachnoid haemmorhage80 and rhinorrheoa81 have also been reported. Targeting the sphenopalatine ganglion82, particularly using advanced imaging including CT-guidance83 and virtual reality techniques84 has higher efficacy and reduced risk of complications. Radiofrequency neurolysis of the infra-orbital nerve has been done when trigeminal ganglion or posterior root ablation is contraindicated85. Pulsed radiofrequency has been used in the treatment of occipital neuralgia with the pain improving substantially in more than half the number of patients86,87. Several other neuropathic pain conditions have been treated with radiofrequency with good to exceptional results as reported in case series.

Pulsed radiofrequency of the lateral cutaneous nerve of the thigh has been used in successfully treating meralgia paraesthetica88. It has also been used with success in managing groin pain and orchialgia89 and also refractory pudendal neuralgia90. There are case reports of effective radiofrequency lesioning for obturator nerve neuropathy91 for conditions such as hip arthritis. The effects of producing a radiofrequency lesion adjacent to the dorsal root ganglion in patients with thoracic segmental pain has also been reported, with 67% of patients reporting pain relief at 8 weeks and half the patients having relief at 36 weeks92. More recently it has been shown that pulsed radiofrequency of the dorsal root ganglion is superior to pharmacotherapy or pulsed radiofrequency of the intercostal nerves in the treatment of chronic postsurgical thoracic pain93. The five subjects with thoracic post-herpetic neuralgia had highly significant changes in pain ratings, especially during the last 2 hours of observation, from a baseline mean of 44.2 mm±21.6 mm to a low of 12.8 mm±8.7 mm (P=0.001 ). Thermal perception and thermal pain are measured using a thermode, or using other devices that operate on the thermoelectric effect [29, 45, 46].

Half of the patients used analgesic medication on the day of treatment for application site-related pain; this number rapidly decreased on subsequent days, with only 4 patients requiring medication on Day 1 and no patients requiring pain medication by Day 7. The patients reported improved prosthetic tolerance and reduction of oral analgesic medications. The analgesic effect is thought to be due to inhibition of evoked synaptic activity97. It has also been reported that there could be increased pain, new pain syndromes and also abnormal sweating in the limb stump98. Pulsed radiofrequency has also been used in treating myofascial trigger points and scar neuromas with 67% of the patients reporting pain relief lasting between 6 to 12 weeks99. It has also been used in treating patients with chronic neuropathic spinal pain after failed conservative management100. A 12-year long-term retrospective analysis of using radiofrequency application to areas of pain in the treatment of neurogenic heel pain has shown a high success rate with few associated risks and less post-operative morbidity101.

Radiofrequency ablation has been used with success for the management of prolonged moderate to severe heel pain associated with plantar fasciitis102. Cervico-thoracic or lumbar sympathectomy for neuropathic pain and complex regional pain syndrome (CRTS) has poor evidence in literature due to lack of large well-designed studies103. However, radiofrequency lesions of the stellate ganglion have been used with success in CRPS Type 2, ischaemic pain, cervicobrachialgia and post-thoracotomy pain104. Pulsed radiofrequency lumbar sympatholysis has also been used in the management of CRPS in a patient with spinal injury105. However, the evidence base for the use of radiofrequency ablation for these conditions has not yet been validated by randomised controlled trials106. Topical agents such as 5% Lidocaine plasters, 8% Capsaicin patch and procedures Isuch as PENS Therapy give the added option of delivering pain relief locally without the side-effects of systemic drugs for localised neuropathic pain. Evans RW, Tepper SJ, Shapiro, RE, et al.

26. Wehrfritz A, Leffler A, Namer B, Müller C, Koppert W. Topical lidocaine in a human pain model reduces pain sensation and quantity of epidermal nerve fibres. Poster 425: EFIC-Congress 2009. 44. Backonja MM, et al. High-concentration capsaicin for the treatment of post-herpetic neuralgia and other types of peripheral neuropathic pain European Journal of Pain Supplements Volume 4, Issue 2, August 2010, Pages 170–174.

54. Bhaskar A, Chatha H. Proximal application of Percutaneous Electrical Nerve Stimulation (PENS) for treating neuropathic thigh and knee pain following radical trachelectomy and laparoscopic pelvic lymph node dissection surgery. Proceeding of 3rd Neuropathic Pain Congress (NeuPSIG), Athens 2010. 56. Raheem T, Raphael J, Duarte R, Akinwunmi J, Cooper R, Bennett A.: A multi-centre open prospective study of percutaneous electrical neuro- stimulation in post-surgical scar pain. Sheets measuring 20×30 cm were used.

This product binds to primary nociceptive fibers that phosphorylate sodium channels, transmitting the pain signal to the central nervous system. Moreover, tolerability appears comparable with the tolerability observed in the clinical trials using 4% lidocaine cream as pretreatment, in terms of intended application duration, extent of application site-related pain, use of medication for treatment-related discomfort, dermal irritation, AE profile, and transient blood pressure changes. Percutaneous Electrical Nerve Stimulation (PENS) Therapy for the management of focal neuropathic pain — a case series of 42 cancer patients. Proceeding of 10th INS World Congress, London 2011. 60. Bhaskar A, Patel K, White A. Trigeminal Field Stimulation Using Percutaneous Electrical Nerve Stimulation (PENS) Therapy – preliminary case series of 8 patients.

Proceeding of 10th INS World Congress, London 2011. 61. Khan El, O’Keeffe D, Eller M, McFarland J, Walsh R, Gallagher H, Goroszenuik T. Combined Spinal Cord and Subcutaneous Electrical Nerve Stimulation for the Treatment of Lower Extremity and Testicular Pain. Proceedings of 6th INS World Congress, 2003.

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